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Functional selectivity of brain Gα‐subunit proteins in the cardiovascular and renal excretory responses evoked by central α 2 ‐adrenoceptor activation in vivo
Author(s) -
Wainford Richard David,
Kapusta Daniel R
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1009.2
Subject(s) - guanabenz , in vivo , agonist , chemistry , saline , protein subunit , endocrinology , medicine , excretory system , receptor , biology , biochemistry , microbiology and biotechnology , gene
Hypothesis Brain 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 α 2 ‐adrenoceptors in vivo.Methods The α 2 ‐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 Gαi 1 ,Gi 2 , Gi 3 , 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). Resultsi.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 Gαi 1 −88 ± 11 −19 ± 2 +153 ± 16 +6.1 ± 0.8 Gαi 2 −90 ± 13 −1 ± 1 ** +125 ± 11 +0.6 ± 0.3 ** Gαi 3 −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 groupBrain Gαi 2 subunit protein‐gated signal‐transduction pathways selectively mediate the hypotensive and natriuretic, but not bradycardic or diuretic, responses evoked by central α 2 ‐adrenoceptor activation in vivo . In contrast, the profound α 2 ‐agoinst‐stimulated diuretic response is mediated, in part, via opposing Gαz and Gαq subunit protein gated pathways (stimulatory versus inhibitory, respectively). Conclusions These 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 α 2 ‐adrenoceptors. RDW‐AHA 2250585; DRK‐DK43337, HL071212 , AHA 0855293E, and RDW/DRK‐ P20 RR018766