Low‐Dose IV Acetylcholine Acts As a “Preconditioning‐Mimetic” in the Canine Model

Brief episodes of ischemia paradoxically protect or “precondition” the heart and reduce infarct size caused by a subsequent, more sustained, coronary artery occlusion, perhaps by stimulation of adenosine receptors coupled to muscarinic receptors via the inhibitory G protein. However, brief ischemia is not a desirable form of therapy. Using the anesthetized canine model, we therefore sought to determine if small intravenous (IV) doses of the muscarinic agonist acetylcholine would provide a therapeutically feasible means to mimic preconditioning. Four groups of dogs underwent a 40‐minute intervention period, followed by 1 hour of coronary occlusion and 5 hours of reperfusion: 8 received two IV doses of acetylcholine (0.01 mg each) at 40 minutes and 5 minutes before the sustained occlusion; 8 received equipotent doses of nitroglycerin (0.05 mg; a vasodilator that does not act via the M₂ muscarinic receptor); 7 received conventional ischemic preconditioning (four 5‐minute episodes of coronary occlusion, each interrupted by 5 minutes of reperfusion); and 8 controls received no intervention. Coronary blood flow and hemodynamic parameters were monitored throughout the protocol, regional myocardial blood flow was measured during the sustained occlusion by injection of radiolabeled microspheres, and infarct size was assessed by tetrazolium staining. All four groups were equally ischemic during coronary occlusion. However, infarct size was reduced significantly in both the preconditioned and acetylcholine‐treated dogs when compared with controls (6%± 2% [p < 0.01 vs controls], 10%± 2% [p < 0.05 vs controls], and 19%± 3% of the myocardium at risk). The protection achieved with acetylcholine was not due simply to the brief and transient vasodilation associated with the IV boluses because equipotent doses of nitroglycerin failed to limit infarct size (17%± 4% of the risk region; p = NS vs controls). Thus, small IV bolus doses of acetylcholine act as a therapeutically feasible “preconditioning‐mimetic” in the anesthetized canine model.