Angiotensin-II type 1 receptor-mediated hypertension in D4 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.