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Objectives: This study sought to establish the effect of amiloride on stunned myocardium and to determine the role of hemodynamic alterations and inhibition of sodium/proton (Na+/H+) exchange and L-type cytosolic calcium (Ca2+) channels., Background: Amiloride is a nonspecific agent that may reduce reperfusion injury, but its effect on reversible dysfunction or stunned myocardium is unclear., Methods: Ninety-seven open chest dogs undergoing 15 min of left anterior descending coronary artery occlusion and 3 h of reperfusion with monitoring of hemodynamic variables, systolic shortening and myocardial blood flow were randomized to seven intracoronary infusions: control dogs (5% dextrose, n = 16); low dose amiloride (1 mg/min, n = 14); high dose amiloride (5 mg/min) with (n = 12) and without (n = 16) atrial pacing; sodium nitroprusside (20 micrograms/min, n = 16); hexamethylene amiloride (a specific inhibitor of Na+/H+ exchange, 60 micrograms/min, n = 14); and nifedipine (a specific inhibitor of L-type Ca2+ channels, 5 micrograms/min, n = 9). Drug infusions were started 40 min before occlusion and stopped at 30 min after reperfusion., Results: Forty-three dogs were excluded because of ventricular fibrillation or high collateral flow. The incidence of ventricular fibrillation was similar in all groups to that in control dogs. Systolic shortening completely recovered (p = NS vs. baseline; p < 0.01 vs. control group) by 2 h after reperfusion in the low dose amiloride group and 30 min in the high dose group (p < 0.01 vs. low dose). High dose amiloride increased myocardial blood flow and had positive inotropic and negative chronotropic effects (p < 0.05 vs. control group). Atrial pacing did not attenuate recovery. The only effect of low dose amiloride was increased myocardial blood flow after reperfusion. Systolic shortening did not deteriorate after washout of drug effects. Sodium nitroprusside and nifedipine similarly increased myocardial blood flow, but systolic shortening never recovered. Hexamethylene amiloride had no hemodynamic effects, and systolic shortening never recovered., Conclusions: Amiloride prevented the contractile dysfunction of myocardial stunning but did not prevent arrhythmias. Hemodynamic alterations, increased myocardial blood flow and inhibition of Na+/H+ exchange or L-type Ca2+ channels alone did not account for the improved function. Inhibition of Na+/Ca2+ exchange may be the mechanism of improved postischemic function.