Hypotensive effects of ghrelin receptor agonists mediated through a novel receptor

BACKGROUND AND PURPOSE
Some agonists of ghrelin receptors cause rapid decreases in BP. The mechanisms by which they cause hypotension and the
pharmacology of the receptors are unknown.
EXPERIMENTAL APPROACH
The effects of ligands of ghrelin receptors were investigated in rats in vivo, on isolated blood vessels and on cells transfected
with the only molecularly defined ghrelin receptor, growth hormone secretagogue receptor 1a (GHSR1a).
KEY RESULTS
Three agonists of GHSR1a receptors, ulimorelin, capromorelin and CP464709, caused a rapid decrease in BP in the
anaesthetized rat. The effect was not reduced by either of two GHSR1a antagonists, JMV2959 or YIL781, at doses that
blocked effects on colorectal motility, in vivo. The rapid hypotension was not mimicked by ghrelin, unacylated ghrelin or
the unacylated ghrelin receptor agonist, AZP531. The early hypotension preceded a decrease in sympathetic nerve activity.
Early hypotension was not reduced by hexamethonium or by baroreceptor (sino-aortic) denervation. Ulimorelin also relaxed
isolated segments of rat mesenteric artery, and, less potently, relaxed aorta segments. The vascular relaxation was not reduced
by JMV2959 or YIL781. Ulimorelin, capromorelin and CP464709 activated GHSR1a in transfected HEK293 cells at nanomolar
concentrations. JMV2959 and YIL781 both antagonized effects in these cells, with their pA2 values at the GHSR1a receptor
being 6.55 and 7.84.
CONCLUSIONS AND IMPLICATIONS
Our results indicate a novel vascular receptor or receptors whose activation by ulimorelin, capromorelin and CP464709
lowered BP. This receptor is activated by low MW GHSR1a agonists, but is not activated by ghrelin.