Angiotensin-II Type 1 Receptor–Mediated Hypertension in D ₄ Dopamine Receptor–Deficient Mice

Dopamine receptors are important in systemic blood pressure regulation. D4 receptors are expressed in the kidney and brain, but their role in cardiovascular regulation is unknown. In pentobarbital-anesthetized mice, systolic and diastolic blood pressures were elevated in sixth-generation D4 receptor-deficient (D4(-/-)) mice and in tenth-generation D4(-/-) mice compared with D4 wild-type (D4(+/+)) littermates. The conscious blood pressures measured via a chronic arterial (femoral) catheter or telemetry (carotid) were also higher in D4(-/-) mice than in D4 littermates. Basal renal and plasma renin concentrations were similar in the 2 mouse strains. The protein expression of angiotensin II type 1 receptor was increased in homogenates of kidney (330+/-53%, n=5) and brain (272+/-69%, n=5) of D4(-/-) mice relative to D4(+/+) mice (kidney: 100+/-12%, n=5; brain: 100+/-32%, n=5). The expression of the receptor in renal membrane was also increased in D4(-/-) mice (289+/-28%, n=8) relative to D4(+/+) mice (100+/-14%, n=10). In contrast, the expression in the heart was similar in the 2 strains. Bolus intravenous injection of angiotensin II type 1 receptor antagonist losartan initially decreased mean arterial pressures to a similar degree in D4(-/-) and D4(+/+) littermates. However, the hypotensive effect of losartan dissipated after 10 minutes in D4(+/+) mice, whereas the effect persisted for >45 minutes in D4(-/-) mice. We conclude that the absence of the D(4) receptor increases blood pressure, possibly via increased angiotensin II type 1 receptor expression.