Analysis of the ghrelin receptor-independent vascular actions of ulimorelin

Ulimorelin (TZP101) is a ghrelin receptor agonist that stimulates intestinal motility, but also reduces blood pressure in rodents and humans and dilates blood vessels. It has been proposed as a treatment for intestinal motility disorders. Here we investigated the mechanisms through which ulimorelin affects vascular diameter. Actions of ulimorelin on wall tension of rodent arteries were investigated and compared with other ghrelin receptor agonists. Saphenous, mesenteric and basilar arteries were obtained horn Sprague-Dawley rats (male, 8 weeks) and saphenous at were obtained from wild type or ghrelin receptor null mice. These were mounted in myography chambers to record at wall tension. Ulimorelin (0.03-30 mu M) inhibited phenylephrine-induced contractions of rat saphenous (IC50=0.6 mu M; I-max=66 +/- 5%; n=3-6) and mesenteric arteries (IC50=5 mu M, I-max=113 +/- 16%; n=3-4). but not those contracted by U46619. ET-1 or 60 mM [K+]. Relaxation of phenylephrine-constricted arteries was not observed with ghrelin receptor agonists TZP102, capromorelin or AZP-531. In rat saphenous and basilar arteries, ulimorelin (10-100 mu M) and TZP102 (10-100 mu M) constricted arteries (EC50=9.9 mu M; E-max= 50 +/- 7% and EC50=8 mu M; E-max= 99 +/- 16% respectively), an effect not attenuated by the ghrelin receptor antagonist YIL 781 3 mu M or mimicked by capromorelin or AZP-531. In mesenteric arteries, ulimorelin, 1-10 mu M, caused a surmountable rightward shift in the response to phenylephrine (0.01-1000 mu M; pA(2)= 5.7; n=3-4). Ulimorelin had similar actions in mouse saphenous artery from both wild type and ghrelin receptor null mice. We conclude that ulimorelin causes vasorelaxation through competitive antagonist action at alpha(1)-adrenoceptors and a constrictor action not mediated via the ghrelin receptor. (C) 2015 Elsevier B.V. All rights reserved,