Cardiovascular pharmacologyAnalysis of the ghrelin receptor-independent vascular actions of ulimorelin
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).
References (21)
- et al.
Ghrelin and glucose homeostasis
Peptides
(2011) - et al.
Effect of the ghrelin receptor agonist TZP-101 on colonic transit in a rat model of postoperative ileus
Eur. J. Pharmacol.
(2009) - et al.
Identification of potent, selective, CNS-targeted inverse agonists of the ghrelin receptor
Bioorg. Med. Chem. Lett.
(2013) - et al.
Discovery and optimization of novel 4-[(aminocarbonyl)amino]-N-[4-(2-aminoethyl) phenyl]benzenesulfonamide ghrelin receptor antagonists
Bioorg. Med. Chem. Lett.
(2009) - et al.
Sites of action of ghrelin receptor ligands in cardiovascular control
Am. J. Physiol.
(2012) - et al.
Hypotensive effects of ghrelin receptor agonists mediated through a novel receptor
Br. J. Pharmacol.
(2014) - et al.
Novel and conventional receptors for ghrelin, desacyl-ghrelin and pharmacologically related compounds
Pharmacol. Rev.
(2014) - et al.
Differential vasomotor action of noradrenaline, serotonin, and histamine in isolated basilar artery from rat and guinea-pig
Acta Physiol. Scand.
(1988) - et al.
Safety and efficacy of ghrelin agonist TZP-101 in relieving symptoms in patients with diabetic gastroparesis: a randomized, placebo-controlled study
Neurogastroenterol. Motil.
(2010) - et al.
Small-molecule ghrelin receptor antagonists improve glucose tolerance, suppress appetite, and promote weight loss
Endocrinology
(2007)
Cited by (7)
The Physiology and Pharmacology of Diabetic Gastropathy Management
2022, Comprehensive PharmacologyZ-505 hydrochloride, an orally active ghrelin agonist, attenuates the progression of cancer cachexia via anabolic hormones in Colon 26 tumor-bearing mice
2017, European Journal of PharmacologyCitation Excerpt :Previous reports have demonstrated therapeutic effects of GHSR1a agonists in humans (Vodnik et al., 2016). However, some of these inhibit L-type Ca2+ channels, resulting in adverse cardiovascular effects (Ma et al., 2007; Broad et al., 2015; Stokes et al., 2015). Although Z-505 possesses almost the same GHSR1a agonistic activity as ghrelin and other GHSR1a agonists, it has no binding affinity to ion channels related to the cardiovascular system, including Na+, K+ and Ca2+ channels.
2-Phenethylamines in Medicinal Chemistry: A Review
2023, MoleculesGrowth hormone secretagogues: history, mechanism of action, and clinical development
2020, Journal of Cachexia, Sarcopenia and MuscleGhrelin and Blood Pressure Regulation
2016, Current Hypertension ReportsGhrelin and motilin receptors as drug targets for gastrointestinal disorders
2016, Nature Reviews Gastroenterology and Hepatology