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Evaluation and Prevention of Diabetic Neuropathy

Diabetic neuropathy is a debilitating disorder that occurs in nearly 50 percent of patients with diabetes. It is a late finding in type 1 diabetes but can be an early finding in type 2 diabetes. The primary types of diabetic neuropathy are sensorimotor and autonomic. Patients may present with only one type of diabetic neuropathy or may develop combinations of neuropathies (e.g., distal symmetric polyneuropathy and autonomic neuropathy). Distal symmetric polyneuropathy is the most common form of diabetic neuropathy. Diabetic neuropathy also can cause motor deficits, silent cardiac ischemia, orthostatic hypotension, vasomotor instability, hyperhidrosis, gastroparesis, bladder dysfunction, and sexual dysfunction. Strict glycemic control and good daily foot care are key to preventing complications of diabetic neuropathy. (am Fam Physician 2005;71:2123-8,2129-30. Coppyright 2005 American Academy of Family Physicians.)

Classification of Diabetic Neuropathy

  • Sensorimotor neuropathy
    • Distal symmetric polyneuropathy
    • Focal neuropathy
      • Diabetic mononeuropathy (cranial, truncal, peripheral nerves)
      • Mononeuropathy multiplex
    • Diabetic amyotrophy

Autonomic Neuropathy

  • Hypoglycemic unawareness
  • Abnormal pupillary function
  • Cardiovascular autonomic neuropathy
  • Vasomotor neuropathy
  • Sudomotor neuropathy (sweat glands)
  • Gastrointestinal autonomic neuropathy
    • Gastric atony
    • Diabetic diarrhea or constipation
    • Fecal incontinence
  • Genitourinary autonomic neuropathy
    • Bladder dysfunction
    • Sexual dysfunction

Sensorimotor Neuropathy

In sensory nerve damage, the nerves with the longest axons usually are affected first, resulting in a stocking-and-glove distribution.

Symptoms of Diabetic Neuropathy

Sensorimotor neuropathy

  • Muscular symptoms: muscle weakness (not fatigue), atrophy, balance problems, ataxic gait
  • Sensory symptoms: pain, paresthesia, numbness, paralysis, cramping, nighttime falls, antalgic gait

Autonomic neuropathy

  • Cardiovascular symptoms: exercise intolerance, fatigue, sustained heart rate, syncope, dizziness, lightheadedness, balance problems
  • Gastrointestinal symptoms: dysphagia, bloating, nausea and vomiting, diarrhea, constipation, loss of bowel control
  • Genitourinary symptoms: loss of bladder control, urinary tract infection, urinary frequency or dribbling, erectile dysfunction, loss of libido, dyspareunia, vaginal dryness, anogasmia
  • Sudomotor (sweat glands) symptoms: pruritus, dry skin, limb hair loss, calluses, reddened areas
  • Endocrine symptoms: dypoglycemic unawareness
  • Other symptoms: difficulty driving at night, depression, anxiety, sleep disorders, cognitive changes

Distal Symmetric Polyneuropathy

Distal symmetric polyneuropathy, the most common form of diabetic neuropathy, affects approximately 40 percent of patients who have had diabetes for 25 years or longer. Most often, this neuropathy develops in the feet. The course is chronic and progressive.

Focal Neuropathy

Diabetic mononeuropathy has an acute onset and usually is asymmetric. Cranial, truncal, and peripheral nerves are involved. The neuropathy generally resolves spontaneously in three to 12 months, but in rare cases it may last for years.

Diabetic Amyotrophy

Diabetic amyotrophy, also known as femoral neuropathy or proximal motor neuropathy, usually is bilateral and freqently is associated with weight loss. diabetic amyotrophy tends to occur more often in older male patients with type 2 diabetes.

Thigh muscle atrophy is prominent, disabling, and usually limited to the iliopsoas, quadriceps, and adductor muscles.

Diabetic Autonomic Neuropathy

Diabetic autonomic neuropathy can develop in patients with type 1 or type 2 diabetes. Although autonomic neuropathy may occur at any stage of diabetes, usually it develops in patients who have had the disease for 20 years or more with poor glycemic control.

Cardiovascular Autonomic Neuropathy

The risk of cardiovascular events is at least two to four times higher in patients with diabetes. Cardiovascular neuropathy is a result of damage to vagal and sympathetic nerves.

Vasomotor Neuropathy

Vasomotor neuropathy frequently causes orthostatic hypotension by affecting the splanchnic and peripheral vascular beds. Symptoms of syncope or dizziness often have day-to-day variability and may be exacerbated by insulin therapy or the postprandial state.

Sudomotor Neuropathy

Sudomotor neuropathy may cause hyperhidrosis and heat intolerance in the upper torso or anhidrosis in the lower extremities.

Gastrointestinal Autonomic Neuropathy

Gastrointestinal autonomic neuropathy may cause paresis anywhere in the digestive tract, with damage to small myelinated and unmyelinated splanchnic nerves.

Diabetic diarrhea is caused by increased or uncoordinated transit time in the small intestine, bacterial overgrowth, or increased intetinal secretion.

Decreased transit time in the large intestine may cause constipation or impacted stool.

Diabetic Bladder Dysfunction

In patients with diabetic bladder dysfunction, inability to sense a full bladder and detrusor muscle hypoactivity cause retention and incomplete voiding of urine. These conditions can progress to overflow incontinence and urinary tract infections.

Erectile Dysfunction

Erectile dysfunction can occur at any early age in men with diabetes. It develops in 35 percent of men with diabetes between 20 and 59 years of age and 65 percent of men with diabetes 60 years or older. The primary cause is pelvic plexus neuropathy; a decrease in nitric oxide, which is required to initiate and erection, contributes to the condition.

Female Sexual Dysfunction

In women, diabetic neuropathy may cause vaginal dryness, decreased perineal sensation, dyspareunia, reduced libido, or anogasmy.

Preventing Complications of Diabetic Neuropathy

Early detection and control of diabetes and coexisting risk factors for neuropathy (e.g., smoking, alcohol abuse, hypertension) can prevfent, delay , or slow the progression of diabetic neuropathy.

Glycemic Control

The Diabetes Control Complications Trial (DCCT) demonstrated that tight glycemic control may result in a 60 percent reduction in the risk of developing clinical neuropathy.

The American Association of Clinical Endocrinologists recommends an A1C value of less than 6.5 percent inpatients with type 1 or type 2 diabetes.

Foot Care

Daily foot care is essential for preventing complications of diabetic neuropathy. Patient should be instructed to inspect their feet daily.

Properly fitted footwear is crucial.

Treatment Options 

Acupuncture for the treatment of chronic painful peripheral diabetic neuropathy: a long-term study.

Abuaisha BB, Costanzi JB, Boulton AJ.

Department of Medicine, Manchester Royal Infirmary, University of Manchester, UK.

Forty-six diabetic patients with chronic painful peripheral neuropathy were treated with acupuncture analgesia to determine its efficacy and long-term effectiveness. Twenty-nine (63%) patients were already on standard medical treatment for painful neuropathy. Patients initially received up to six courses of classical acupuncture analgesia over a period of 10 weeks, using traditional Chinese Medicine acupuncture points. Forty-four patients completed the study with 34 (77%) showing significant improvement in their primary and/or secondary symptoms (P < 0.01). These patients were followed up for a period of 18-52 weeks with 67% were able to stop or reduce their medications significantly. During the follow-up period only eight (24%) patients required further acupuncture treatment. Although 34 (77%) patients noted significant improvement in their symptoms, only seven (21%) noted that their symptoms cleared completely. All the patients but one finished the full course of acupuncture treatment without reported or observed side effects. There were no significant changes either in the peripheral neurological examination scores, VPT or in HbA1c during the course of treatment. These data suggest that acupuncture is a safe and effective therapy for the long-term management of painful diabetic neuropathy, although its mechanism of action remains speculative.

PMID: 9597381 [PubMed - indexed for MEDLINE]

Low-intensity laser therapy for painful symptoms of diabetic sensorimotor polyneuropathy: a controlled trial.

Zinman LH, Ngo M, Ng ET, Nwe KT, Gogov S, Bril V.

