Patrick Vallance

Guidelines for the Ultrasound Assessment of Endothelial-Dependent Flow-Mediated Vasodilation of the Brachial Artery A Report of the International Brachial Artery Reactivity Task Force

Endothelial function is thought to be an important factor in the pathogenesis of atherosclerosis, hypertension and heart failure. In the 1990s, high-frequency ultrasonographic imaging of the brachial artery to assess endothelium-dependent flow-mediated vasodilation (FMD) was developed. The technique provokes the release of nitric oxide, resulting in vasodilation that can be quantitated as an index of vasomotor function. The noninvasive nature of the technique allows repeated measurements over time to study the effectiveness of various interventions that may affect vascular health. However, despite its widespread use, there are technical and interpretive limitations of this technique. State-of-the-art information is presented and insights are provided into the strengths and limitations of high-resolution ultrasonography of the brachial artery to evaluate vasomotor function, with guidelines for its research application in the study of endothelial physiology.

Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure

Nitric oxide (NO), synthesised from L-arginine, contributes to the regulation of blood pressure and to host defence. We describe in-vitro and in-vivo evidence that NO synthesis can be inhibited by an endogenous compound, NG,NG-dimethylarginine (asymmetrical dimethylarginine, ADMA). In man, this inhibitor is found in plasma and more than 10 mg is excreted in urine over 24 h. However, in patients with end-stage chronic renal failure, who have little or no urine output, elimination is blocked and circulating concentrations of the inhibitor rise sufficiently to inhibit NO synthesis. Accumulation of endogenous ADMA, leading to impaired NO synthesis, might contribute to the hypertension and immune dysfunction associated with chronic renal failure.

Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man

NG monomethyl-L-arginine (L-NMMA), a specific inhibitor of the synthesis of endothelium-derived nitric oxide (NO), was infused into the brachial arteries of healthy volunteers to study the role of NO in the control of forearm blood flow. L-NMMA caused a 50% fall in basal blood flow and attenuated the dilator response to infused acetylcholine but not that to glyceryl trinitrate. These results indicate that the dilator action of endothelium-derived NO contributes to the control of basal and stimulated regional blood flow in man. Impairment of production of NO might account for the abnormalities in vascular reactivity that characterise a wide variety of disease states.

Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock

Hypotension during septic shock, which may reflect increased synthesis of the potent vasodilator nitric oxide (NO), is often refractory to vasoconstrictors. We describe the effects of NO synthase inhibition in two patients with life-threatening septic shock in whom conventional therapy had failed to restore blood pressure. NG-monomethyl-L-arginine (L-NMMA) caused dose-dependent increases in blood pressure and systemic vascular resistance in both patients, and a similar effect was observed in the second patient after treatment with NG-nitro-L-arginine methyl ester (L-NAME). These findings indicate that NO synthase induction contributes to the pathogenesis of septic shock, and that inhibition of NO synthase may represent a novel therapeutic option.

Effect of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renal outcomes : systematic review and meta-analysis

BACKGROUND A consensus has emerged that angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-II receptor blockers (ARBs) have specific renoprotective effects. Guidelines specify that these are the drugs of choice for the treatment of hypertension in patients with renal disease. We sought to determine to what extent this consensus is supported by the available evidence. METHODS Electronic databases were searched up to January, 2005, for randomised trials assessing antihypertensive drugs and progression of renal disease. Effects on primary discrete endpoints (doubling of creatinine and end-stage renal disease) and secondary continuous markers of renal outcomes (creatinine, albuminuria, and glomerular filtration rate) were calculated with random-effect models. The effects of ACE inhibitors or ARBs in placebo-controlled trials were compared with the effects seen in trials that used an active comparator drug. FINDINGS Comparisons of ACE inhibitors or ARBs with other antihypertensive drugs yielded a relative risk of 0.71 (95% CI 0.49-1.04) for doubling of creatinine and a small benefit on end-stage renal disease (relative risk 0.87, 0.75-0.99). Analyses of the results by study size showed a smaller benefit in large studies. In patients with diabetic nephropathy, no benefit was seen in comparative trials of ACE inhibitors or ARBs on the doubling of creatinine (1.09, 0.55-2.15), end-stage renal disease (0.89, 0.74-1.07), glomerular filtration rate, or creatinine amounts. Placebo-controlled trials of ACE inhibitors or ARBs showed greater benefits than comparative trials on all renal outcomes, but were accompanied by substantial reductions in blood pressure in favour of ACE inhibitors or ARBs. INTERPRETATION The benefits of ACE inhibitors or ARBs on renal outcomes in placebo-controlled trials probably result from a blood-pressure-lowering effect. In patients with diabetes, additional renoprotective actions of these substances beyond lowering blood pressure remain unproven, and there is uncertainty about the greater renoprotection seen in non-diabetic renal disease.

Hyperdynamic circulation in cirrhosis: a role for nitric oxide?

