title: Interactions between nitric oxide and endothelin in the regulation of vascular tone of human resistance vessels in vivo.
abstract: Endothelial release of nitric oxide (NO) contributes to the regulation of vascular tone by inducing vascular relaxation. In addition, NO may inhibit the synthesis and hemodynamic effects of endothelin-1 (ET-1), a powerful endothelium-derived vasoconstrictor peptide that may stimulate NO production. However, whether NO and ET-1 physiologically interact to regulate vascular tone in humans has not been defined. In this study, the interactions between the L-arginine NO pathway and the ET-1 system in the regulation of vascular tone in human forearm resistance vessels were examined in vivo. Vasomotor response to the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA, 4 micromol/min for 30 minutes) was measured during either saline infusion or blockade of ET-1 receptors. Endothelin-A (ET(A)) and endothelin-B (ET(B)) receptor blockade was achieved by infusion of BQ-123 (100 nmol/min) and BQ-788 (50 nmol/min), respectively, separately and in combination. Drugs were infused into the brachial artery, and the forearm blood flow (FBF) response was measured by strain-gauge plethysmography. During saline infusion, L-NMMA administration significantly decreased FBF (25%, P<0.01 versus baseline). This effect was significantly blunted during nonselective blockade of ET-1 receptors (7% decrease in FBF, P=0.02 versus the effect of L-NMMA during saline infusion). Selective ET(A) blockade did not modify the vasoconstrictor response to L-NMMA (26% decrease in FBF, P=0.66 versus the effect of L-NMMA during saline infusion), but selective ET(B) receptor antagonism caused significant diminution of the hemodynamic response to NO inhibition (8% decrease in FBF, P=0.04 versus the effect of L-NMMA during saline infusion). Thus ET-1 contributes to the regulation of vascular tone by stimulating NO activity. This effect is mediated through endothelial ET(B) receptors and may be relevant in conditions associated with endothelial dysfunction.
authors.affiliation: Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: C
authors.initials: C
authors.lastname: Cardillo
authors.forename: C M
authors.initials: CM
authors.lastname: Kilcoyne
authors.forename: R O
authors.initials: RO
authors.lastname: Cannon
authors.forename: J A
authors.initials: JA
authors.lastname: Panza
mesh_terms: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors; D016232:Endothelins / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005542:Forearm / Q000098:blood supply; D006801:Humans; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D012039:Regional Blood Flow / Q000187:drug effects; D014655:Vascular Resistance / Q000502:physiology*; D014666:Vasomotor System / Q000502:physiology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu)