Adrenergic and endothelin B receptor-dependent hypertension in dopamine receptor type-2 knockout mice

Polymorphism of the dopamine receptor type-2 (D₂) gene is associated with essential hypertension. To assess whether D₂ receptors participate in regulation of blood pressure (BP), we studied mice in which the D₂ receptor was disrupted. In anesthetized mice, systolic and diastolic BPs (in millimeters of mercury) were higher in D₂ homozygous and heterozygous mutant mice than in D₂+/+ littermates. BP after α-adrenergic blockade decreased to a greater extent in D₂-/- mice than in D₂+/+ mice. Epinephrine excretion was greater in D₂-/- mice than in D₂+/+ mice, and acute adrenalectomy decreased BP to a similar level in D₂-/- and D₂+/+ 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 D₂-/- mice but not D₂+/+ mice. ET(B) receptor expression was greater in D₂-/- mice than in D₂+/+ mice. In contrast, blockade of ET(A) and V₁ vasopressin receptors had no effect on BP in either D₂-/- or D₂+/+ mice. The hypotensive effect of an AT₁ antagonist was also similar in D₂-/- and D₂+/+ mice. Basal Na⁺,K⁺-ATPase activities in renal cortex and medulla were higher in D₂+/+ mice than in D₂-/- mice. Urine flow and sodium excretion were higher in D₂-/- mice than in D₂+/+ mice before and after acute saline loading. Thus, complete loss of the D₂ receptor results in hypertension that is not due to impairment of sodium excretion. Instead, enhanced vascular reactivity in the D₂ mutant mice may be caused by increased sympathetic and ET(B) receptor activities.