Toronto General Hospital, Toronto, Ontario, Canada.

OBJECTIVE: Low-intensity laser therapy (LILT) has been advocated for treatment of chronic pain disorders. Although the mechanism of pain relief is uncertain, this therapy has been suggested for relief of painful symptoms of diabetic sensorimotor polyneuropathy (DSP). The objective of this study was to determine whether LILT relieves the pain of DSP. RESEARCH DESIGN AND METHODS: We conducted a randomized, double-masked, sham therapy-controlled clinical trial in 50 patients with painful DSP diagnosed with the Toronto Clinical Neuropathy Score. All patients received sham therapy over a 2-week baseline period and were then randomized to receive biweekly sessions of either sham or LILT for 4 weeks. The primary efficacy parameter was the difference in the weekly mean pain scores on a visual analog scale (VAS). RESULTS: The patients had similar baseline characteristics for pain intensity, HbA(1c), and duration of DSP. Both groups noted a decrease in weekly mean pain scores during sham treatment. After the 4-week intervention, the LILT group had an additional reduction in weekly mean pain scores of -1.0 +/- 0.4 compared with -0.0 +/- 0.4 for the sham group (P = 0.07). LILT had no effect on the Toronto Clinical Neuropathy Score, nerve conduction studies, sympathetic skin response, or quantitative sensory testing. CONCLUSIONS: Although an encouraging trend was observed with LILT, the study results do not provide sufficient evidence to recommend this treatment for painful symptoms of DSP.

PMID: 15047649 [PubMed - indexed for MEDLINE]

[Infrared laser therapy in distal diabetic polyneuropathy]

[Article in Russian]

Kalinina OV, Alekseeva NV, Burtsev EM.

A course of laser therapy was applied to 50 patients with diabetic polyneuropathy by laser irradiation of low intensiveness in the nearest infrared spectrum. 20 patients from the group were treated by monotherapy only by laser exposure. Control group consisted of 24 patients treated by conventional therapy without laser exposure. According to the changes of vibratory and algesic sensitivity and electromyographic data the efficiency of therapy was estimated. It was found that laser exposure resulted in more pronounced restoration of functional state of nervous fibers than conventional therapy. Application of laser irradiation of low intensiveness was effective while in combined therapy of distal diabetic polyneuropathy as well as monotherapy.

PMID: 9677693 [PubMed - indexed for MEDLINE]

Diabetic peripheral neuropathy: amelioration of pain with transcutaneous electrostimulation.

Kumar D, Marshall HJ.

Department of Medicine, Los Angeles County University of Southern California Medical Center 90033, USA.

OBJECTIVE: To evaluate the efficacy of transcutaneous electrotherapy for chronic painful peripheral neuropathy in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Thirty-one patients with symptoms and signs of peripheral neuropathy were randomized to the electrotherapy or sham treatment (control) group. The electrostimulation was given by a portable unit (H-Wave machine) than generated a biphasic, exponentially decaying waveform (pulse width 4 ms, 25-35 V, > or = 2 Hz). Patients treated each of their lower extremities for 30 min daily for 4 weeks at home. Nine patients from the sham-treatment group participated for a second period, during which all of them received the active electrotherapy. Patient's degree of pain and discomfort was graded on a scale of 0 to 5. RESULTS: In the sham-treated group (n = 13), the neuropathic symptoms improved in five (38%) patients, and the pain score declined from 2.92 +/- 0.13 to 2.38 +/- 0.26 (P < 0.04), suggesting a procedure-related placebo effect. In the electrotherapy group (n = 18), symptomatic improvement was seen in 15 (83%) cases, 3 of which were completely asymptomatic; the pain score declined from 3.17 +/- 0.12 to 1.44 +/- 0.25 (P < 0.01) and the posttreatment pain scores were considerably lower (P < 0.03), indicating a substantial treatment effect over and above any placebo influence. Patients in the electrotherapy group reported greater reduction in symptoms (52 +/- 7% vs. 27 +/- 10% in control subjects, P < 0.05) on an analog scale. Moreover, the electrotherapy decreased pain scores (from 3.0 +/- 0.62 to 1.56 +/- 0.32, P < 0.02) in nine patients who had received sham treatment earlier. CONCLUSIONS: A form of transcutaneous electrotherapy ameliorated the pain and discomfort associated with peripheral neuropathy. This novel modality offers a potential non-pharmacological treatment option.

PMID: 9353612 [PubMed - indexed for MEDLINE]

Effective treatment of symptomatic diabetic polyneuropathy by high-frequency external muscle stimulation.

Reichstein L, Labrenz S, Ziegler D, Martin S.

German Diabetes Clinic, German Diabetes Center, Leibniz Institute, Heinrich-Heine-University Düsseldorf, Auf'm Hennekamp 65, 40225 Düsseldorf, Germany.

AIMS/HYPOTHESIS: Diabetic distal symmetrical sensory polyneuropathy (DSP) affects 20-30% of diabetic patients. Transcutaneous electrical nerve stimulation (TENS) and electrical spinal cord stimulation have been proposed as physical therapies. We performed a controlled, randomised pilot trial to compare the effects of high-frequency external muscle stimulation (HF) with those of TENS in patients with symptomatic DSP. METHODS: Patients with type 2 diabetes and DSP (n=41) were randomised to receive treatment with TENS or HF using strata for non-painful (n=20) and painful sensory symptoms (n=21). Both lower extremities were treated for 30 min daily for three consecutive days. The patients' degree of symptoms and pain were graded daily on a scale of one to ten, before, during and 2 days after treatment termination. Responders were defined by the alleviation of one or more symptoms by at least three points. RESULTS: The two treatment groups were similar in terms of baseline characteristics, such as age, duration of diabetes, neurological symptoms scores and neurological disability scores. The responder rate was significantly higher (p<0.05) in the HF group (80%, 16 out of 20) than in the TENS group (33%, seven out of 21). Subgroup analysis revealed that HF was more effective than TENS in relieving the symptoms of non-painful neuropathy (HF: 100%, seven out of seven; TENS: 44%, four out of nine; p<0.05) and painful neuropathy (HF: 69%, nine out of 13; TENS: 25%, three out of 12; p<0.05). The responders did not differ in terms of the reduction in mean symptom intensity during the trial. CONCLUSIONS/INTERPRETATION: This pilot study shows, for the first time, that HF can ameliorate the discomfort and pain associated with DSP, and suggests that HF is more effective than TENS. External muscle stimulation offers a new therapeutic option for DSP.

PMID: 15830180 [PubMed - indexed for MEDLINE]

Effectiveness of frequency-modulated electromagnetic neural stimulation in the treatment of painful diabetic neuropathy.

Bosi E, Conti M, Vermigli C, Cazzetta G, Peretti E, Cordoni MC, Galimberti G, Scionti L.

Diabetes and Endocrinology Unit, Department of General Medicine, Vita-Salute San Raffaele University Hospital, Via Olgettina 60, 20132 Milan, Italy. bosi.emanuele@hsr.it

AIMS/HYPOTHESIS: The largely unsatisfactory results reported for the pharmacological treatment of diabetic neuropathy has spurred the search for alternative therapies. The aim of this study was to evaluate the efficacy of frequency-modulated electromagnetic neural stimulation (FREMS) as a novel treatment for painful diabetic neuropathy. METHODS: Patients (n=31) with painful neuropathy associated with decreased nerve conduction velocity (<40 m/s) and increased vibration perception threshold (>25 V) were enrolled in a randomised, double-blind, crossover study designed to compare the effects of FREMS with those of placebo. Each patient received two series of ten treatments of either FREMS or placebo in random sequence, with each series lasting no more than 3 weeks. The primary efficacy end point was the change in pain measured by a visual analogue scale (VAS). RESULTS: FREMS induced a significant reduction in daytime and night-time VAS pain score (all p<0.02). Furthermore, FREMS induced a significant increase in sensory tactile perception, as assessed by monofilament; a decrease in foot vibration perception threshold, as measured by a biothesiometer; and an increase in motor nerve conduction velocity (all p<0.01). No significant changes were observed after placebo. Comparison of measurements at the 4-month follow-up with those at baseline revealed that a significant benefit persisted for all measures that showed an improvement at the end of treatment, with an additional improvement in quality of life evaluated by the Short Form-36 questionnaire (all p<0.05). No significant side effects were recorded during the study. CONCLUSIONS/INTERPRETATION: FREMS is a safe and effective therapy for neuropathic pain in patients with diabetes and is able to modify some parameters of peripheral nerve function.

