Analysis of the ghrelin receptor-independent vascular actions of ulimorelin

Abstract

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 from Sprague-Dawley rats (male, 8 weeks) and saphenous arteries were obtained from wild type or ghrelin receptor null mice. These were mounted in myography chambers to record artery wall tension. Ulimorelin (0.03-30µM) inhibited phenylephrine-induced contractions of rat saphenous (IC50=0.6µM; Imax=66±5%; n=3-6) and mesenteric arteries (IC50=5µM, Imax=113±16%; n=3-4), but not those contracted by U46619, ET-1 or 60mM [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 (10-100µM) and TZP102 (10-100µM) constricted arteries (EC50=9.9µM; Emax=50±7% and EC50=8µM; Emax=99±16% respectively), an effect not attenuated by the ghrelin receptor antagonist YIL 781 3µM or mimicked by capromorelin or AZP-531. In mesenteric arteries, ulimorelin, 1-10µM, caused a surmountable rightward shift in the response to phenylephrine (0.01-1000µM; pA2=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 α1-adrenoceptors and a constrictor action not mediated via the ghrelin receptor.

Growth hormone secretagogues: history, mechanism of action, and clinical development

“…In patients with diabetic gastroparesis, ulimorelin improved gastrointestinal symptoms such as vomiting and appetite loss, while there were no significant differences in improvement of gastrointestinal function between patients with POI taking ulimorelin and those taking placebo . Because of this insufficient efficacy and the risk of unexpected hypotension, its development for gastrointestinal indications has been discontinued …”

“…In a clinical trial to investigate the safety and efficacy of ulimorelin in patients with diabetic gastroparesis, defaecation was significantly increased as a side effect, supporting a therapeutic potential for impaired lower gastrointestinal function such as POI and chronic constipation . On the other hand, a recent study reported that ulimorelin could unexpectedly cause hypotension through the blockade of α 1 ‐adrenoceptors …”

“…31 On the other hand, a recent study reported that ulimorelin could unexpectedly cause hypotension through the blockade of α 1 -adrenoceptors. 32 Relamorelin Relamorelin, a synthetic pentapeptide, was developed by Rhythm Pharmaceuticals in the USA. Relamorelin binds to GHS-R with approximately three-fold higher affinity than ghrelin itself, and it increases plasma GH, prolactin, and cortisol levels.…”

Site and mechanism of the colokinetic action of the ghrelin receptor agonist, HM01

“…Ulimorelin is potent, gives long‐lasting effects on colorectal activity and appears to desensitize less than other compounds . However, this compound has off‐target effects at alpha receptors for catecholamines . Thus it is desirable to find other high potency stimulants of colorectal propulsion with limited desensitization.…”