Muscarinic receptor subtypes mediating myocardial blood flow redistribution

Selective M1 and M2 muscarinic receptor antagonists pirenzepine and AF-DX 116, respectively, were administered to open-chest, pentobarbital-anesthetized dogs to determine the muscarinic receptor subtype responsible for the preferential vasodilation of subendocardial blood vessels during intracoronary methacholine infusion. There were no changes in systemic hemodynamics responsible for the myocardial blood flow redistribution produced by methacholine. Selective M1 receptor blockade with pirenzepine attenuated increases in transmural perfusion and prevented the redistribution of blood flow favoring the subendocardium during methacholine infusion. M2 receptor blockade with AF-DX 116 also attenuated the increase in transmural perfusion produced by methacholine but did not selectively block increases in subendocardial blood flow. These results support the hypothesis that M1 muscarinic coronary receptors are responsible for the redistribution of blood flow to the subendocardium (increased endo/epi) during cholinergic coronary vasodilation, whereas M2 receptors mediate an increase in total coronary blood flow. In additional experiments in isolated rabbit aorta, AF-DX 116 was 0.38 times less potent than pirenzepine with respect to endothelium-dependent muscarinic vasodilation but 1.47 times more potent with respect to endothelium-independent muscarinic vasoconstriction. This suggests that differences exist in the receptors found on the vascular smooth muscle and endothelium and that the preferential distribution of blood flow to the subendocardium may be due to stimulation of M1 receptors located on the vascular endothelium.