PMID: 15834546 [PubMed - indexed for MEDLINE]

Transcutaneous electrostimulation: emerging treatment for diabetic neuropathic pain.

Alvaro M, Kumar D, Julka IS.

California College of Podiatric Medicine, San Francisco, California, USA.

Three independent studies utilizing transcutaneous electrical nerve stimulation to relieve diabetic peripheral neuropathic pain were reviewed. The proprietary equipment, an H-wave machine, administered all electrotherapy. The first two studies assessed the efficacy of electrotherapy alone and electrotherapy with amitriptyline. The treated electrotherapy group reported an overall greater reduction of symptoms, 52% with 2-3 weeks of active treatment. Amitriptyline alone produced a 26% reduction of pain after 4 weeks. The addition of active electrotherapy to amitriptyline produced a 66% reduction of pain. The final study looked at patients who have utilized electrotherapy for over one year. A reported 44% improvement of symptoms was attained with continuous electrotherapy treatment. The data also suggested that a maintenance treatment protocol for long-term pain relief would have to be developed.

PMID: 11475308 [PubMed - indexed for MEDLINE]

L-arginine improves vascular function by overcoming the deleterious effects of ADMA, a novel cardiovascular risk factor

Alternative Medicine Review,  March, 2005  by Rainer H. Boger,  Eyal S. Ron

There is abundant evidence that the endothelium plays a crucial role in the maintenance of vascular tone and structure. One of the major endothelium-derived vasoactive mediators is nitric oxide (NO), an endogenous messenger molecule formed in healthy vascular endothelium from the amino acid precursor L-arginine. Endothelial dysfunction is caused by various cardiovascular risk factors, metabolic diseases, and systemic or local inflammation. One mechanism that explains the occurrence of endothelial dysfunction is the presence of elevated blood levels of asymmetric dimethylarginine (ADMA)--an L-arginine analogue that inhibits NO formation and thereby can impair vascular function. Supplementation with L-arginine has been shown to restore vascular function and to improve the clinical symptoms of various diseases associated with vascular dysfunction.

(Altern Med Rev 2005;10(1):14-23)

Introduction

The endothelium plays a crucial role in the maintenance of vascular tone and structure. One endothelium-derived vasoactive mediator with major importance is nitric oxide (NO), which is formed from the amino acid precursor L-arginine by the enzyme endothelial nitric oxide synthase (eNOS). NO is involved in a wide variety of regulatory mechanisms of the cardiovascular system, including vascular tone (it is the major mediator of endothelium-dependent vasodilation), vascular structure (inhibition of smooth muscle cell proliferation), and cell-cell interactions in blood vessels (inhibition of platelet adhesion and aggregation; inhibition of monocyte adhesion).

Dysfunction of the endothelial L-arginine/ nitric oxide pathway is a common mechanism by which several cardiovascular risk factors mediate certain deleterious effects on the vascular wall. Among these are hypercholesterolemia, hypertension, smoking, diabetes mellitus, homocysteine, and vascular inflammation? (1-6)

Supplementation with L-arginine in animals with experimentally-induced vascular dysfunction atherosclerosis improves endothelium-dependent vasodilation. (7-10) Moreover, L-arginine supplementation results in enhanced endothelium-dependent inhibition of platelet aggregation, inhibition of monocyte adhesion, and reduced vascular smooth muscle proliferation. (11-13) The mechanism by which dietary L-arginine brings about these beneficial effects has long been poorly understood. Experimental evidence derived from studying cloned, purified eNOS in a cell-free system in vitro, and in the presence of optimal concentrations of all co-factors, suggests L-arginine concentrations as low as 3 [micro]mol/L are sufficient to induce half-maximal activity of this enzyme. (14) In contrast, circulating L-arginine measured in plasma of healthy humans as well as in plasma of patients with vascular disease is in the range of 40-100 [micro]mol/L (15,16)--which is 15- to 30-fold higher.

ADMA is a Novel Cardiovascular Risk Factor

In 1992, Vallance et al first described the presence of asymmetric dimethylarginine (ADMA) as an endogenous inhibitor of eNOS in human plasma and urine. (17) Since then, the role of this molecule in the regulation of eNOS has attracted increasing attention. ADMA inhibits vascular NO production within the concentration range found in patients with vascular disease. ADMA also causes local vasoconstriction when infused intra-arterially, and increases systemic vascular resistance and impairs renal function when infused systemically. Currently available experimental and clinical evidence suggests even small modifications of ADMA levels significantly change vascular NO production, vascular tone, and systemic vascular resistance (for review, see Boger (18). Thus, elevated ADMA levels may explain the "L-arginine paradox;" i.e., the observation that supplementation with exogenous L-arginine improves NO-mediated vascular functions in vivo, although its baseline plasma concentration is about 25-fold higher than the Michaelis Constant (Km) of the isolated, purified endothelial NO synthase in vitro.

Elevated ADMA concentration has a high prevalence in hypercholesterolemia, hyperhomocysteinemia, diabetes mellitus, peripheral arterial occlusive disease, hypertension, chronic heart failure, coronary artery disease, pregnancy-induced hypertension and preeclampsia, erectile dysfunction, and other clinical conditions (Table 1). (1,19-28)

Several recent studies have supplied evidence to support a pathophysiological role of ADMA in the pathogenesis of vascular dysfunction and cardiovascular disease. High ADMA levels were found to be associated with carotid artery intima-media-thickness in a study with 116 clinically healthy human subjects. (29) Taking this observation further, another study performed with hemodialysis patients reported that ADMA prospectively predicted the progression of intimal thickening during one year of follow-up. (30) In a nested, case-control study involving 150 middle-aged, non-smoking men, high ADMA levels were associated with a 3.9-fold elevated risk for acute coronary events. (31)

In the first prospective clinical trial, ADMA was determined to be the strongest predictor of cardiovascular events and total mortality in 225 hemodialysis patients during three years of follow-up. Patients whose ADMA levels were within the highest quartile at the beginning of the study had a three-fold higher risk of death from any cause than patients with ADMA levels below the median. (25) Another study investigated factors related to outcome of patients undergoing intensive care unit treatment for multiple causes. Patients whose ADMA levels were in the highest quartile had a 17-fold increase in mortality compared to patients with ADMA levels in the lowest quartile. (32) In a third prospective study, the outcome of patients with stable angina pectoris after coronary balloon angioplasty was addressed, and patients with high ADMA levels were found to have an elevated risk of developing severe cardiovascular complications. (33) In each of these studies, other cardiovascular risk factors and confounding variables were included in the analyses, and ADMA was found to predict cardiovascular risk independent of other variables. Thus, it has recently been concluded that ADMA can be considered to be a novel cardiovascular risk factor. (34-36)

The Role of ADMA for Explaining the Beneficial

Effects of Nutritional L-Arginine Supplementation

Circulating L-arginine concentrations have been found to be within the normal range in most clinical conditions associated with endothelial dysfunction. Few patients experience pathologically low L-arginine concentrations. However, clinical and experimental evidence suggests elevation of ADMA can cause a relative L-arginine deficiency, even in the presence of "normal" L-arginine levels (which may, in fact, be too low in these conditions). As ADMA is a competitive inhibitor of eNOS, its inhibitory action can be overcome by increasing the concentration of the enzyme's substrate, L-arginine (Figure 2). The studies cited above indicate ADMA levels may be increased in conditions associated with cardiovascular diseases. Elevated ADMA concentration is one possible explanation for endothelial dysfunction and decreased NO production in these diseases. In this respect, the authors recently observed improved endothelium-dependent vasodilation after L-arginine administration in patients with congestive heart failure (who had elevated ADMA concentrations); whereas, L-arginine did not affect endothelium-dependent vasodilation in healthy human subjects (who had low ADMA concentrations). (37) Thus, nutritional supplementation with L-arginine may help to restore the physiological status by normalizing the L-arginine/ ADMA ratio; whereas, its effects are less pronounced in humans without a disturbed L-arginine/ADMA balance. Normally, L-arginine/ADMA ratio is in the range of 50:1 to 100:1, given a range of L-arginine levels between 50 and 100 umol/L, and ADMA concentrations between 0.3 and 0.7 [micro]mol/L.

