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(Hypertension. 2006;47:288.)
© 2006 American Heart Association, Inc.

Original Articles

Angiotensin-II Type 1 Receptor–Mediated Hypertension in D₄ Dopamine Receptor–Deficient Mice

Martin J. Bek; Xiaoyan Wang; Laureano D. Asico; John E. Jones; Shaopeng Zheng; XiaoXi Li; Gilbert M. Eisner; David K. Grandy; Robert M. Carey; Patricio Soares-da-Silva; Pedro A. Jose

From the Departments of Pediatrics (M.J.B., X.W., L.D.A., J.E.J., S.Z., X.L., P.A.J.) and Medicine (G.M.E.), Georgetown University Medical Center, Washington, DC; Department of Medicine (M.J.B.), University Clinics Muenster, Muenster, Germany; Department of Physiology and Pharmacology (D.K.G.), Oregon Health and Science University, Portland, Ore; University of Virginia Health Sciences Center (R.M.C.), Charlottesville, Va; and Institute of Pharmacology and Therapeutics (P.S-d-S.), Faculty of Medicine of Porto, Porto, Portugal.

Correspondence to Xiaoyan Wang, Dept of Pediatrics, Georgetown University Medical Center, 4000 Reservoir Rd, NW, Washington, DC 20057. E-mail xw22{at}georgetown.edu

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 D₄ receptor increases blood pressure, possibly via increased angiotensin II type 1 receptor expression.

Key Words: dopamine • receptors, angiotensin II • mice • hypertension • angiotensin II • endothelin • vasopressins

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