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Muscarinic (M) Receptors in Coronary Circulation Gene-Targeted Mice Define the Role of M2 and M3 Receptors in Response to Acetylcholine

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 the M receptors mediating responses 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.