Peptides 25 (2004) 1767–1774 Cellular distribution of immunoreactive urotensin-II in human tissues with evidence of increased expression in atherosclerosis and a greater constrictor response of small compared to large coronary arteries Janet J. Maguire ∗ , Rhoda E. Kuc, Katherine E. Wiley, Matthias J. Kleinz, Anthony P. Davenport a Clinical Pharmacology Unit, University of Cambridge, Level 6 Centre for Clinical Investigation, Box 110, Addenbrooke’s Hospital, Cambridge CB22QQ, UK Received 29 October 2003; accepted 9 January 2004 Available online 11 September 2004 Abstract We detected urotensin-II-like immunoreactivity in the endothelium of normal human blood vessels from heart, kidney, placenta, adrenal, thyroid and umbilical cord. Immunoreactivity was also detected in endocardial endothelial and kidney epithelial cells. In atherosclerotic coronary artery, immunoreactivity localized to regions of macrophage infiltration. Urotensin-II constricted human atherosclerotic epicardial coronary arteries with pD 2 = 10.58 ± 0.46 (mean ± S.E.M.) and E max = 11.4 ± 4.2% KCl and small coronary arteries with pD 2 = 9.25 ± 0.38 and E max = 77 ± 16% KCl. Small coronary arteries clearly exhibited a greater maximum response to urotensin-II than epicardial vessels. This enhanced responsiveness may be of importance in heart failure, where circulating concentrations of U-II are increased, or in atherosclerosis where focally up-regulated urotensin-II production may act down stream to produce significant vasospasm, compromising blood flow to the myocardium. We conclude that urotensin-II is a locally released vasoactive mediator that may be an important regulator of blood flow particularly to the myocardium and may have a specific role in human atherosclerosis. © 2004 Elsevier Inc. All rights reserved. Keywords: Atherosclerosis; Coronary artery; Endothelium; Human pharmacology; Immunocytochemistry; Urotensin-II 1. Introduction A cardiovascular role for the fish peptide urotensin-II (U- II) in mammals was initially suggested by its remarkably po- tent constrictor action on isolated arteries from non-human primates and the dramatic effect on myocardial contractility and systemic pressure observed following infusion of intra- venous bolus U-II in the same species that resulted in death [2]. Recently, the plasma concentration of this vasoactive pep- tide has been reported to be significantly elevated in human diseases such as heart failure [16,18,19], diabetes mellitus [23] and liver cirrhosis [8]. U-II receptors (UT) have been ∗ Corresponding author. E-mail address: jjm1003@medschl.cam.ac.uk (J.J. Maguire). identified in human heart and vascular smooth muscle us- ing radioligand binding methods [12] and U-II elicits both constrictor [12,9] and dilator [22] actions in human blood vessels in vitro obtained from some, but not all, patients. In- fusion of U-II, in vivo, decreased forearm blood flow in one study [3], suggesting that the predominant effect of U-II may be vasoconstriction, although a second study was unable to detect an effect of U-II [1]. The inconsistency and modest maximum constrictor response observed in the human vas- culature both in vitro and in vivo contrasts markedly with effects in non-human primate and is indicative of the mani- fest species variation exhibited by U-II in mammals [5,11]. Therefore, although these data support the hypothesis that U-II may be an important cardiovascular peptide in man, this remains contentious. 0196-9781/$ – see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.peptides.2004.01.028