Dilator actions of arginine in human peripheral vasculature

Calver, Alison; Collier, Joe; Vallance, Patrick

doi:10.1042/cs0810695

Cited by 89 publications

(47 citation statements)

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“…In contrast, higher doses of arginine (resulting in plasma levels of 5 mmol/L) can produce a nonstereospecific vascular response as a result of greater release of these vasodilator hormones. 17 Second, the stereospecific nature of our results was confirmed directly. D-Arginine produced no measurable hemodynamic effects with slight falls in HF measures of HRV (RMSSD and HF power) and BRS (␣-HF) compared with saline (in contrast to the effects of L-arginine).…”

Section: Discussionsupporting

confidence: 72%

l -Arginine Augments Cardiac Vagal Control in Healthy Human Subjects

et al. 2002

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Abstract-Cardiac vagal control has prognostic significance in cardiac disease, but the control mechanisms of this system remain poorly understood. We have previously demonstrated a role for NO in promoting vagal control of heart rate in humans. Here we examine the influence of L-arginine, the substrate for NO synthase, on this mechanism in healthy human subjects. Eleven healthy volunteers (9 men; age, 20 to 25 years) underwent measurement of heart rate variability and baroreflex sensitivity before and during a systemic infusion of L-arginine (1 g/min; total, 30 g). To control for the fall in blood pressure, comparison was made with an infusion of the control vasodilator hydralazine. Stereospecificity of observed effects was investigated by infusion of D-arginine. Urinary nitrate and nitrite (NO x ) and cGMP concentrations were measured as indexes of NO generation. L-Arginine infusion produced a drop in mean arterial pressure of 5 mm Hg. This fall in blood pressure was matched by hydralazine infusion and was not observed with either D-arginine or saline infusion. Although RR interval duration, heart rate variability, and baroreflex sensitivity all fell significantly with hydralazine, the same degree of baroreflex unloading with L-arginine produced an increase in RR interval duration and no change or even slight increases in heart rate variability and baroreflex sensitivity. In contrast, D-arginine produced falls in high-frequency indexes of heart rate variability compared with saline. Only L-arginine increased urinary NO x and cGMP excretion. In conclusion, these data demonstrate that short-term L-arginine infusion facilitates vagal control of heart rate in healthy humans, probably via increased NO synthesis. Key Words: L-arginine Ⅲ nitric oxide Ⅲ baroreflex Ⅲ autonomic nervous system Ⅲ heart rate variability I mpaired autonomic regulation of the heart exerts a powerful influence on prognosis in cardiac disease. In large-scale studies, depressed markers of cardiac vagal function-heart rate variability (HRV) and baroreflex sensitivity (BRS)-have been shown to be powerfully and independently predictive of an adverse prognosis in heart failure 1 and after myocardial infarction. 2 However, the mechanisms controlling cardiac autonomic function in both health and cardiac disease are poorly understood. A growing body of animal evidence suggests that NO may have a significant role as a neuromodulator within this control system. NO synthase (NOS) is expressed in many localized neuronal populations, both central and peripheral, that regulate cardiovascular autonomic function. The NO generated at these sites appears to have a significant neuromodulator activity, with the net effect of cardiac vagal activation and sympathetic inhibition. 3 In humans, we have previously used both systemic NOS inhibitors and exogenous NO donors to demonstrate a facilitatory role for NO in the modulation of cardiac vagal control in healthy volunteers. 4 We therefore hypothesize that enhancement of NOS activity might result in a therapeutically ...

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Section: Discussionsupporting

confidence: 72%

l -Arginine Augments Cardiac Vagal Control in Healthy Human Subjects

et al. 2002

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“…This possibility was unlikely, however, because our subjects were young and healthy and had normal cholesterol levels. 28 In our study, L-arginine not only dilated forearm blood vessels but also augmented vasodilator responses to acetyicholine, and there were no such effects for D-arginine. Thus, we believe that effects of L-arginine on forearm vessels are not nonspecific but rather are related to activation of the pathway from L-arginine to nitric oxide.…”

Section: Direct Vasodilation and Augmented Responses To Acetylcholinementioning

confidence: 70%

Effects of L-arginine on forearm vessels and responses to acetylcholine.

