Functional selectivity of central Gα‐subunit proteins in mediating the cardiovascular and renal excretory responses evoked by central α 2 ‐adrenoceptor activation in vivo

BACKGROUND AND PURPOSE Activation of brain α 2 ‐adrenoceptors in conscious rodents decreases heart rate (HR) and mean arterial blood pressure (MAP) and increases urine output and urinary sodium excretion. In vitro , α 2 ‐adrenoceptor stimulation activates Gα i(1–3) , Gα o and Gα s ‐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 α 2 ‐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 Gα i1 , Gα i2 , Gα i3 , Gα o , Gα s or a scrambled (SCR) ODN sequence (25 µg, 24 h). On the day of study, the α 2 ‐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 Gα i2 ‐subunit proteins abolished the central guanabenz‐induced hypotension and natriuresis. In contrast, following selective Gα s 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 Gα i2 and Gα s subunit protein‐gated signal transduction pathways in mediating the hypotensive and natriuretic, but not bradycardic or diuretic, responses evoked by central α 2 ‐adrenoceptor activation in vivo .