Abstract 1295: The Vasomotor Effects of Apelin in vivo in Man

Abstract

BACKGROUND In preclinical models, apelin, the endogenous ligand for the G protein-coupled APJ receptor, lowers systemic venous tone, causes nitric oxide (NO)-mediated arterial vasodilatation and is the most potent inotrope yet studied. We aimed to establish the in vivo vasomotor effects of apelin in man. METHODS Dorsal hand vein diameter was measured by the Aellig technique in 6 subjects during local intravenous infusions (0.1–3 nmol/min) of two apelin agonists, apelin-36 and (Pyr1)apelin-13, and sodium nitroprusside (SNP; 0.6 nmol/min) in the presence and absence of norepinephrine preconstriction. Forearm blood flow (FBF) responses to intrabrachial infusions of apelin-36 and (Pyr1)apelin-13 (0.1–30 nmol/min) were measured by venous occlusion plethysmography in 8 subjects on 4 occasions. In a 2×2 factorial design, a further 8 subjects received an intrabrachial infusion of (Pyr1)apelin-13 (0.3–3 nmol/min) in the presence or absence of the NO clamp (NO synthase inhibitor, L-N-monomethylarginine (8 micromol/min), co-infused with SNP (1–128 ng/min) to maintain basal flow and clamp endogenous NO production), and following a single oral dose of aspirin (600 mg) or matched placebo. RESULTS Although SNP caused venodilatation (P<0.0001), apelin-36 and (Pyr1)apelin-13 had no effect on dorsal hand vein diameter in the presence or absence of norepinephrine (P=0.2). Both apelin-36 and (Pyr1)apelin-13 caused reproducible dose-dependent vasodilatation in forearm resistance vessels (P<0.0001): maximal increase of 198+/−27% and 90+/−7% respectively. Vasodilatation had a rapid onset (within 6 min) and slow offset that remained 36 min post-infusion (P<0.01). Plasma apelin concentrations and non-infused FBF (P<0.05) were increased at doses >3 nmol/min, consistent with systemic spillover. (Pyr1)apelin-13-mediated vasodilatation was attenuated by the NO clamp (AUC reduced by 64%; P=0.004) but was unaffected by aspirin (P=0.7). CONCLUSION Although having no apparent effect on venous tone, apelin causes a rapid onset and sustained NO-dependent arterial vasodilatation in vivo in man. The apelin-APJ system merits further clinical investigation to determine its role in cardiovascular homeostasis and its therapeutic potential in heart failure.