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CLINICAL RESEARCH: VASCULAR MEDICINE

Vascular Effects of Apelin In Vivo in Man

Alan G. Japp, MRCP^_*,_*, Nicholas L. Cruden, PhD^_*, David A.B. Amer^_*, Vivienne K.Y. Li, BSc^_*, Ewan B. Goudie, BSc^_*, Neil R. Johnston, MSc^_*, Sushma Sharma, PhD, Ilene Neilson, BSc, David J. Webb, MD, FRCP^_*, Ian L. Megson, PhD, Andrew D. Flapan, MD, MRCP and David E. Newby, PhD, FRCP^_*

^_* Centre for Cardiovascular Science, University of Edinburgh, Chancellor's Building, Edinburgh, United Kingdom
Department of Diabetes, UHI Millennium Institute, Inverness, United Kingdom
Department of Cardiology, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom

Manuscript received November 12, 2007; revised manuscript received March 26, 2008, accepted June 3, 2008.

^_* Reprint requests and correspondence: Dr. Alan G. Japp, Centre for Cardiovascular Science, The University of Edinburgh, Chancellor's Building, Edinburgh, EH16 4SB, United Kingdom (Email: alan.japp{at}ed.ac.uk).

Objectives: This study was designed to establish the direct vascular effects of apelin in vivo in man.

Background: Apelin is the endogenous ligand for the previously orphaned G-protein–coupled receptor, APJ. This novel pathway is widely expressed in the cardiovascular system and is emerging as an important mediator of cardiovascular homeostasis. In pre-clinical models, apelin causes venous and arterial vasodilation.

Methods: Vascular effects of apelin were assessed in 24 healthy volunteers. Dorsal hand vein diameter was measured by the Aellig technique during local intravenous infusions (0.1 to 3 nmol/min) of apelin-36, (Pyr¹)apelin-13, and sodium nitroprusside (0.6 nmol/min). Forearm blood flow was measured by venous occlusion plethysmography during intrabrachial infusions of apelin-36 and (Pyr¹)apelin-13 (0.1 to 30 nmol/min) and subsequently in the presence or absence of a "nitric oxide clamp" (nitric oxide synthase inhibitor, L-N ^G-monomethylarginine [8 µmol/min], coinfused with nitric oxide donor, sodium nitroprusside [90 to 900 ng/min]), or a single oral dose of aspirin (600 mg) or matched placebo.

Results: Although sodium nitroprusside caused venodilation (p < 0.0001), apelin-36 and (Pyr¹)apelin-13 had no effect on dorsal hand vein diameter (p = 0.2). Both apelin isoforms caused reproducible vasodilation in forearm resistance vessels (p < 0.0001). (Pyr¹)apelin-13–mediated vasodilation was attenuated by the nitric oxide clamp (p = 0.004) but unaffected by aspirin (p = 0.7).

Conclusions: 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.

Key Words: apelin • APJ receptor • endothelium • vasodilator

Abbreviations and Acronyms   ANOVA = analysis of variance   APJ = apelin receptor   AUC = area under the curve   DHV = dorsal hand vein   FBF = forearm blood flow   NO = nitric oxide   SNP = sodium nitroprusside

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