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CARDIOVASCULAR

Differential Cardiovascular Regulatory Activities of the _1B- and _1D-Adrenoceptor Subtypes

Department of Molecular and Biomedical Pharmacology, University of Kentucky, College of Medicine (D.C., D.F.M., S.E.E., M.T.P.), Cardiovascular Development Research Program, Department of Pediatrics, University of Kentucky (K.T., B.B.K.), and Department of Cardiothoracic Surgery, University of Kentucky, College of Medicine (R.D.L.), Lexington, Kentucky; Department of Molecular Cardiology (D.M.P.), The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio; Department of Molecular (A.T., G.T.), Cell Pharmacology, National Center for Child Health and Development Research Institute, Tokyo, Japan; and Division of Pharmaceutical Sciences (G.R.P.), University of Kentucky, College of Pharmacy, Lexington, Kentucky

The regulation of cardiac and vascular function by the _1B- and _1D-adrenoceptors (ARs) has been assessed in two lines of transgenic mice, one over-expressing a constitutively active _1B-AR mutation (_1B-AR_C128F) and the other an _1D-AR knockout line. The advantage of using mice expressing a constitutively active _1B-AR is that the receptor is tonically active, thus avoiding the use of nonselective agonists that can activate all subtypes. In hearts from animals expressing _1B-AR_C128F, the activities of the mitogen-activated protein kinases, extracellular signal-regulated kinase, and c-Jun N-terminal kinase were significantly elevated compared with nontransgenic control animals. Mice over-expressing the _1B-AR_C128F had echocardiographic evidence of contractile dysfunction and increases in chamber dimensions. In isolated-perfused hearts or left ventricular slices from _1B-AR_C128F-expressing animals, the ability of isoproterenol to increase contractile force or increase cAMP levels was significantly decreased. In contrast to the prominent effects on the heart, constitutive activation of the _1B-AR had little effect on the ability of phenylephrine to induce vascular smooth muscle contraction in the isolated aorta. The ability of phenylephrine to stimulate coronary vasoconstriction was diminished in _1D-AR knockout mice. In _1D-AR knockout animals, no negative effects on cardiac contractile function were noted. These results show that the ₁-ARs regulate distinctly different physiologic processes. The _1B-AR appears to be involved in the regulation of cardiac growth and contractile function, whereas the _1D-AR is coupled to smooth muscle contraction and the regulation of systemic arterial blood pressure.

Address correspondence to: Dr. Michael T. Piascik, Professor, Department of Molecular and Biomedical Pharmacology, The University of Kentucky College of Medicine, 800 Rose Street, UKMC MS 305, Lexington, KY 40536-0084. E-mail: mtp{at}uky.edu

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