A beneficial effect of L-arginine on vascular function has been found by several different groups of investigators in patients with impaired vascular function (see below); whereas, little or no effect is usually noted in healthy controls. (16) This makes sense, as the molecular function of L-arginine, as detailed above, is to restore endothelial NO production to normal, thereby normalizing vascular function. By replenishing eNOS with its natural substrate, no vasodilator effects beyond the physiological range can be expected. Thus, no exaggerated hypotensive action, orthostatic dysregulation, or adverse cardiac events related to reflex tachycardia need be considered. In contrast to L-arginine, exogenous NO donors such as the organic nitrates, which release NO after enzymatic conversion by the activity of enzymes different from eNOS, are associated with tolerance development and oxidative stress to the arterial wall. (38) In this respect, there is ample evidence to consider L-arginine a safe and beneficial dietary supplement.

One other aspect in the vascular effects of ADMA and L-arginine may be of therapeutic relevance. The beneficial vascular effects of HMG-Co A reductase inhibiting, cholesterol-lowering drugs (statins) have been shown to partially be due to their ability to up-regulate eNOS gene expression. (39) However, statins failed to improve endothelium-dependent vasodilation in about 50 percent of studies that examined their effects on vasodilation. (40-43) This discrepancy may be resolved by examining ADMA. Janatuinen et al (44) recently found pravastatin enhanced myocardial blood flow, measured by positron electron resonance tomography (PET), in patients with low ADMA; however, the drug was ineffective in patients with elevated ADMA. The authors speculate that ADMA may block eNOS despite its up-regulated gene expression after statin treatment, and that this blockade may be overcome by L-arginine supplementation. (18) In a randomized, controlled trial of patients with elevated ADMA concentration, simvastatin enhanced endothelium-dependent vasodilation only when combined with a sustained-release L-arginine formulation. (45) Endothelium-dependent vasodilation was 5.5 [+ or -] 0.5 percent at baseline in this study, compared to an expected 8-12 percent in healthy humans. Simvastatin alone did not improve endothelium-mediated vasodilation (6.2 [+ or -] 1.2%); whereas, the combination of simvastatin with L-arginine significantly enhanced endothelium-dependent vasodilation (9.8 [+ or -] 1.5%).

Thus, it may be that ADMA levels explain the inconsistent results of clinical trials in which statin drugs improved endothelial function or failed to do so--a discrepancy so far unexplained. The observation of elevated ADMA concentration in a given patient may warrant supplementing with L-arginine in order to improve the ability of the endothelium to counteract offenses to the vascular wall by circulating blood cells, vasoconstrictors, and oxygen-derived free radicals.

Beneficial Effects of Supplemental L-Arginine on Vascular Function Angina

Arginine supplementation has been effective in the treatment of cardiovascular dysfunction. In an uncontrolled trial, seven of 10 people with intractable angina showed significant improvement after taking 9 g arginine daily for three months. (46) Significant decreases in cell adhesion molecules and pro-inflammatory cytokine levels were also observed. A double-blind trial in 22 patients with stable angina and healed myocardial infarction showed oral supplementation with 6 g arginine daily for three days increased exercise capacity. (47)

In men with stable angina, two weeks of supplementation with arginine (15 g per day) was not associated with improvement in endothelium-dependent vasodilation, oxidative stress, or exercise performance. (48) In patients with coronary artery disease, oral supplementation of arginine (6 g per day for three days) did not affect exercise-induced changes in QT-interval duration, QT dispersion, or the magnitude of ST-segment depression; (49) however, it did significantly increase exercise tolerance. The therapeutic effect of arginine in patients with microvascular angina is considered to be the result of improved endothelium-dependent coronary vasodilation. (50)

Congestive Heart Failure

Patients with congestive heart failure (CHF) have reduced peripheral blood flow at rest, during exercise, and in response to endothelium-dependent vasodilators. Nitric oxide formed from arginine metabolism in endothelial cells can contribute to regulation of blood flow under these conditions. A randomized, double-blind trial (51) found six weeks of arginine supplementation (5.6-12.6 g per day) significantly improved blood flow, arterial compliance, and functional status compared to placebo. Another double-blind trial found arginine supplementation (5 g three times per day) improved renal function in individuals with CHF. (52)

Hypertension

Hypertension is a major healthcare problem afflicting nearly 50 million people in the United States. (53) Despite its strong causal association with cardiovascular disease complications, including myocardial infarction, heart failure, and stroke, the majority of patients with hypertension do not achieve optimal blood pressure control. The prevalence of hypertension is expected to increase with the aging population, growing obesity, and rising incidence of metabolic syndrome.

Endothelial dysfunction and reduced NO bioactivity represent prominent pathophysiological abnormalities associated with hypertensive cardiovascular disease. Individuals with hypertension exhibit blunted epicardial and resistance vascular dilation to NO in the peripheral and coronary circulation that likely contributes to mechanisms of altered vascular tone in hypertension. L-arginine has been shown to reduce systemic blood pressure in some forms of experimental hypertension. (54)

Erectile Dysfunction

Erectile dysfunction (ED) is defined as the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual intercourse. According to the National Institutes of Health, ED has been reported to affect as many as 20-30 million men in the United States and 152 million men worldwide. The risk for ED increases progressively with advancing age, with an estimated 54 percent of men ages 65-70 reporting some degree of impotence. (55) It is believed 85-90 percent of ED cases are related to a physical or medical condition, while 10-15 percent are due to psychological causes.

Erectile dysfunction is an important part of the total clinical picture in primary care, not only for its psychosocial significance, but also as a possible early indicator of general vascular compromise. (55) ED can be an early indicator of cardiovascular disease, caused by an underlying dysfunction of the arteries and vascular system. ED is commonly associated with a number of conditions frequently occurring in aging men, including prostatic hypertrophy, ischemic heart disease, peripheral vascular disease, hypertension, atherosclerosis, hyperlipidemia, stroke, and diabetes mellitus.

In a group of 15 men with ED, six in the group taking 2.8 g arginine daily for two weeks experience benefit, compared to no improvement in the placebo group. Although little is known about how effective arginine will be for men with erectile dysfunction or which subset of men would most likely be helped, available research looks promising and suggests that at least some men will benefit. (56) In a controlled clinical trial, 50 patients with ED were treated with 5 g L-arginine daily or placebo for six weeks. Nine of 29 patients taking L-arginine (31%), but only two of 17 patients taking placebo (11.7%), reported significant improvement of sexual function. In the nine responders, significant increases in plasma and urinary nitrate were measured after treatment with L-arginine, indicating improved NO production secondary to this treatment. (57)

Sickle Cell Disease and Pulmonary Hypertension

Pulmonary hypertension is a life-threatening complication of sickle cell disease reported to occur in up to 30 percent of adults with this disease. The etiology of sickle cell disease-related pulmonary hypertension is unclear. Treatment options are limited, and the prognosis is poor. Patients who develop this complication have a shortened lifespan. Its presence is an independent predictor of death, with an average time to death after diagnosis as short as 12 months.

