Abstract
The regulation of cardiac and vascular function by the α1B- and α1D-adrenoceptors (ARs) has been assessed in two lines of transgenic mice, one over-expressing a constitutively active α1B-AR mutation (α1B-ARC128F) and the other an α1D-AR knockout line. The advantage of using mice expressing a constitutively active α1B-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 α1B-ARC128F, 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 α1B-ARC128F had echocardiographic evidence of contractile dysfunction and increases in chamber dimensions. In isolated-perfused hearts or left ventricular slices from α1B-ARC128F-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 α1B-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 α1D-AR knockout mice. In α1D-AR knockout animals, no negative effects on cardiac contractile function were noted. These results show that the α1-ARs regulate distinctly different physiologic processes. The α1B-AR appears to be involved in the regulation of cardiac growth and contractile function, whereas the α1D-AR is coupled to smooth muscle contraction and the regulation of systemic arterial blood pressure.
Footnotes
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↵ 1 These two authors contributed equally to this work.
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This work was supported by National Institutes of Health Grant HL38120 (M.T.P.), a Predoctoral Fellowship from the Pharmaceutical Research and Manufacturers of America Foundation (D.F.M.), and a Predoctoral Fellowship from the American Heart Association (D.C.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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DOI: 10.1124/jpet.102.048553.
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ABBREVIATIONS: AR, adrenergic receptor; E-64, trans-epoxysuccinyl-leucylamido-[4-guanido]butane; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; LV, left ventricular; PSS, physiologic salt solution; BMY-7378, 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione.
- Received December 24, 2002.
- Accepted March 12, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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