on May 6, 2004
Published online before print May 6, 2004, doi: 10.1161/01.ATV.0000130661.82773.ca
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Submitted on February 11, 2004
Accepted on April 22, 2004
Muscarinic (M) Receptors in Coronary Circulation: Gene-Targeted Mice Define the Role of M2 and M3 Receptors in Response to Acetylcholine
Kathryn G. Lamping *;
From the Department of Internal Medicine and Pharmacology (K.G.L., D.W.N., F.M.F.), University of Iowa, Roy J. and Lucille A. Carver School of Medicine and the Veterans Administration Medical Center (K.G.L., D.W.N.), Iowa City, IA; and the Laboratory of Bioorganic Chemistry (J.W., Y.C.), National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD.
* To whom correspondence should be addressed. E-mail: kathryn-lamping{at}uiowa.edu.
Objective--Determining the role of specific muscarinic (M) receptor subtypes mediating responses to acetylcholine (ACh) has been limited by the specificity of pharmacological agents. Deletion of the gene for M5 receptors abolished response to ACh in cerebral blood vessels but did not affect dilation of coronary arteries. The goal of this study was to determine mediating responses of the M receptors to ACh in coronary circulation using mice deficient in M2 or M3 receptors (M2-/-, M3-/-, respectively).
Methods and Results--Coronary arteries from respective wild-type, M2-/-, or M3-/- mice were isolated, cannulated, and pressurized. Diameter was measured with video microscopy. After preconstriction with U46619, ACh produced dose-dependent dilation of coronary arteries that was similar in wild-type and M2-/- mice. In contrast, dilation of coronary arteries from M3-/- mice to ACh was reduced by 
80% compared with wild type. The residual response to ACh was atropine insensitive. Relaxation of coronary arteries to other stimuli was similar in M2-/- and M3-/- mice. Similar results were obtained in aorta rings.
Conclusion--These findings provide the first direct evidence that relaxation to ACh in coronary circulation is mediated predominantly by activation of M3 receptors.
Key words: acetylcholine • muscarinic receptors • genetically altered mice
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