Several studies in non-sickle cell disease patients demonstrate therapeutic benefits of L-arginine therapy for pulmonary hypertension. (58,59) Low plasma L-arginine concentrations have been discovered in infants with persistent pulmonary hypertension of the newborn, (60) correlating with low nitric oxide metabolite levels. (61) L-arginine infusion has decreased pulmonary vascular resistance and improved blood oxygenation in infants with this disease process. (62) L-arginine supplementation also improves pulmonary artery pressures and hemodynamics in patients with primary and secondary pulmonary hypertension, (59) with one recent study demonstrating these effects after only one week of therapy. (58)

Recent studies found that oral L-arginine normalizes red blood cell density and induces Gardos channel inhibition in sickle cell transgenic mice. (63) There is otherwise limited information available on the impact of L-arginine supplementation in sickle cell disease. (64)

There is growing evidence that pulmonary hypertension is a disease process that involves altered L-arginine metabolism or decreased bioavailability. Arginase, the enzyme that converts L-arginine to ornithine and urea, may limit NO bioavailability in sickle cell disease through increased use of its substrate. (65) In one recent study, L-arginine at a dose of 0.1 g/kg three times daily produced a 15.2-percent mean reduction in estimated pulmonary artery systolic pressure (63.9 [+ or -] 13 to 54.2 [+ or -] 12 mm Hg, p = 0.002) after five days of therapy in 10 patients. Arginase activity was elevated almost two-fold (p = 0.07) in patients with pulmonary hypertension and may limit L-arginine bioavailability. (65) Because L-arginine supplementation improves pulmonary artery pressures in non-sickle cell patients with pulmonary hypertension, L-arginine may also be therapeutic for sickle cell disease patients with pulmonary hypertension by providing increased substrate for NO production.

Beneficial Effects of Supplemental Sustained-release L-Arginine

From the above-mentioned studies of L-arginine, it appears an effective method of improving endothelial function would be to supplement with L-arginine. Oral L-arginine, however, is absorbed and metabolized quickly; the half-life of L-arginine in human circulating plasma is less than one hour. (66) A controlled-release formulation of L-arginine would increase the length of time in which L-arginine achieves an effective concentration.

Boger et al found 1.5 g of a sustained-release L-arginine taken twice daily improved endothelium-dependent vasodilation in patients with high plasma ADMA levels. (45) In previous studies, the same group of researchers showed at least 6 g L-arginine in a nonsustained release formulation was needed to achieve a similar effect. (67)

In a preliminary study of five patients with coronary artery disease in whose myocardial perfusion had been maximized and stabilized on conventional cardiovascular medications, 3 g sustained-release L-arginine was given twice daily for 12 weeks. Significant improvements in heart function and myocardial perfusion were seen via PET imaging. (68)

Conclusions

ADMA is an endogenous and competitive inhibitor of NO synthase. Plasma levels of this inhibitor are elevated in patients with atherosclerosis and in those with risk factors for atherosclerosis. (34,36) In these patients, plasma ADMA levels are correlated with the severity of endothelial dysfunction and atherosclerosis. By inhibiting the production of NO, ADMA can impair blood flow, accelerate atherogenesis, and interfere with angiogenesis.

Supplemental L-arginine improves endothelial function, myocardial perfusion, angina, erectile dysfunction, and exercise tolerance, regardless of ADMA status. However, many patients exhibiting one of these impairments demonstrate elevated blood ADMA. Therefore, testing for plasma ADMA levels may give the physician a better idea of those patients who may respond best to prolonged L-arginine supplementation, as data are accumulating to show that patients with elevated ADMA are the most likely to benefit. The ratio of L-arginine to ADMA is considered to be the most accurate measure of eNOS substrate availability. This ratio will increase during L-arginine supplementation, regardless of initial ADMA concentration. Due to the pharmacokinetics of oral L-arginine and the positive results from preliminary studies, it appears supplementation with a sustained-release L-arginine preparation will achieve positive therapeutic results at lower dosing levels

Table 1. Clinical Conditions with Elevated ADMA

Condition                                                 Fold increase                            Ref
                                                                vs. controls

Hypercholesterolemia                                     2-3                                     [1]
Hypertriglyceridemia                                         2                                     [19]
Hypertension                                                    2                                     [20]
Pulmonary Hypertension                                 2-3                                    [21]
Peripheral Arterial Disease                              2-4                                 [22, 23]
Chronic Renal Failure                                     2-12                                [24, 25]
Congestive Heart Failure                                 2-3                                   [26]
Type 2 Diabetes                                               2                                     [27]
Preeclampsia                                                    2                                     [28]

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(68.) Ron ES, Gould KL. Unpublished results.

Rainer H. Boger, MD--Professor and Head, Clinical Pharmacology Unit, Institute of Experimental and Clinical Pharmacology, Center of Experimental Medicine, University Hospital Hamburg-Eppendorf, Germany. Correspondence address: Martinistr. 52, D-20246 Hamburg, Germany. E-mail: boeger@uke.uni-hamburg.de

Eyal S. Run, PhD--Chief Scientific Officer, eNOS Pharmaceuticals, Inc., Cambridge, MA. eNOS Pharmaceuticals is involved in research and development of time-release arginine.

COPYRIGHT 2005 Thorne Research Inc.
COPYRIGHT 2005 Gale Group

Rainer H. Boger "L-arginine improves vascular function by overcoming the deleterious effects of ADMA, a novel cardiovascular risk factor". Alternative Medicine Review. March 2005. FindArticles.com. 17 Mar. 2008. http://findarticles.com/p/articles/mi_m0FDN/is_1_10/ai_n13557315

Non-invasive treatment for diabetic neuropathy shows promise

A new, non-invasive device that uses near-infrared light to increase blood flow in diabetic peripheral neuropathy (DPN) has shown promising results in early clinical trials.

Treatment with the Anodyne Therapy System (ATS) appears to restores sensation, reduce pain, and improve balance in patients with diabetic peripheral neuropathy (DPN), according to a report published in the January issue of Diabetes Care.

ATS is thought to increase blood flow by dilating arteries and veins.

The auhors assessed the outcomes of 27 patients with DPN who were treated with placebo or active ATS for 2 weeks and then active therapy for 2 more weeks three times a week.

The study group included 9 patients who were insensitive to 5.07 and 6.65 test filaments and 18 who were only insensitive to the 5.07 filament.

In the group with milder sensory impairment, both 6 and 12 weeks of ATS were associated with a significant drop in the number of insensate sites. In contrast, no sensory improvements were seen with sham therapy.

ATS therapy was also tied to a reduction in neuropathic symptoms scores and with a fall in visual analog pain scores and the percentage of patients with substantial balance problems decreased from 90% to 17% with ATS.

But in the patients insensate to both test filaments, ATS did not produce significant improvements in sensation, neuropathic symptoms, or pain.

Although the results are 'encouraging,' the authors conclude 'more discreet quantitative sensory tests would be helpful in determining the exact degree of sensory improvement experienced after the administration of ATS treatments.'

Reference: Leonard D, Farooqi M and Myers S (2003) Restoration of Sensation, Reduced Pain, and Improved Balance in Subjects With Diabetic Peripheral Neuropathy: A double-blind, randomized, placebo-controlled study with monochromatic near-infrared treatment Diabetes Care 27 (1) 168-172

Anodyne therapy for recalcitrant diabetic foot ulcers: a report of four cases.

Nather A, Sim YE, Chew LLj, Neo SH.

Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Four patients with diabetic foot ulcers that failed to heal after one month of treatment underwent anodyne therapy. Each therapy session lasted half an hour and was conducted 3 times a week for patients at home or daily for patients in hospital, for one to 2 months. The wound sizes and depths were graded according to the Wagner classification. Pictures were taken to evaluate the effects of anodyne therapy. All 4 patients had good healing of their foot ulcers. Anodyne therapy augments the effects of conservative treatment. Proper wound care and appropriate antibiotic coverage remain the basis of treatment.

PMID: 18162687 [PubMed - in process]

Restoration of sensation, reduced pain, and improved balance in subjects with diabetic peripheral neuropathy: a double-blind, randomized, placebo-controlled study with monochromatic near-infrared treatment.

Leonard DR, Farooqi MH, Myers S.

Joslin Center for Diabetes, Morton Plant Mease Healthcare, Clearwater, Florida 33756, USA.

