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(Hypertension. 2001;38:303.)
© 2001 American Heart Association, Inc.

Scientific Contributions

Adrenergic and Endothelin B Receptor-Dependent Hypertension in Dopamine Receptor Type-2 Knockout Mice

Xiao Xi Li; Martin Bek; Laureano D. Asico; Zhiwei Yang; David K. Grandy; David S. Goldstein; Marcelo Rubinstein; Gilbert M. Eisner; Pedro A. Jose

From the Departments of Pediatrics (X.X.L., M.B., L.D.A., Z.Y., P.A.J.), Physiology and Biophysics (Z.Y., P.A.J.), and Medicine (G.M.E.), Georgetown University Medical Center, Washington, DC; the Departments of Physiology and Pharmacology (D.K.G.), Oregon Health Sciences University, The Vollum Institute, Portland, Ore; the National Institute of Neurological Disorders and Stroke (D.S.G.), Bethesda, Md; and Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (M.R.), Universidad de Buenos Aires, Argentina.

Correspondence to Pedro A. Jose, MD, PhD, Professor of Pediatrics and Physiology and Biophysics, Georgetown University Medical Center, 3800 Reservoir Rd NW, Washington, DC 20007. E-mail josep{at}gunet.georgetown.edu

Abstract—— Polymorphism of the dopamine receptor type-2 (D₂) gene is associated with essential hypertension. To assess whether D₂ receptors participate in regulation of blood pressure (BP), we studied mice in which the D₂ receptor was disrupted. In anesthetized mice, systolic and diastolic BPs (in millimeters of mercury) were higher in D₂ homozygous and heterozygous mutant mice than in D₂+/+ littermates. BP after -adrenergic blockade decreased to a greater extent in D₂-/- mice than in D₂+/+ mice. Epinephrine excretion was greater in D₂-/- mice than in D₂+/+ mice, and acute adrenalectomy decreased BP to a similar level in D₂-/- and D₂+/+ mice. An endothelin B (ET[B]) receptor blocker for both ET(B1) and ET(B2) receptors decreased, whereas a selective ET(B1) blocker increased, BP in D₂-/- mice but not D₂+/+ mice. ET(B) receptor expression was greater in D₂-/- mice than in D₂+/+ mice. In contrast, blockade of ET(A) and V₁ vasopressin receptors had no effect on BP in either D₂-/- or D₂+/+ mice. The hypotensive effect of an AT₁ antagonist was also similar in D₂-/- and D₂+/+ mice. Basal Na⁺,K⁺-ATPase activities in renal cortex and medulla were higher in D₂+/+ mice than in D₂-/- mice. Urine flow and sodium excretion were higher in D₂-/- mice than in D₂+/+ mice before and after acute saline loading. Thus, complete loss of the D₂ receptor results in hypertension that is not due to impairment of sodium excretion. Instead, enhanced vascular reactivity in the D₂ mutant mice may be caused by increased sympathetic and ET(B) receptor activities.

Key Words: dopamine • receptors, dopamine • receptors, endothelin • Na⁺,K⁺ transporting ATPase • kidney

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