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

Polymorphism of the dopamine receptor type-2 (D-2) gene is associated with essential hypertension. To assess whether D-2 receptors participate in regu lation of blood pressure (BP), we studied mice in which the D-2 receptor wa s disrupted. In anesthetized mice, systolic and diastolic BPs (in millimete rs of mercury) were higher in D-2 homozygous and heterozygous mutant mice t han in D-2+/+ littermates. BP after alpha -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 de creased BP to a similar level in D-2-/- and D-2+/+ mice. An endothelin B (E T[B]) receptor blocker for both ET(B1) and ET(B2) receptors decreased, wher eas 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+/+ m ice. In contrast, blockade of ET(A) and V-1 vasopressin receptors had no ef fect 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+-ATP ase 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 l oss of the D-2 receptor results in hypertension that is not due to impairme nt of sodium excretion. Instead, enhanced vascular reactivity in the D-2 mu tant mice may be caused by increased sympathetic and ET(B) receptor activit ies.