OBJECTIVE: Diabetic peripheral neuropathy (DPN) has been thought to be progressive and irreversible. Recently, symptomatic reversal of DPN was reported after treatments with a near-infrared medical device, the Anodyne Therapy System (ATS). However, the study was not controlled nor was the investigator blinded. We initiated this study to determine whether treatments with the ATS would decrease pain and/or improve sensation diminished due to DPN under a sham-controlled, double-blind protocol. RESEARCH DESIGN AND METHODS: Tests involved the use of the 5.07 and 6.65 Semmes Weinstein monofilament (SWM) and a modified Michigan Neuropathy Screening Instrument (MNSI). Twenty-seven patients, nine of whom were insensitive to the 6.65 SWM and 18 who were sensitive to this filament but insensitive to the 5.07 SWM, were studied. Each lower extremity was treated for 2 weeks with sham or active ATS, and then both received active treatments for an additional 2 weeks. RESULTS: The group of 18 patients who could sense the 6.65 SWM but were insensitive to the 5.07 SWM at baseline obtained a significant decrease in the number of sites insensate after both 6 and 12 active treatments (P < 0.02 and 0.001). Sham treatments did not improve sensitivity to the SWM, but subsequent active treatments did (P < 0.002). The MNSI measures of neuropathic symptoms decreased significantly (from 4.7 to 3.1; P < 0.001). Pain reported on the 10-point visual analog scale decreased progressively from 4.2 at entry to 3.2 after 6 treatments and to 2.3 after 12 treatments (both P < 0.03). At entry, 90% of subjects reported substantial balance impairment; after treatment, this decreased to 17%. However, among the group of nine patients with greater sensory impairment measured by insensitivity to the 6.65 SWM at baseline, improvements in sensation, neuropathic symptoms, and pain reduction were not significant. CONCLUSIONS: ATS treatments improve sensation in the feet of subjects with DPN, improve balance, and reduce pain.

PMID: 14693984 [PubMed - indexed for MEDLINE]

Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial.

Ziegler D, Ametov A, Barinov A, Dyck PJ, Gurieva I, Low PA, Munzel U, Yakhno N, Raz I, Novosadova M, Maus J, Samigullin R.

FRCPE, Deutsche Diabetes-Klinik, Deutsches Diabetes-Zentrum, Leibniz-Institut an der Heinrich-Heine-Universität, Auf'm Hennekamp 65, 40225 Düsseldorf, Germany. dan.ziegler@ddz.uni-duesseldorf.de

OBJECTIVE: The aim of this trial was to evaluate the effects of alpha-lipoic acid (ALA) on positive sensory symptoms and neuropathic deficits in diabetic patients with distal symmetric polyneuropathy (DSP). RESEARCH DESIGN AND METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial, 181 diabetic patients in Russia and Israel received once-daily oral doses of 600 mg (n = 45) (ALA600), 1,200 mg (n = 47) (ALA1200), and 1,800 mg (ALA1800) of ALA (n = 46) or placebo (n = 43) for 5 weeks after a 1-week placebo run-in period. The primary outcome measure was the change from baseline of the Total Symptom Score (TSS), including stabbing pain, burning pain, paresthesia, and asleep numbness of the feet. Secondary end points included individual symptoms of TSS, Neuropathy Symptoms and Change (NSC) score, Neuropathy Impairment Score (NIS), and patients' global assessment of efficacy. RESULTS: Mean TSS did not differ significantly at baseline among the treatment groups and on average decreased by 4.9 points (51%) in ALA600, 4.5 (48%) in ALA1200, and 4.7 (52%) in ALA1800 compared with 2.9 points (32%) in the placebo group (all P < 0.05 vs. placebo). The corresponding response rates (>/=50% reduction in TSS) were 62, 50, 56, and 26%, respectively. Significant improvements favoring all three ALA groups were also noted for stabbing and burning pain, the NSC score, and the patients' global assessment of efficacy. The NIS was numerically reduced. Safety analysis showed a dose-dependent increase in nausea, vomiting, and vertigo. CONCLUSIONS: Oral treatment with ALA for 5 weeks improved neuropathic symptoms and deficits in patients with DSP. An oral dose of 600 mg once daily appears to provide the optimum risk-to-benefit ratio.

PMID: 17065669 [PubMed - indexed for MEDLINE]

The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial.

Ametov AS, Barinov A, Dyck PJ, Hermann R, Kozlova N, Litchy WJ, Low PA, Nehrdich D, Novosadova M, O'Brien PC, Reljanovic M, Samigullin R, Schuette K, Strokov I, Tritschler HJ, Wessel K, Yakhno N, Ziegler D; SYDNEY Trial Study Group.

Russian Medical Academy for Advanced Studies, Moscow, Russia.

OBJECTIVE: Because alpha-lipoic acid (ALA), a potent antioxidant, prevents or improves nerve conduction attributes, endoneurial blood flow, and nerve (Na(+) K(+) ATPase activity in experimental diabetes and in humans and may improve positive neuropathic sensory symptoms, in this report we further assess the safety and efficacy of ALA on the Total Symptom Score (TSS), a measure of positive neuropathic sensory symptoms. RESEARCH DESIGN AND METHODS: Metabolically stable diabetic patients with symptomatic (stage 2) diabetic sensorimotor polyneuropathy (DSPN) were randomized to a parallel, double-blind study of ALA (600 mg) (n = 60) or placebo (n = 60) infused daily intravenously for 5 days/week for 14 treatments. The primary end point was change of the sum score of daily assessments of severity and duration of TSS. Secondary end points were sum scores of neuropathy signs (NIS), symptoms (NSC), attributes of nerve conduction, quantitative sensation tests (QSTs), and an autonomic test. RESULTS: At randomization, the groups were not significantly different by the criteria of metabolic control or neuropathic end points. After 14 treatments, the TSS of the ALA group had improved from baseline by an average of 5.7 points and the placebo group by an average of 1.8 points (P < 0.001). Statistically significant improvement from baseline of the ALA, as compared with the placebo group, was also found for each item of the TSS (lancinating and burning pain, asleep numbness and prickling), NIS, one attribute of nerve conduction, and global assessment of efficacy. CONCLUSIONS: Intravenous racemic ALA, a potent antioxidant, rapidly and to a significant and meaningful degree, improved such positive neuropathic sensory symptoms as pain and several other neuropathic end points. This improvement of symptoms was attributed to improved nerve pathophysiology, not to increased nerve fiber degeneration. Because of its safety profile and its effect on positive neuropathic sensory symptoms and other neuropathic end points, this drug appears to be a useful ancillary treatment for the symptoms of diabetic polyneuropathy.

PMID: 12610036 [PubMed - indexed for MEDLINE]

Acetyl-L-carnitine (levacecarnine) in the treatment of diabetic neuropathy. A long-term, randomised, double-blind, placebo-controlled study.

De Grandis D, Minardi C.

Department of Neuroscience, Ospedale Civile, Rovigo, Italy. ddegrandis@iol.it

OBJECTIVE: To assess the efficacy and tolerability of acetyl-L-carnitine (levacecarnine; LAC) versus placebo in the treatment of diabetic neuropathy, mainly by evaluating the effects of treatment on electrophysiological parameters and pain symptoms. DESIGN: This was a multicentre (n = 20), randomised, double-blind, placebo-controlled, parallel-group study. PATIENTS: 333 patients meeting clinical and/or neurophysiological criteria for diabetic neuropathy were enrolled. INTERVENTIONS: Patients were randomised to treatment with LAC or placebo. LAC (or placebo) was started intramuscularly at a dosage of 1000 mg/day for 10 days and continued orally at a dosage of 2000 mg/day for the remainder of the study (355 days). MAIN OUTCOME PARAMETERS AND RESULTS: The main efficacy parameter was the effect of treatment on 6- and 12-month changes from baseline in nerve conduction velocity (NCV) and amplitude in the sensory (ulnar, sural and median) and motor (median, ulnar and peroneal) nerves. The effect of treatment on pain was also evaluated by means of a visual analogue scale (VAS). Among the 294 patients with impaired electrophysiological parameters at baseline, those treated with LAC showed a statistically significant improvement in mean NCV and amplitude compared with placebo (p < 0.01). The greatest changes in NCV (at 12 months) were observed in the sensory sural nerve (7 m/sec in the LAC group vs +1.0 m/sec in the placebo group), sensory ulnar nerve (+2.9 vs +0.1 m/sec, respectively) and motor peroneal nerve (+2.7 vs -0.2 m/sec), whereas the greatest changes in amplitude were recorded in the motor peroneal nerve (+2.2 vs +0.1 mV). After 12 months of treatment, mean VAS scores for pain were significantly reduced from baseline by 39% in LAC-treated patients (p < 0.0 vs baseline) compared with 8% in placebo recipients. LAC was well tolerated over the study period. CONCLUSIONS: LAC was effective and well tolerated in improving neurophysiological parameters and in reducing pain over a 1-year period. LAC is, therefore, a promising treatment option in patients with diabetic neuropathy.