Hypotension, low systemic vascular resistance, and a reduced sensitivity to vasoconstrictors are features of cirrhosis. These cardiovascular changes might be the result of increased synthesis of a vasodilator. Nitric oxide (NO), a potent vasodilator, is synthesised in and released from peripheral blood-vessels in man. Studies in animals indicate that bacterial endotoxin and cytokines induce NO synthase expression in vessel walls, with sustained NO release and consequent hypotension. Endotoxaemia is a common feature of cirrhosis; persistent induction of NO synthase may account for the associated haemodynamic changes.

Acute Systemic Inflammation Impairs Endothelium-Dependent Dilatation in Humans

BackgroundWe tested the hypothesis that endothelial dysfunction underlies the association between an acute inflammatory episode and the transiently increased risk of a cardiovascular event by examining the effects of an experimental inflammatory stimulus on endothelium-dependent vasodilation. Methods and ResultsSalmonella typhi vaccine was used to generate a systemic inflammatory response in healthy volunteers. In 12 subjects, dilatation of the brachial artery to flow and to sublingual nitroglycerin (NTG) was recorded (conduit vessel response), and in 6 subjects, venous occlusion plethysmography was used to measure forearm blood flow during intrabrachial infusion of the endothelium-dependent dilators acetylcholine (ACh) and bradykinin (BK) and the endothelium-independent dilators NTG and verapamil (resistance vessel response). Responses were assessed 16 hours before and 8 and 32 hours after vaccination. Vaccination resulted in elevations in white cell count and serum levels of interleukin-6 and interleukin-1 receptor antagonist. Eight hours after vaccination, resistance vessel responses to BK (P =0.0099) and ACh (P =0.0414) were markedly attenuated, and brachial artery flow-mediated dilatation was depressed. Resistance vessel responses to verapamil and NTG were unchanged, as was the conduit vessel response to NTG. Thirty-two hours after vaccination, resistance vessel responses to BK and ACh had returned to normal. ConclusionsS typhi vaccine generates a mild inflammatory reaction associated with temporary but profound dysfunction of the arterial endothelium in both resistance and conduit vessels to both physical and pharmacological dilator stimuli. This finding might explain the association between infection and inflammation and the enhanced risk of an acute cardiovascular event.

Asymmetric Dimethylarginine Causes Hypertension and Cardiac Dysfunction in Humans and Is Actively Metabolized by Dimethylarginine Dimethylaminohydrolase

Objective—Plasma levels of an endogenous nitric oxide (NO) synthase inhibitor, asymmetric dimethylarginine (ADMA), are elevated in chronic renal failure, hypertension, and chronic heart failure. In patients with renal failure, plasma ADMA levels are an independent correlate of left ventricular ejection fraction. However, the cardiovascular effects of a systemic increase in ADMA in humans are not known. Methods and Results—In a randomized, double-blind, placebo-controlled study in 12 healthy male volunteers, we compared the effects of intravenous low-dose ADMA and placebo on heart rate, blood pressure, cardiac output, and systemic vascular resistance at rest and during exercise. We also tested the hypothesis that ADMA is metabolized in humans in vivo by dimethylarginine dimethylaminohydrolase (DDAH) enzymes. Low-dose ADMA reduced heart rate by 9.2±1.4% from 58.9±2.0 bpm (P <0.001) and cardiac output by 14.8±1.2% from 4.4±0.3 L/min (P <0.001). ADMA also increased mean blood pressure by 6.0±1.2% from 88.6±3.4 mm Hg (P <0.005) and SVR by 23.7±2.1% from 1639.0±91.6 dyne · s · cm−5 (P <0.001). Handgrip exercise increased cardiac output in control subjects by 96.8±23.3%, but in subjects given ADMA, cardiac output increased by only 35.3±10.6% (P <0.05). DDAHs metabolize ADMA to citrulline and dimethylamine. Urinary dimethylamine to creatinine ratios significantly increased from 1.26±0.32 to 2.73±0.59 after ADMA injection (P <0.01). We estimate that humans generate approximately 300 &mgr;mol of ADMA per day, of which approximately 250 &mgr;mol is metabolized by DDAHs. Conclusions—This study defines the cardiovascular effects of a systemic increase in ADMA in humans. These are similar to changes seen in diseases associated with ADMA accumulation. Finally, our data also indicate that ADMA is metabolized by DDAHs extensively in humans in vivo.

Cardiovascular Biology of the Asymmetric Dimethylarginine:Dimethylarginine Dimethylaminohydrolase Pathway

An increasing number of reports indicate that endogenously produced inhibitors of nitric oxide synthase, particularly asymmetric dimethylarginine (ADMA), regulate nitric oxide generation in disease states. This article describes the biology of ADMA and the implications for cardiovascular physiology and pathophysiology.

Endogenous dimethylarginine as an inhibitor of nitric oxide synthesis.

Summary: Nitric oxide (NO) is a widespread biological mediator with myriad functions. We have demonstrated that methylated arginines capable of inhibiting NO synthesis circulate in the plasma of healthy volunteers and are excreted unchanged in the urine. Up to 10 mg of asymmetric dimethylarginine is excreted in the urine every day, and this compound inhibits NO synthesis in vitro and in vivo, in animals and in humans. This finding raises the possibility that these compounds may act as endogenous regulators of the L‐arginine:NO pathway in health and disease.