Angiotensin-II type 1 receptor-mediated hypertension in D4 dopamine receptor-deficient mice

Dopamine receptors are important in systemic blood pressure regulation. D-4 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 D-4 receptor - deficient (D-4(-/-)) mice and in tenth-generation D-4(-/-) mice compared with D-4 wild-type (D-4(+/+)) littermates. The conscious blood pressures measured via a chronic arterial ( femoral) catheter or telemetry ( carotid) were also higher in D-4(-/-) 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 D-4(-/-) mice relative to D-4(+/+) mice ( kidney: 100 +/- 12%, n = 5; brain: 100 +/- 32%, n = 5). The expression of the receptor in renal membrane was also increased in D-4(-/-) mice (289 +/- 28%, n = 8) relative to D-4(+/)+ 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 D-4(-/-) and D-4(+/+) littermates. However, the hypotensive effect of losartan dissipated after 10 minutes in D-4(+/+) mice, whereas the effect persisted for > 45 minutes in D-4(-/-) mice. We conclude that the absence of the D-4 receptor increases blood pressure, possibly via increased angiotensin II type 1 receptor expression.