Functional selectivity of central Gα-subunit proteins in mediating the cardiovascular and renal excretory responses evoked by central α2-adrenoceptor activation in vivo
Article first published online: 10 APR 2012
Published 2011. This article is a U.S. Government work and is in the public domain in the USA.
British Journal of Pharmacology
Special Issue: Themed Section: Secretin Family (Class B) G Protein-Coupled Receptors - from Molecular to Clinical Perspectives. Guest Editors: David R Poyner and Debbie L Hay
Volume 166, Issue 1, pages 210–220, May 2012
How to Cite
Wainford, R. and Kapusta, D. (2012), Functional selectivity of central Gα-subunit proteins in mediating the cardiovascular and renal excretory responses evoked by central α2-adrenoceptor activation in vivo. British Journal of Pharmacology, 166: 210–220. doi: 10.1111/j.1476-5381.2011.01662.x
- Issue published online: 10 APR 2012
- Article first published online: 10 APR 2012
- Accepted manuscript online: 6 SEP 2011 08:39AM EST
- Received; 22 December 2010; Revised; 3 June 2011; Accepted; 24 August 2011
- Brain Gα-subunit proteins;
- cardiovascular function;
- renal excretory function;
BACKGROUND AND PURPOSE Activation of brain α2-adrenoceptors in conscious rodents decreases heart rate (HR) and mean arterial blood pressure (MAP) and increases urine output and urinary sodium excretion. In vitro, α2-adrenoceptor stimulation activates Gαi(1–3), Gαo and Gαs-subunit protein-gated signal transduction pathways. Here we have investigated whether these same Gα-subunit protein-gated pathways mediate the cardiovascular and renal excretory responses to central α2-adrenoceptor activation in conscious Sprague-Dawley rats.
EXPERIMENTAL APPROACH Rats were pre-treated by intracerebroventricular injection (i.c.v.) with an oligodeoxynucleotide (ODN) targeted to a Gαi1, Gαi2, Gαi3, Gαo, Gαs or a scrambled (SCR) ODN sequence (25 µg, 24 h). On the day of study, the α2-adrenoceptor agonist guanabenz (50 µg) or saline vehicle, was injected i.c.v. into ODN-pre-treated conscious rats. MAP and HR were recorded, and urine was collected for 150 min.
KEY RESULTS In vehicle- and SCR ODN-pre-treated rats, i.c.v. guanabenz decreased MAP and HR, and produced marked diuretic and natriuretic responses. Selective ODN-mediated down-regulation of brain Gαi2-subunit proteins abolished the central guanabenz-induced hypotension and natriuresis. In contrast, following selective Gαs down-regulation, the characteristic hypotensive response to i.c.v. guanabenz was converted to an immediate increase in MAP. The bradycardic and diuretic responses to i.c.v. guanabenz were not blocked by pre-treatment with any ODN.
CONCLUSIONS AND IMPLICATIONS There was functional selectivity of Gαi2 and Gαs subunit protein-gated signal transduction pathways in mediating the hypotensive and natriuretic, but not bradycardic or diuretic, responses evoked by central α2-adrenoceptor activation in vivo.