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Cardiovascular Research 2006 69(1):227-235; doi:10.1016/j.cardiores.2005.09.001
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Copyright © 2005, European Society of Cardiology

Functional and immunocytochemical evidence for a role of ghrelin and des-octanoyl ghrelin in the regulation of vascular tone in man

Matthias J. Kleinza,*, Janet J. Maguirea, Jeremy N. Skepperb and Anthony P. Davenporta

aClinical Pharmacology Unit, University of Cambridge, Level 6, Centre for Clinical Investigation, Box 110 Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK
bMulti-Imaging Centre, Department of Anatomy, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK

* Corresponding author. Tel.: +44 1223762564; fax: +44 1223336899. Email address: mk395{at}medschl.cam.ac.uk

Objective: Ghrelin is the recently identified endogenous ligand for the ghrelin receptor GHS-R1a and known to regulate growth hormone secretion and appetite. Ghrelin also is a potent vasodilator and improves cardiac performance after systemic administration. Generally, the octanoyl modification on Ser3 has been considered essential for biological activity. Recently however, cardiovascular actions of des-octanoyl ghrelin have been reported in rodents. Our aim was to investigate if ghrelin and ghrelin receptor protein are expressed within the human vasculature, to determine if des-octanoyl ghrelin, like ghrelin, is a vasodilator in human artery and to test the acute effect of ghrelin peptides on cardiac contractility.

Methods: Distribution of ghrelin and ghrelin receptor was determined using standard immunocytochemistry and confocal microscopy. Ghrelin peptides were tested for vasodilator actions in human isolated arteries and their effect on cardiac contractility was investigated in human isolated paced atria.

Results: Immunoreactive ghrelin was detected in endothelial cells of human arteries and veins where it localized to intracellular vesicles but not to the Weibel–Palade bodies of the regulated pathway, suggesting constitutive ghrelin production. Specific antisera detected ghrelin receptor on vascular smooth muscle cells and cardiomyocytes. Ghrelin (pD2=8.60 ± 0.1, Emax=55.8 ± 8.9, mean ± standard error of the mean) and des-octanoyl ghrelin (pD2=8.8 ± 0.2, Emax=54.7 ± 5.3) showed comparable (P>0.05) endothelium independent vasodilator potency and efficacy in reversing endothelin-1 induced constriction in human artery. Neither ghrelin nor des-octanoyl ghrelin had effects on contractile force in paced atria.

Conclusions: We show widespread expression of ghrelin and its cognate receptor in the human cardiovascular system with functional evidence suggesting a role for both ghrelin and the more abundant endogenous form des-octanoyl ghrelin in the paracrine regulation of vascular tone in man.

KEYWORDS Hypertension; G protein; Receptor; Myocytes; Vasodilation

Time for primary review 28 days


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