Abstract 17928: Upregulation of Type 1 Angiotensin Ii Receptor in Arterioles is Associated With the Hypertension in D3 Dopamine Receptor Heterozygous Mice
D3 dopamine receptor (D3R) homozygous (D3−/−) and heterozygous knockout (D3−/+) mice have renin-dependent hypertension that is normalized by type 1 angiotensin II (AngII) receptor (AT1R) blockade; renal AT1R expression is also increased in D3−/− mice. To determine if D3R expression in the cardiovascular system also plays a role in the pathogenesis of hypertension, we studied the protein abundance of AT1R in the heart, conduit (aorta) and resistance vessels (mesenteric arterioles), and kidney, as well as the responses to D3 agonist, AngII, and AT1R blocker (candesartan) in mesenteric arterioles. On normal NaCl diet, systolic blood pressures (BP, telemetry, n=5/group) were higher in conscious D3−/+ (143±2, mmHg) mice than their wild-type (D3+/+, 120±2) littermates; urinary Na+ excretions were similar, in spite of the higher BP in D3−/+ mice. AT1R protein expression in homogenates of the whole heart and aorta was similar in D3 −/+ and D3+/+ mice (n=6/group). However, AT1R expression in mesenteric arterioles was increased in D3−/+ relative to D3+/+ mice (D3−/+:204±40% of D3+/+, n=6–7/group). In isolated mesenteric arterioles, D3R agonist (PD168907, 10−9-10−5M)-induced relaxation was decreased and AngII (10−11-10−7M)-induced contraction was increased to a greater extent in D3−/+ than D3+/+ mice (n=5/group); candesartan (10−5M), enhanced the relaxing effect of PD168907 (10−6M) from 16±2 to 30±4% and completely abolished the contracting effect of AngII. Renal membrane (172±29%) and total AT1R (196±24%) expressions were increased in D3−/+ relative to D3+/+ mice (n=6/group). These differences have relevance in vivo because BPs were decreased by the AT1R blocker, losartan (20 mg/kg/x1), in D3−/+ (133±1) but not in D3+/+ (123±1) mice (n=5/group). Our data suggest that D3R regulates blood pressure, in part, by inhibition of AT1R expression and action in resistance but not in conduit vessels. We conclude that the increased protein expression and function of AT1R in the mesenteric arterioles contribute to the hypertension in D3−/+ mice.
- © 2010 by American Heart Association, Inc.