Impaired dopamine D(1) receptor-mediated vasorelaxation of mesenteric arteries in obese Zucker rats

BACKGROUND: Obesity plays an important role in the pathogenesis of hypertension. Renal dopamine D(1)-like receptor-mediated diuresis and natriuresis are impaired in the obese Zucker rat, an obesity-related hypertensive rat model. The role of arterial D(1) receptors in the hypertension of obese Zucker rats is not clear. METHODS: Plasma glucose and insulin concentrations and blood pressure were measured. The vasodilatory response of isolated mesenteric arteries was evaluated using a small vessel myograph. The expression and phosphorylation of D(1) receptors were quantified by co-immunoprecipitation and immunoblotting To determine the effect of hyperinsulinemia and hyperglycemia on the function of the arterial D(1) receptor, we studied obese Zucker rats (six to eight-weeks old) fed (6 weeks) vehicle or rosiglitazone, an insulin sensitizer (10 mg/kg per day) and lean Zucker rats (eight to ten-weeks old), fed high-fat diet to induce hyperinsulinemia or injected intraperitoneally with streptomycin (STZ) to induce hyperglycemia. RESULTS: In obese Zucker rats, the vasorelaxant effect of D(1)-like receptors was impaired that could be ascribed to decreased arterial D(1) receptor expression and increased D(1) receptor phosphorylation. In these obese rats, rosiglitazone normalized the arterial D(1) receptor expression and phosphorylation and improved the D(1)-like receptor-mediated vasorelaxation. We also found that D(1) receptor-dependent vasorelaxation was decreased in lean Zucker rats with hyperinsulinemia or hyperglycemia but the D(1) receptor dysfunction was greater in the former than in the latter group. The ability of insulin and glucose to decrease D(1) receptor expression and increase its phosphorylation were confirmed in studies of rat aortic smooth muscle cells. CONCLUSIONS: Both hyperinsulinemia and hyperglycemia caused D(1) receptor dysfunction by decreasing arterial D(1) receptor expression and increasing D(1) receptor phosphorylation. Impaired D(1) receptor-mediated vasorelaxation is involved in the pathogenesis of obesity-related hypertension.