The class Ic antiarrhythmic agent flecainide has recently become available in this country for management of ventricular arrhythmias. The pharmacologic and electrophysiologic features of this class of drug--marked sodium channel blockade producing inhibition of phase 0 of the myocardial action potential, moderate blockade of slow inward (calcium) channels, and general lack of systemic toxicity--suggest that these agents may exert significant myocardial protective effects. This hypothesis was tested in isolated, perfused rat hearts subjected to 30 minutes of global normothermic ischemia followed by 30 minutes of reperfusion after pretreatment with (1) Krebs-Henseleit buffer (n = 7); (2) Krebs-Henseleit buffer with potassium adjusted to 20.9 mmol/L with potassium chloride (n = 10); and (3) Krebs-Henseleit buffer plus flecainide acetate 50 mg/L (0.12 mmol/L) (n = 11). Severity of ischemic injury was assessed by time to ischemic contracture: 9.9 +/- 1.3 (Krebs-Henseleit buffer), 18.4 +/- 1.1 (potassium chloride), and 25.4 +/- 1.0 (flecainide) minutes (mean +/- standard error of the mean) (p less than 0.05 among all groups). Functional recovery after ischemia and reperfusion was measured by developed pressure (expressed as percent of preischemic control): 19.6 +/- 5.4 (Krebs-Henseleit buffer), 70.8 +/- 3.2 (potassium chloride), and 67.3 +/- 2.7 (flecainide). These results suggest that class Ic agents afford significant myocardial protection from global normothermic ischemia.