et al. 1992

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This study was designed to Investigate the effects of L-arginine (the substrate of endothelium-derived nitric oxide) in human forearm vessels. We examined whether intra-arterial infusion of L-arginine dilated forearm vessels and augmented vasodilatory responses to acetylcholine in young, healthy humans. The left brachial artery was cannulated for drug infusions and direct measurement of arterial pressure. Forearm blood flow was measured by a strain gauge plethysmograph. Intra-arterial infusions of L-arginine at 10, 20, 40, and 60 mg/min increased forearm blood flow from 4.7±0.6 to 4.9±0.5, 5.7±0.5, 7.2±0.8, and 8.2±0.9 ml • min" 1 • 100 ml" 1 , respectively (n=8, p<0.01), whereas D-arginine at the same doses did not alter forearm blood flow (n=7). Intra-arterial infusions of acetylcholine (n=7) (4,8,16, and 24 /ig/min) and sodium nltroprusside (n=5) (0.2, 0.4, 0.8, and 12 /tg/mln) increased forearm blood flow dose dependently (p<0.01 for both). Arterial pressure was not altered with infusions of these drugs. Responses to acetylcholine were augmented with simultaneous intra-arterial infusion of L-arginine at 10 mg/ml (p<0.01) but not with D-arginine. Responses to sodium nitroprusside were not altered by L-arginine. These results in human forearm resistance vessels support the notion that vasodilation induced by acetylcholine is a result of the conversion from L-arginine to endothelium-derived nitric oxide. Our results suggest that intra-arterial infusion of L-arginine may facilitate production of nitric oxide in the forearm and that L-arginine contributes to the modulation of vascular smooth muscle tone in healthy humans. 1 - 4 The biosynthesis of nitric oxide by the endothelium accounts for the vasorelaxation, and nitric oxide is now considered one of the endothelium-derived relaxing factors (EDRF).5 -7 Nitric oxide is a potent and direct activator of soluble guanylate cyclase and increases the production of cyclic guanosine 3',5' monophosphate (cGMP). 5 -7 It is thought that acetylcholine dilates vessels by releasing nitric oxide from the endothelium. 8În in vitro experiments with normal vessels, it has been shown that L-arginine does not dilate vessels or augment acetylcholine-induced vasorelaxation. - 10- 15 It also has been shown that intravenous infusion of L-arginine does not augment acetylcholine-induced vasorelaxation in the hindquarter resistance vessels of normal rabbits. 16 In humans, it is not known whether L-arginine augments acetylcholine-induced vasodilation and whether L-arginine itself dilates blood vessels. In the present study, by measuring forearm blood flow with a plethysmograph, we examined whether intra-arterial infusion of L-arginine dilated forearm blood vessels and whether L-arginine augmented acetylcholine-induced vasodilation in the forearm of healthy humans. Methods General ProceduresSubjects were all young, healthy male students (age, 20-23 years) at our university who volunteered for the study. The protocol was explained, and written informed consent was obtained from each subject...

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“…Several in vivo studies corroborate this observation. D-arginine was found to increase venous diameter in humans and hypotension in rats (30,40). Rhodes et al (31) have found that D-isomer of arginine was more potent than L-isomer as vasodilator of human forearm.…”

Section: Discussionmentioning

confidence: 99%

“…This finding strongly indicated that arginine may be acting as a ligand on membrane receptor(s). D-arginine was shown to act as a vasodilator in human forearm when locally infused (30,31).…”

Section: D-arginine Activated No and Its Inhibition With Antagonists mentioning

confidence: 99%

Receptor-mediated activation of nitric oxide synthesis by arginine in endothelial cells

Joshi¹,

Ferguson²,

Johnson

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Arginine contains the guanidinium group and thus has structural similarity to ligands of imidazoline and ␣-2 adrenoceptors (␣-2 AR). Therefore, we investigated the possibility that exogenous arginine may act as a ligand for these receptors in human umbilical vein endothelial cells and activate intracellular nitric oxide (NO) synthesis. Idazoxan, a mixed antagonist of imidazoline and ␣-2 adrenoceptors, partly inhibited L-arginine-initiated NO formation as measured by a Griess reaction. Rauwolscine, a highly specific antagonist of ␣-2 AR, at very low concentrations completely inhibited NO formation. Like L-arginine, agmatine (decarboxylated arginine) also activated NO synthesis, however, at much lower concentrations. We found that dexmedetomidine, a specific agonist of ␣-2 AR was very potent in activating cellular NO, thus indicating a possible role for ␣-2 AR in L-arginine-mediated NO synthesis. D-arginine also activated NO production and could be inhibited by imidazoline and ␣-2 AR antagonists, thus indicating nonsubstrate actions of arginine. Pertussis toxin, an inhibitor of G proteins, attenuated L-arginine-mediated NO synthesis, thus indicating mediation via G proteins. L-type Ca 2؉ channel blocker nifedipine and phospholipase C inhibitor U73122 inhibited NO formation and thus implicated participation of a second messenger pathway. Finally, in isolated rat gracilis vessels, rauwolscine completely inhibited the L-arginine-initiated vessel relaxation. Taken together, these data provide evidence for binding of arginine to membrane receptor(s), leading to the activation of endothelial NO synthase (eNOS) NO production through a second messenger pathway. These findings provide a previously unrecognized mechanistic explanation for the beneficial effects of L-arginine in the cardiovascular system and thus provide new potential avenues for therapeutic development. agmatine ͉ rauwolscine ͉ calcium A rginine is critical to normal growth and multiple physiological processes. It serves as a precursor for the synthesis not only of proteins but also of NO, urea, polyamines, and agmatine. The unequivocal demonstration that NO is the product of NO synthase (NOS)-catalyzed oxidation of L-arginine led to widespread interest in the actions of L-arginine. The K m of L-arginine for endothelial NOS (eNOS) is determined to be 2.9 M (1), and the intracellular L-arginine concentrations are in the range of 0.8-2.0 mM. In other words, cells maintain saturating levels of L-arginine as a substrate for NO synthases. However, an external supply of L-arginine is still required for the cellular production of NO (2). This requirement of exogenous arginine for the cellular NO production is termed ''arginine paradox.'' A number of mechanisms have been proposed to address this phenomenon, including endogenous NOS inhibitors and compartmentalization of intracellular L-arginine. Some have proposed that endogenous NOS inhibitors [e.g., asymmetric dimethylarginine (ADMA)] modulate NO levels by antagonizing intracellular L-arginine (3). An alternative...

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Dilator actions of arginine in human peripheral vasculature

Cited by 89 publications

References 0 publications

l -Arginine Augments Cardiac Vagal Control in Healthy Human Subjects

l -Arginine Augments Cardiac Vagal Control in Healthy Human Subjects

Effects of L-arginine on forearm vessels and responses to acetylcholine.

Receptor-mediated activation of nitric oxide synthesis by arginine in endothelial cells

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