Hypotensive effects of ghrelin receptor agonists mediated through a novel receptor

Brid Callaghan, Sam KOSARI, Ruslan Pustovit, Daniela Sartor, Dorota Ferens, Ban Kung, Jonathon Baell, Trung Nguyen, Leni Rivera, James Brock, John Furness

Research output: Contribution to journalArticle

12 Citations (Scopus)

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
Externally publishedYes

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Ghrelin Receptor
Hypotension
Ghrelin
Blood Vessels
Hexamethonium
Pressoreceptors
Mesenteric Arteries
HEK293 Cells
Denervation
Aorta

Cite this

Callaghan, B., KOSARI, S., Pustovit, R., Sartor, D., Ferens, D., Kung, B., ... Furness, J. (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, Sam ; Pustovit, Ruslan ; Sartor, Daniela ; Ferens, Dorota ; Kung, Ban ; Baell, Jonathon ; Nguyen, Trung ; Rivera, Leni ; Brock, James ; Furness, John. / Hypotensive effects of ghrelin receptor agonists mediated through a novel receptor. In: British Journal of Pharmacology. 2014 ; Vol. 171, No. 5. pp. 1275-1286.
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Callaghan, B, KOSARI, S, Pustovit, R, Sartor, D, Ferens, D, Kung, B, Baell, J, Nguyen, T, Rivera, L, Brock, J & Furness, J 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, Sam; Pustovit, Ruslan; Sartor, Daniela; Ferens, Dorota; Kung, Ban; Baell, Jonathon; Nguyen, Trung; Rivera, Leni; Brock, James; Furness, John.

In: British Journal of Pharmacology, Vol. 171, No. 5, 2014, p. 1275-1286.

Research output: Contribution to journalArticle

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T1 - Hypotensive effects of ghrelin receptor agonists mediated through a novel receptor

AU - Callaghan, Brid

AU - KOSARI, Sam

AU - Pustovit, Ruslan

AU - Sartor, Daniela

AU - Ferens, Dorota

AU - Kung, Ban

AU - Baell, Jonathon

AU - Nguyen, Trung

AU - Rivera, Leni

AU - Brock, James

AU - Furness, John

N1 - © 2013 The British Pharmacological Society.

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

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KW - ghrelin

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KW - Mesenteric Arteries/drug effects

KW - Blood Pressure/drug effects

KW - Hypotension/chemically induced

KW - HEK293 Cells

KW - Pyrazoles/pharmacology

KW - Aorta, Thoracic/drug effects

KW - Macrocyclic Compounds/pharmacology

KW - Piperidines/pharmacology

KW - Receptors, Ghrelin/agonists

KW - In Vitro Techniques

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