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 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-/-, M-3-/-, respectively). Methods and Results - Coronary arteries from respective wild-type, M-2-/-, or M-3-/- 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-/- mice. In contrast, dilation of coronary arteries from M-3-/- mice to ACh was reduced by approximate to80% compared with wild type. The residual response to ACh was atropine insensitive. Relaxation of coronary arteries to other stimuli was similar in M-2-/- and M-3-/- 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.