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Functional selectivity of central Galpha-subunit proteins in mediating the cardiovascular and renal excretory responses evoked by central alpha(2) -adrenoceptor activation in vivo.

Authors: Wainford, RD  Kapusta, DR 
Citation: Wainford RD and Kapusta DR, Br J Pharmacol. 2011 Sep 6. doi: 10.1111/j.1476-5381.2011.01662.x.
Pubmed: (View Article at PubMed) PMID:21895632
DOI: Full-text: DOI:10.1111/j.1476-5381.2011.01662.x

Background and purpose: Activation of brain alpha(2) -adrenoceptors in conscious rodents decreases heart rate and mean arterial pressure and increases urine output and urinary sodium excretion. In vitro, alpha(2) -adrenoceptor stimulation activates Galphai((1-3)) , Galphao and Galphas-subunit protein-gated signal-transduction pathways. Since it remains essentially unknown, these studies investigated whether these same Galpha-subunit protein-gated pathways mediate the cardiovascular and renal excretory responses to central alpha(2) -adrenoceptor activation in conscious Sprague-Dawley rats. Experimental approach: Rats were pre-treated intracerbroventricularly (i.c.v.) with an oligodeoxynucleotide (ODN) targeted to a Galphai(1) , Galphai(2) , Galphai(3) , Galphao, Galphas or a scrambled ODN sequence (25 microg, 24 h, n= 6 per group). On the day of study the alpha(2) -adrenoceptor agonist, guanabenz (50 microg/5 microl), or saline vehicle (5 microl), was injected i.c.v. into ODN pre-treated conscious rats. Mean arterial pressure (MAP) and heart rate (HR) were recorded, and urine was collected for 150-min. Key results: In vehicle and scrambled ODN pre-treated rats, i.c.v. guanabenz decreased MAP and HR and produced a profound diuretic and natriuretic response. Selective ODN-mediated down-regulation of brain Galphai(2) -subunit proteins abolished the central guanabenz-induced hypotension and natriuresis. In contrast, following selective Galphas down-regulation, the characteristic hypotensive response to i.c.v. guanabenz was converted to an immediate increase in MAP. The bradycardia and diuretic responses to i.c.v. guanabenz were not prevented in any ODN pre-treatment group. Conclusions and implications: We have established the functional selectivity of Galphai(2) and Galphas subunit protein-gated signal-transduction pathways in mediating the hypotensive and natriuretic, but not bradycardic or diuretic, responses evoked by central alpha(2) -adrenoceptor activation in vivo.

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CRRD Object Information
CRRD ID: 5509797
Created: 2011-11-04
Species: All species
Last Modified: 2011-11-04
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.