Cardiovascular pharmacology
Analysis of the ghrelin receptor-independent vascular actions of ulimorelin

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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 (0.03–30 µM) inhibited phenylephrine-induced contractions of rat saphenous (IC50=0.6 µM; Imax=66±5%; n=3–6) and mesenteric arteries (IC50=5 µM, Imax=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 µM) and TZP102 (10–100 µM) constricted arteries (EC50=9.9 µM; Emax=50±7% and EC50=8 µM; Emax=99±16% respectively), an effect not attenuated by the ghrelin receptor antagonist YIL 781 3 µM or mimicked by capromorelin or AZP-531. In mesenteric arteries, ulimorelin, 1–10 µM, caused a surmountable rightward shift in the response to phenylephrine (0.01–1000 µM; 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.

Introduction

The peptide hormone, ghrelin, has major roles in the control of appetite, growth hormone release and metabolic functions (Kojima and Kangawa, 2005, Kojima and Kangawa, 2010, Delhanty and van der Lely, 2011). It reduces blood pressure in human and animals when administered intravenously (Nagaya et al., 2001, Okumura et al., 2002) and reduces sympathetic nerve activity when administered into the lower brain stem of rats and rabbits (Matsumura et al., 2002, Lin et al., 2004). Ghrelin has no direct vasodilator action on vessels from rat and the ghrelin receptor, growth hormone secretagogue receptor 1a (GHSR1a), is not expressed in rat vessels (Callaghan et al., 2012).

Ulimorelin, also known as TPZ101, is a macrocyclic molecule that is a potent agonist of the ghrelin receptor (Hoveyda et al., 2011). Due to its ability to stimulate gastrointestinal motility, ulimorelin has been evaluated as a possible treatment in gastroparesis (Ejskjaer et al., 2010), ileus (Fraser et al., 2009) and constipation (Pustovit et al., 2014).

We previously showed, in rats, that ulimorelin caused a biphasic reduction in blood pressure with an initial rapid decrease (resistant to ghrelin receptor antagonists), followed by a slower decrease (Callaghan et al., 2014). Ulimorelin also relaxed rat mesenteric arteries preconstricted with phenylephrine, an action not blocked by ghrelin receptor antagonists. Whether ulimorelin relaxes vessels constricted with other agents, or affects arteries in other vascular beds was not investigated, and mechanisms of action were also not investigated. In the current study, we investigated the mechanism(s) by which ulimorelin mediates its effects on vascular constriction, and investigated arteries supplying the viscera, limbs and central nervous system.

Section snippets

Materials and methods

Male Sprague-Dawley rats, mice with knockout of the gene for the ghrelin receptor, and wild-type C57BL6 mice were used. The knockout was created by inserting a transcriptional blocking cassette into intron 1 of GHSR1a in C57BL6 mice, creating a GHSR1a-null allele (Zigman et al., 2005). All animal procedures were approved by the University of Melbourne Animal Experimentation Ethics Committee. The procedures abided by the Australian Code of Practice for the Care and Use of Animals for Scientific

Rat saphenous artery

In rat saphenous artery, ulimorelin (100 nM–30 µM) caused a concentration-dependent inhibition of vasoconstriction elicited by the α1-adrenceptor agonist phenylephrine (3 µM; pIC50=6.2±0.2; Imax=66±5%; n=3–6; Fig. 1). This effect was not mimicked by other ghrelin receptor agonists investigated, including ghrelin (1 nM–1 µM; n=3–4), desacyl ghrelin (1 nM–1 µM; n=3–4), TZP102 (10 nM–30 µM; n=3–4), capromorelin (10 nM–10 µM), and AZP-531 (1 nM–1 µM; n=3–4; Table 1) or the vehicles used (data not shown). Table 2

Discussion

In a previous study of ulimorelin׳s effects, a vasodilatator effect on arteries preconstricted with phenylephrine was reported (Callaghan et al., 2014). Ghrelin receptor antagonists, JMV2959 and YIL 781 (Esler et al., 2007), did not inhibit this effect and ghrelin receptor expression was not detected in the arteries. In the current work, we observed that ulimorelin caused vasodilatation in saphenous arteries from rats, as well as wild type and Ghsr null mice, which supports the conclusion that

Conclusion

Here, for the first time, the ghrelin receptor agonist ulimorelin has been shown to have two distinct, regionally selective, non-ghrelin receptor mediated actions on arteries in rodents, namely a reduction in α1-adrenoceptor-mediated constriction and, at a higher concentrations, a vasoconstrictor action. The vasodilatator mechanisms are unknown; however the evidence presented suggests inhibition of α1-adrenoceptors, and activation of muscarinic acetylcholine receptors, mediates this action of

Acknowledgements

John Broad was supported by the Outstanding Young Investigator Award of the British Pharmacological Society and the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists. Research support was provided by the National Health and Medical Research Council of Australia (Project Grant 1005811) and the Transport Accident Commission through the Institute for Safety Compensation and Recovery Research (Grant N-13-085).

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