Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 1275 - 1286 |
| Number of pages | 12 |
| Journal | British Journal of Pharmacology |
| Volume | 171 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 2014 |
Cite this
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Hypotensive effects of ghrelin receptor agonists mediated through a novel receptor. / Callaghan, Brid; Kosari, Samin; Pustovit, Ruslan V; Sartor, Daniela Maria; Ferens, Dorota Maria; Ban, Kung; Baell, Jonathan Bayldon; Nguyen, Trung Van; Rivera, Leni Rose; Brock, James A; Furness, John Barton.
In: British Journal of Pharmacology, Vol. 171, No. 5, 2014, p. 1275 - 1286.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Hypotensive effects of ghrelin receptor agonists mediated through a novel receptor
AU - Callaghan, Brid
AU - Kosari, Samin
AU - Pustovit, Ruslan V
AU - Sartor, Daniela Maria
AU - Ferens, Dorota Maria
AU - Ban, Kung
AU - Baell, Jonathan Bayldon
AU - Nguyen, Trung Van
AU - Rivera, Leni Rose
AU - Brock, James A
AU - Furness, John Barton
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
UR - http://onlinelibrary.wiley.com/doi/10.1111/bph.12527/epdf
U2 - 10.1111/bph.12527
DO - 10.1111/bph.12527
M3 - Article
VL - 171
SP - 1275
EP - 1286
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
SN - 1476-5381
IS - 5
ER -