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 M 5 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 M 2 or M 3 receptors (M 2 Ϫ/Ϫ, M 3 Ϫ/Ϫ,

more »

... tively). Methods and Results-Coronary arteries from respective wild-type, M 2 Ϫ/Ϫ, or M 3 Ϫ/Ϫ 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 M 2 Ϫ/Ϫ mice. In contrast, dilation of coronary arteries from M 3 Ϫ/Ϫ mice to ACh was reduced by Ϸ80% compared with wild type. The residual response to ACh was atropine insensitive. Relaxation of coronary arteries to other stimuli was similar in M 2 Ϫ/Ϫ and M 3 Ϫ/Ϫ 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 M 3 receptors. (Arterioscler Thromb Vasc Biol. 2004;24:1253-1258.)