PMID: 12455197 [PubMed - indexed for MEDLINE]

Nitric oxide: From menace to marvel of the decade

A briefing document prepared for the Royal Society and Association of British Science Writers

Pearce Wright


May 1996

Nitric oxide: From menace to marvel of the decade

Summary Research papers continue to flood the scientific journals with insights into the biological activity and potential clinical uses of nitric oxide (NO): a gas controlling a seemingly limitless range of functions in the body. Each revelation adds to nitric oxide's already lengthy resume in controlling the circulation of the blood, and regulating activities of the brain, lungs, liver, kidneys, stomach, gut, genitals and other organs.

The molecule governs blood pressure, through a recently recognised process that contradicts textbook wisdom. It causes penile erections by dilating blood vessels, and controls the action of almost every orifice from swallowing to defecation. The immune system uses nitric oxide in fighting viral, bacterial and parasitic infections, and tumours. Nitric oxide transmits messages between nerve cells and is associated with the processes of learning, memory, sleeping, feeling pain, and, probably, depression. It is a mediator in inflammation and rheumatism.

Clinically, newborn babies with breathing problems are getting relief by an experimental inhalation treatment developed from this new understanding. A novel class of drugs that block the production of nitric oxide is being assessed as a possible treatment for septic shock. Drugs that liberate or enhance the action of nitric oxide may be useful in the treatment of pulmonary hypertension, and could prevent the formation of blood clots and counteract impotence. Animal experiments show how to manipulate nitric oxide production to stop the development of arthritis and kidney disease.

In the longer term, drugs that alter the amount or activity of nitric oxide might help protect the brain in conditions such as stroke, Alzheimers and Parkinsons disease.


Nitric oxide: From menace to marvel of the decade

Five years ago the Wellcome Institute for the History of Medicine began a series of events called Witness Seminars. They provide a forum for recording for the archive, first-hand accounts of the circumstances leading to major advances in contemporary biomedical science, like the discovery of monoclonal antibodies and unravelling the cause of thalassaemias, a group of inherited blood disorders that are widely spread across the Mediterranean, Middle East and Far East, and cause severe anaemia.

They capture the sort of reminiscences and perspectives that could only come from the intimacy of an autobiography of those in the front line of the research.

A similar chance to savour a first-hand narrative of an area of research, though at an earlier stage of science in the making, was provided by Professor Salvador Moncada, Dr Patrick Vallance, Professor John Garthwaite and Professor Eddy Liew. They distilled the significance of a welter of basic and clinical research by scores of international laboratories into how nitric oxide, synthesised from the amino acid L-arginine, literally in cells from head to foot, can keep us fit and healthy.

The research is now yielding over 3 000 papers a year. It began with the discovery that the nitric oxide molecule was the regulator of the muscle tone of blood vessels. While the finding astonished some scientists and provoked scepticism in others, it opened a floodgate. The potential importance of the torrent of research results, which showed nitric oxide governed numerous other biological processes, received an accolade guaranteeing wider public attention when nitric oxide was chosen as the cover story by Science for its "Molecule of the Year" in 1992, and was wreathed with puns: NO sex; NO wonder; NO way.

However, it couldn't match the vivid account of "the fascinating adventure" Salvador Moncada lives when recalling the research that unmasked the biological role of nitric oxide and the subsequent avalanche of work it triggered.

He was a senior author of the paper, published in 1987, which revealed how nitric oxide is produced to control the relaxation of the muscles of blood vessels. He clearly recalls the surprise expressed by other researchers when they realised that such a crucial activity, with profound implications for understanding the cardiovascular disease, was under the control of such an apparently simple molecule.

The story had its origins seven years earlier. In effect, the gauntlet was thrown down by R F Furchgott and J V Zawadski who showed that when strips of blood vessels, nurtured in an organ bath, were chemically stimulated, the muscles relaxed. If the inner layer of cells of an artery or vein, the endothelium, was absent, the smooth muscles of the blood vessel lost their capacity to make the vessel expand. This showed that a previously unrecognised substance must exist that regulated the tone of the smooth muscles of blood vessels. They referred to the mystery agent as endothelium dependent relaxing factor, EDRF. Curiosity provoked several laboratories to start searching among the body's complex biomolecules to find a candidate for EDRF among the array of amines, peptides, fatty acids and other chemicals.

Salvador Moncada and his colleagues devised two experiments to test whether nitric oxide could account for the actions of EDRF. The first was to determine whether nitric oxide was released by endothelial cells. Equipment developed for the study included a highly sensitive, miniaturised version of an instrument used in the car industry to measure nitric oxide in the exhaust of petrol engines. When linked to endothelial cells, repeated measurements demonstrated that nitric oxide was indeed the relaxing factor released by these cells.

The second experiment compared the effects of natural EDRF on muscle tone with the effects produced by mimicking the relaxing factor with "off the shelf" nitric oxide, bought from the British Oxygen Company, the specialist that made industrial gases by the ton rather than in the picogram amounts of nitric oxide made by endothelial cells.

Salvador Moncada recalled that nobody had the remotest suspicion that EDRF would turn out to be a simple molecule like nitric oxide; or that it was synthesised not just in the blood vessels, but as an essential part of the physiology of most organs and tissues.

Previously, nitric oxide was regarded as an environmental pollutant and little else: at best a chemically reactive nuisance, at worst a poison. In the exhaust fumes of cars it reacted readily with oxygen to produce smog, increasing the risk of asthma. When discharged into the atmosphere from power station chimneys it contributed to the ecological damage from acid rain. Consequently, a response bordering on disbelief greeted the discovery that cells lining the walls of blood vessels, endothelial cells, intentionally synthesised nitric oxide as a muscle relaxant. The molecule is short-lived, and a constant supply is generated by endothelial cells in response to the sheer stress of the blood flow on the artery wall. The notion that such a noxious little molecule should also hold a key to a healthy body and mind was counter-intuitive, and is still disconcerting to some people.

Compared with the complexity of the hundreds of other molecules that keep us ticking, where size seems to equate with biological relevance, the free radical form of nitric oxide that constitutes the muscle relaxing factor is simplicity itself: just one atom of oxygen and one of nitrogen. However, this seemingly uncomplicated molecule has a number of reactive forms, which helps explain the diversity of its chemistry and the range of biological effects they stimulate.

A year after identifying nitric oxide as the mystery molecule, Salvador Moncada's group reported on how it was formed in endothelial cells. The biochemistry depends on the action of one of a family of enzymes, nitric oxide synthases or NOS, converting the amino acid L-arginine to L-citrulline and forming nitric oxide in the process.

While sceptics still thought it inconceivable that a biochemical pathway for producing nitric oxide was likely to exist in endothelial cells, they were batting against evolution. It transpires that the ability of organisms to produce nitric oxide is an ancient one, developed long before mammals emerged. Indeed, the horseshoe crab, with origins going back 500 million years, depends on the L-arginine: nitric oxide process to prevent its blood cells from aggregating.

The early research overturned some basic views of the cardiovascular system whereby blood pressure was seen as resulting from a constant balancing act between factors influencing the constriction and the dilation of vessels. Changes in blood pressure and blood flow happened if the balance was tipped too far one way or the other. Now, it seems, the normal cardiovascular state is tilted in one direction, and the dilation of vessels is sustained by a steady flow of nitric oxide. So any interruption to the production of nitric oxide interferes with the tone of the smooth muscle.

If normality means that blood vessels are dilated constantly, then the prevailing perception of blood pressure and the approach to managing hypertension may need a major overhaul. From the new point of view, raised blood pressure may be as much a problem of lack of dilator tone as it may be due to constriction caused by some unknown factor.

