Functional selectivity of brain Gα‐subunit proteins in the cardiovascular and renal excretory responses evoked by central α2‐adrenoceptor activation in vivo

Abstract

HypothesisBrain Gα‐subunit proteins signal in a functionally selective manner to mediate the integrated cardiovascular depressor and renal excretory responses evoked by pharmacological activation of central α2‐adrenoceptors in vivo.MethodsThe α2‐agonist guanabenz (50 μg) was administered by intracerebroventricular (i.c.v.) injection to conscious instrumented Sprague‐Dawley rats pre‐treated (24‐h) i.c.v. with saline or oligodeoxynucleotides (ODN) targeted to Gαi1,Gi2, Gi3, Gαo, Gαq, Gαz or a scrambled (S) sequence (25 μg, 24‐h, N=5/group). Mean arterial pressure (MAP) and heart rate (HR) were recorded and was urine collected for 150‐min (10‐min periods).Results i.c.v. ODN pre‐ treatment (24h; 5 μg) Peak Δ HR (bpm) Peak Δ MAP (mmHg) Peak Δ urine output (μl/min) Peak Δ UNaV (μeq/min) Saline Vehicle −92 ± 9 −19 ± 2 +136 ± 9 +6.2 ± 0.8 S −94 ± 12 −18 ± 1.2 +132 ± 11 +5.9 ± 0.6 Gαi1 −88 ± 11 −19 ± 2 +153 ± 16 +6.1 ± 0.8 Gαi2 −90 ± 13 −1 ± 1** +125 ± 11 +0.6 ± 0.3** Gαi3 −66 ± 9 −17 ± 1.3 +143 ± 16 +6.2 ±0.9 Gαo −47 ± 5* −16 ± 1.6 +127 ± 10 +6.2 ± 0.5 Gαq −106 ± 7 −15 ± 2 +214 ± 7** +7.2 ± 1.2 Gαz −92 ± 8 −16 ± 2 +110 ± 6* +5.8 ± 1.2 p<0.05, p<0.01 vs. S ODN group Brain Gαi2 subunit protein‐gated signal‐transduction pathways selectively mediate the hypotensive and natriuretic, but not bradycardic or diuretic, responses evoked by central α2‐adrenoceptor activation in vivo. In contrast, the profound α2‐agoinst‐stimulated diuretic response is mediated, in part, via opposing Gαz and Gαq subunit protein gated pathways (stimulatory versus inhibitory, respectively).ConclusionsThese studies demonstrate that in vivo, brain GPCR Gα‐subunit protein pathways play an essential and physiologically important gating role in mediating functionally selective changes in systemic cardiovascular function and the renal excretion of water and sodium post‐ligand binding at central α2‐adrenoceptors. RDW‐AHA 2250585; DRK‐DK43337, HL071212, AHA 0855293E, and RDW/DRK‐ P20 RR018766