Adrenergic and Endothelin B Receptor-Dependent Hypertension in Dopamine Receptor Type-2 Knockout Mice

Abstract

Polymorphism of the dopamine receptor type-2 (D 2 ) gene is associated with essential hypertension. To assess whether D 2 receptors participate in regulation of blood pressure (BP), we studied mice in which the D 2 receptor was disrupted. In anesthetized mice, systolic and diastolic BPs (in millimeters of mercury) were higher in D 2 homozygous and heterozygous mutant mice than in D 2 +/+ littermates. BP after α-adrenergic blockade decreased to a greater extent in D 2 −/− mice than in D 2 +/+ mice. Epinephrine excretion was greater in D 2 −/− mice than in D 2 +/+ mice, and acute adrenalectomy decreased BP to a similar level in D 2 −/− and D 2 +/+ mice. An endothelin B (ET[B]) receptor blocker for both ET(B1) and ET(B2) receptors decreased, whereas a selective ET(B1) blocker increased, BP in D 2 −/− mice but not D 2 +/+ mice. ET(B) receptor expression was greater in D 2 −/− mice than in D 2 +/+ mice. In contrast, blockade of ET(A) and V 1 vasopressin receptors had no effect on BP in either D 2 −/− or D 2 +/+ mice. The hypotensive effect of an AT 1 antagonist was also similar in D 2 −/− and D 2 +/+ mice. Basal Na + ,K + -ATPase activities in renal cortex and medulla were higher in D 2 +/+ mice than in D 2 −/− mice. Urine flow and sodium excretion were higher in D 2 −/− mice than in D 2 +/+ mice before and after acute saline loading. Thus, complete loss of the D 2 receptor results in hypertension that is not due to impairment of sodium excretion. Instead, enhanced vascular reactivity in the D 2 mutant mice may be caused by increased sympathetic and ET(B) receptor activities.