The new insight also explains at last the discovery made more than 100 years ago that a group of drugs, based on amylnitrite and nitroglycerine, could stop a painful attack of angina: the chest pain now known to be caused when the heart muscle is short of oxygen. By chance, the Victorian physicians had worked out that although it was too dangerous to give people nitric oxide directly, substances that released it slowly could relieve hypertension. The helpful effect on blood pressure of a whiff of amylnitrite vapour was recognised as long ago as 1867, and Conan Doyle credited Sherlock Holmes with that knowledge in The Case of the Resident Patient.

The poisonous effects of nitric oxide were well known. It was easy enough to make in the laboratory by adding copper turnings to concentrated nitric acid, and collecting the colourless gas over water. It nearly killed Sir Humphry Davy, in 1800, when he experimented with breathing it in.

In World War I, doctors noticed that workers packing shells with nitroglycerine in ammunition factories had very low blood pressures. The observation led to the development of a pill containing nitroglycerine, that remains effective as an emergency vasodilator when popped under the tongue to give rapid relief for angina.

Although effective, the precise way in which the nitric oxide is released from nitroglycerine to imitate the L-arginine source of the molecule, is still a bit of a mystery. Nitric oxide is changed rapidly once in the bloodstream because it is highly attracted to the iron in haemoglobin.

As research into nitric oxide gathered momentum nine years ago, investigations spread way beyond the effect of the endothelial derived molecule. Three forms of the NOS enzyme were found: one in the endothelium, one in the brain and one in the immune system. Moreover, the biochemists were intrigued to discover that these enzymes were unusual in that they controlled a two stage reaction that would usually take two enzymes. More recently, molecular biologists have homed in on the different genes that encode for the endothelial, neuronal and immune system nitric oxide synthase enzymes: the genes are on chromosomes 12, 7 and 17 respectively.

From a clinical perspective, Patrick Vallance outlined the far-reaching implications of nitric oxide for treating various forms of cardiovascular diseases, which account for almost half the deaths in Britain. A vast range of research is aimed at translating the laboratory and animal findings about nitric oxide for the benefit of the cardiovascular and heart disease sufferers.

His group used healthy volunteers to test whether nitric oxide acted on the human cardiovascular system in an identical way to that predicted from in vitro and animal work in the laboratory. The study entailed what has become a new class of drug based on N-monomethyl-arginine (L-NMMA - an inhibitor of the NOS enzyme). This drug is one of a class of inhibitors that can be used to explore what happens when nitric oxide production is blocked. In the experiment, one forearm of a volunteer was injected with L-NMMA. The blood flow was then compared with that of the other arm. As L-NMMA was infused gradually, blood flow decreased to a half of that in the control arm.

Complications caused by problems with endothelial production of nitric oxide arise from a variety of causes: the fragile layer of endothelial cells are prone to damage, from among other things, high blood pressure, high sugar in diabetes, furring up with cholesterol and other lipids, and the effect of smoking.

In cases involving a risk of heart attack, attention focuses on nitric oxide deficiency, and the dangers when its release is blocked from a diseased coronary artery so that vasodilator tone needed to regulate the flow of blood is lost. Other diseases can also be treated by increasing the supply of nitric oxide to blood vessels. A trace of nitric oxide gas (25 parts per million) inhaled by patients with pulmonary hypertension can relieve lung congestion. In a treatment for newborn babies, breathing problems are being helped by inhalation of nitric oxide that relaxes constricted blood vessels and dilates the lung's blood vessels.

Generally, low blood pressure is not a problem in healthy people. Occasionally, it is a symptom of serious condition; and an acute drop can signal that an overwhelming infection has caused septic shock and severe tissue damage. The trouble lies in a vicious cycle. Septic shock depresses blood pressure. The loss of blood flow can cause tissue damage, and that in turn increases the production of nitric oxide, leading to a further fall in blood pressure. Low blood pressure induced by septic shock has been restored with a treatment that included the use of an NOS inhibitor.

The remarkable role nitric oxide plays as a messenger between nerve cells was revealed by John Garthwaite and colleagues, at Liverpool University, who first identified it in the brain. Subsequent measurements have shown that the brain contained more of the nitric oxide synthase enzyme than any other organ.

When research into the possible role of nitric oxide in the central nervous system began, the brain was the least expected organ in which to find the molecule. It transpired that the nitric oxide synthase enzyme was not confined to small areas, but was distributed throughout the brain: suggesting an involvement in almost every brain function. It turns out that because the molecule is so small, it is a physically convenient messenger that diffuses into and out of cells easily; and it is now a prime candidate for the much searched for "retrograde messenger" that is the basis of memory.

Animal studies suggest that an effector cell in the brain which releases the chemical messenger glutamate can stimulate the receptor cell with this chemical to release nitric oxide. If it is strongly stimulated, the receptor sends back a nitric oxide molecule to tell the sender that the message has been received, and programmes it to send an even stronger signal next time - the phenomenon of long term potentiation that is thought to be linked to memory formation.

Nitric oxide produced in the brain by the neuronal form of the nitric oxide synthase acts as a chemical messenger at the synapses. The in-vitro and animal experiments showing the role of neuronal nitric oxide in memory has opened a new approach to studies of Alzheimers, Parkinsons and other neurological disorders.

Too much nitric oxide, on the other hand, may be responsible for killing brain cells in conditions such as stroke.

In yet another role, nitric oxide helps the immune system's macrophages, the cells in the body that are activated in injury and illness to get rid of debris, when they seek out invading bacteria or cancer cells to destroy. As the "bin men" of the immune system, the macrophages use the cytotoxic properties of nitric oxide to sweep up parasites, bacteria and other potentially infectious rubbish.

Eddy Liew's work on the role of nitric oxide in the immune system shows the molecule will destroy many organisms that are difficult to kill by other means. And his group has demonstrated the susceptibility to nitric oxide of the vicious parasite that causes Leishmaniasis, a group of potentially fatal tropical diseases caused by parasites transmitted by the bite of sandflies.

Treatment with the inhibitor L-NMMA also appears to block inflammation in the body associated with the development of arthritis and kidney disease. Moreover, mice genetically engineered not to generate nitric oxide during the immune responses display a reduced inflammatory response. If research now underway confirms the scientists' hypotheses, the advances could lead rapidly to a new class of drugs to control inflammatory diseases that are classified as auto-immune diseases because the affected tissue is under continual attack by its own immune system.

Research on nitric oxide, its physiological and pathological roles and clinical potential is currently one of the most exciting sources of knowledge in biology.


Contacts

Professor Salvador Moncada F.R.S.

The Cruciform Project

University College London

140 Tottenham Court Road

London W1P 9LN

tel: 0171 209 6343 fax: 0171 209 0470


Dr Patrick Vallance

The Cruciform Project

University College London

140 Tottenham Court Road

London W1P 9LN

tel: 0171 209 6340 fax: 0171 209 0470


Professor John Garthwaite

Head - Neuroscience Research

Glaxo Wellcome plc

Langley Court

South Eden Park Road

Beckenham BR3 3BS

tel: 0181 658 2211 fax: 0181 650 9862


Professor Eddy Liew

Head of Department of Immunology

University of Glasgow

Western Infirmary

Glasgow G11 6NT

tel: 0141 211 2695 fax: 0141 337 3217


Enquiries to: Ref: PR 23 (96)

Miss Anna Link

Science Promotion Section

The Royal Society

6 Carlton House Terrace

London

SW1Y 5AG

Direct line: 0171 451 2581 14 May 1996

INFORMATION NOTE

Nitric oxide: from menace to marvel of the decade

On 31 May 1995, the Royal Society and Association of British Science Writers held a scientific press briefing on Nitric oxide: from menace to marvel of the decade. The enclosed document was prepared afterwards to summarize key issues raised by the speakers and to provide a list of helpful contacts for future reference.

The document does not necessarily constitute the views of the Royal Society or the Association of British Science Writers, and views expressed in it should not be attributed to either the Society or Association. The document is free of copyright and may be used without reference to source.

Copyright ABSW  © 2008  Last update 11 February 2008

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