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First published on January 21, 2003; DOI: 10.1124/jpet.102.044701

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Vol. 305, Issue 1, 106-113, April 2003

Increased Relaxant Action of Forskolin and Isoproterenol against Muscarinic Agonist-Induced Contractions in Smooth Muscle from M2 Receptor Knockout Mice

Minoru Matsui1 , Michael T. Griffin, Darakhshanda Shehnaz2 , Makoto M. Taketo3 and Frederick J. Ehlert

Laboratory of Biomedical Genetics, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo, Japan (M.M., M.M.T.); Department of Environmental and Chemical Sciences, Chapman University, Orange, California (M.T.G.); and Department of Pharmacology, College of Medicine, University of California, Irvine, Irvine, California (D.S., F.J.E.)

The ability of forskolin and isoproterenol to inhibit the contractile action of the muscarinic agonist, oxotremorine-M, was investigated in smooth muscle from wild-type and M2 muscarinic receptor knockout mice. Forskolin (5.0 µM) caused a significant reduction in the contractile activity of oxotremorine-M in ileum, trachea, and urinary bladder from both wild-type and M2 muscarinic receptor knockout mice. This reduction in contractile activity was characterized by decreases in potency or maximal response, but not always both. Similar results were obtained with isoproterenol (1.0 µM). The relaxant effects of forskolin in ileum, trachea, and urinary bladder from M2 receptor knockout mice were approximately 3- to 9-fold greater than those observed in the same tissues from wild-type mice. Similar results were obtained with isoproterenol in ileum and urinary bladder, although the differences between wild-type and M2 receptor knockout tissues were less than those observed with forskolin. In contrast, there was no significant difference between the relaxant effect of isoproterenol in trachea from wild-type and M2 receptor knockout mice. In contrast to the results observed with oxotremorine-M as the contractile agent, forskolin and isoproterenol did not exhibit greater relaxant activity against KCl-induced contractions in M2 receptor knockout mice compared with wild-type mice. These results suggest that a component of the contractile response to muscarinic agonists in smooth muscle involves an M2 muscarinic receptor-mediated inhibition of the relaxant effects of agents that increase cAMP levels.

1 Present Address: Division of Neuronal Network, Department of Basic Medical Sciences, the Institute of Medical Science, the University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.

2 Present address: Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario, Canada M5G1L6.

3 Present address: Department of Pharmacology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501.

0022-3565/03/3051-0106$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics


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