RESUMEN
<p><b>OBJECTIVE</b>Abnormalities in dopamine production and receptor function have been described in human essential hypertension and rodent models of genetic hypertension. We investigated the role of G protein kinase (GRK) 4gamma in essential hypertension in GRK4gamma mutant A142V transgenic mice.</p><p><b>METHODS</b>Blood pressure, renal sodium excretion, D(1) receptor protein expression and phosphorylation were measured in GRK4gammaA142V transgenic mice and control mice. Moreover, the effects of GRK4 inhibition by antisense oligonucleotides on D(1) receptor expressions were determined in HK-2 cells.</p><p><b>RESULTS</b>As compared with their control mice, GRK4gammaA142V transgenic mice had higher blood pressure, lower D(1) receptor expression (0.6 +/- 0.2 vs. 1.5 +/- 0.2, P < 0.05), higher D(1) receptor phosphorylation [(65 +/- 7) DU vs. (35 +/- 7) DU, P < 0.05] in renal cortical membranes and the diuretic and natriuretic effects after stimulation of renal D(1) receptor were impaired in GRK4gammaA142V transgenic mice. Inhibition of GRK4 expression (0.60 +/- 0.10 vs. 1.30 +/- 0.09, P < 0.05) by GRK4 antisense oligonucleotides upregulated D(1) receptor expression (1.5 +/- 0.2 vs. 0.8 +/- 0.1, P < 0.05) in HK-2 cells.</p><p><b>CONCLUSIONS</b>Our results show that GRK4gammaA142V overexpression induced hypertension is mediated by dowregulated renal D(1) receptor expressions in GRK4gammaA142V transgenic mice.</p>
Asunto(s)
Animales , Femenino , Masculino , Ratones , Presión Sanguínea , Regulación hacia Abajo , Quinasa 4 del Receptor Acoplado a Proteína-G , Genética , Metabolismo , Regulación de la Expresión Génica , Hipertensión , Genética , Metabolismo , Ratones Endogámicos C57BL , Ratones Transgénicos , Oligonucleótidos Antisentido , Fosforilación , Receptores de Dopamina D1 , MetabolismoRESUMEN
<p><b>OBJECTIVE</b>To investigate the mechanisms by which hypertension occurs in D(3) dopamine receptor null mice (D(3)-/-).</p><p><b>METHODS</b>Several parameters, including blood pressure, renal sodium excretion, D(3) receptor protein and mRNA expression, plasma renin activity, norepinephrine concentration and AT(1) receptor expression were checked in D(3)-/- mice and their littermate wild type mice (D(3)+/+). Moreover, the vasorelaxant effect of D(3) receptor stimulation was measured with ex-vivo mesenteric artery isolated from Wistar-Kyoto rats.</p><p><b>RESULTS</b>Blood pressure was higher in D(3)-/- mice compared with that in D(3)+/+ mice, salt-loading had no effect on blood pressure in both groups, at the last period, sodium excretion was lower in D(3)-/- mice as compared with D(3)+/+ mice, renal renin activity and AT(1) receptor expression were higher in D(3) -/- [corrected] mice than in D(3) +/+ [corrected] mice. In contrast, no difference of renal norepinephrine was found in two groups. When using angiotensin II subtype-1 receptor antagonist, the systolic blood pressure declined for a longer duration in mutant mice than in wild-type mice. Vaso-relaxation was found in ex-vivo isolated mesenteric artery when D(3) receptor was stimulated.</p><p><b>CONCLUSIONS</b>Elevation of blood pressure in D(3)-/- mice might be related with impaired renal sodium excretion and vaso-relaxation in resistance artery.</p>