Hypotensive effects of ghrelin receptor agonists mediated through a novel receptor

Brid Callaghan, Samin Kosari, Ruslan V Pustovit, Daniela Maria Sartor, Dorota Maria Ferens, Kung Ban, Jonathan Bayldon Baell, Trung Van Nguyen, Leni Rose Rivera, James A Brock, John Barton Furness

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)1275 - 1286
Number of pages12
JournalBritish Journal of Pharmacology
Volume171
Issue number5
DOIs
Publication statusPublished - 2014

Cite this

Callaghan, B., Kosari, S., Pustovit, R. V., Sartor, D. M., Ferens, D. M., Ban, K., ... Furness, J. B. (2014). Hypotensive effects of ghrelin receptor agonists mediated through a novel receptor. British Journal of Pharmacology, 171(5), 1275 - 1286. https://doi.org/10.1111/bph.12527
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. / Hypotensive effects of ghrelin receptor agonists mediated through a novel receptor. In: British Journal of Pharmacology. 2014 ; Vol. 171, No. 5. pp. 1275 - 1286.
@article{948c9dfe65094f75b0c7e99888e3c55a,
title = "Hypotensive effects of ghrelin receptor agonists mediated through a novel receptor",
abstract = "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.",
author = "Brid Callaghan and Samin Kosari and Pustovit, {Ruslan V} and Sartor, {Daniela Maria} and Ferens, {Dorota Maria} and Kung Ban and Baell, {Jonathan Bayldon} and Nguyen, {Trung Van} and Rivera, {Leni Rose} and Brock, {James A} and Furness, {John Barton}",
year = "2014",
doi = "10.1111/bph.12527",
language = "English",
volume = "171",
pages = "1275 -- 1286",
journal = "British Journal of Pharmacology",
issn = "1476-5381",
publisher = "Wiley-Blackwell",
number = "5",

}

Callaghan, B, Kosari, S, Pustovit, RV, Sartor, DM, Ferens, DM, Ban, K, Baell, JB, Nguyen, TV, Rivera, LR, Brock, JA & Furness, JB 2014, 'Hypotensive effects of ghrelin receptor agonists mediated through a novel receptor' British Journal of Pharmacology, vol. 171, no. 5, pp. 1275 - 1286. https://doi.org/10.1111/bph.12527

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 journalArticleResearchpeer-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 -

Callaghan B, Kosari S, Pustovit RV, Sartor DM, Ferens DM, Ban K et al. Hypotensive effects of ghrelin receptor agonists mediated through a novel receptor. British Journal of Pharmacology. 2014;171(5):1275 - 1286. https://doi.org/10.1111/bph.12527