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ORIGINAL ARTICLE

Two ₁-Adrenergic Receptor Subtypes Regulating the Vasopressor Response Have Differential Roles in Blood Pressure Regulation

Department of Molecular, Cell Pharmacology, National Research Institute for Child Health and Development, Tokyo, Japan (C.H., A.T., T.Ko., H.S., S.O.); Department of Pharmacology, Tokyo University of Pharmacy and Life Science, Horinouchi, Hachioji, Tokyo, Japan (Y.N., R.O., T.T., S.F., S.T.); Department of Urology, Faculty of Medicine, University of Tokyo, Tokyo, Japan (C.H., T.Ki.); Institut de Pharmacologie et Toxicologie, Universit de Lausanne, Lausanne, Switzerland (S.C.); and Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University Faculty of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan (G.T.)

Abstract

To study the functional role of individual ₁-adrenergic (AR) subtypes in blood pressure (BP) regulation, we used mice lacking the _1B-AR and/or _1D-AR with the same genetic background and further studied their hemodynamic and vasoconstrictive responses. Both the _1D-AR knockout and _1B-/_1D-AR double knockout mice, but not the _1B-AR knockout mice, had significantly (p < 0.05) lower levels of basal systolic and mean arterial BP than wild-type mice in nonanesthetized condition, and they showed no significant change in heart rate or in cardiac function, as assessed by echocardiogram. All mutants showed a significantly (p < 0.05) reduced catecholamine-induced pressor and vasoconstriction responses. It is noteworthy that the infusion of norepinephrine did not elicit any pressor response at all in _1B-/_1D-AR double knockout mice. In an attempt to further examine ₁-AR subtype, which is involved in the genesis or maintenance of hypertension, BP after salt loading was monitored by tail-cuff readings and confirmed at the endpoint by direct intra-arterial recording. After salt loading, _1B-AR knockout mice developed a comparable level of hypertension to wild-type mice, whereas mice lacking _1D-AR had significantly (p < 0.05) attenuated BP and lower levels of circulating catecholamines. Our data indicated that _1B- and _1D-AR subtypes participate cooperatively in BP regulation; however, the deletion of the functional _1D-AR, not _1B-AR, leads to an antihypertensive effect. The study shows differential contributions of _1B- and _1D-ARs in BP regulation.

Address correspondence to: Dr. Gozoh Tsujimoto, Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University Faculty of Pharmaceutical Sciences, Kyoto University, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan. E-mail: gtsujimoto{at}nch.go.jp

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