Chief Scientist Office Scotland and British Heart Foundation.

Selective ET(A) receptor antagonism causes vasodilatation of human forearm resistance vessels in vivo. This response appears to result in major part from an increase in nitric oxide generation. ET(B) receptor antagonism either alone or on a background of ET(A) antagonism causes local vasoconstriction, indicating that ET(B) receptors in blood vessels respond to ET-1 predominantly by causing vasodilatation.

Although having no apparent effect on venous tone, apelin causes nitric oxide-dependent arterial vasodilation in vivo in man. The apelin-APJ system merits further clinical investigation to determine its role in cardiovascular homeostasis.

Background-Apelin, the endogenous ligand for the novel G protein-coupled receptor APJ, has major cardiovascular effects in preclinical models. The study objectives were to establish the effects of acute apelin administration on peripheral, cardiac, and systemic hemodynamic variables in healthy volunteers and patients with heart failure. Methods and Results-Eighteen patients with New York Heart Association class II to III chronic heart failure, 6 patients undergoing diagnostic coronary angiography, and 26 healthy volunteers participated in a series of randomized, double-blind, placebo-controlled studies. Measurements of forearm blood flow, coronary blood flow, left ventricular pressure, and cardiac output were made by venous occlusion plethysmography, Doppler flow wire and quantitative coronary angiography, pressure wire, and thoracic bioimpedance, respectively. Intrabrachial infusions of (Pyr 1 )apelin-13, acetylcholine, and sodium nitroprusside caused forearm vasodilatation in patients and control subjects (all PϽ0.0001). Vasodilatation to acetylcholine (Pϭ0.01) but not apelin (Pϭ0.3) or sodium nitroprusside (Pϭ0.9) was attenuated in patients with heart failure. Intracoronary bolus of apelin-36 increased coronary blood flow and the maximum rate of rise in left ventricular pressure and reduced peak and end-diastolic left ventricular pressures (all PϽ0.05). Systemic infusions of (Pyr 1 )apelin-13 (30 to 300 nmol/min) increased cardiac index and lowered mean arterial pressure and peripheral vascular resistance in patients and healthy control subjects (all PϽ0.01) but increased heart rate only in control subjects (PϽ0.01). Conclusions-Acute apelin administration in humans causes peripheral and coronary vasodilatation and increases cardiac output. APJ agonism represents a novel potential therapeutic target for patients with heart failure. (Circulation.

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