We determined the effect of 9-hydroxyellipticine (9HE) on ryanodine receptor (RyR) and cardiac function after global ischemia in isolated rat hearts. The binding of [³H]-ryanodine in rabbit cardiac sarcoplasmic reticulum was displaced by 9HE in a biphasic manner corresponding to the two sites model with IC₅₀ values of 6.1 μM and 55 mM. The increase of the intracellular Ca²⁺ concentration induced by caffeine in CHO cells expressing cardiac-type RyR was suppressed by 9HE in a concentration-dependent manner. Pretreatment of the heart with 9HE decreased the total duration of reperfusion-induced ventricular fibrillation (VF) and delayed the onset of VF. There was also a significant recovery of contractile force of ischemic hearts following 9HE. Unlike nifedipine, an L-type Ca²⁺-channel blocker, 9HE did not suppress the contraction of rat papillary muscles. Thus, 9HE exerts the cardioprotective effects against ischemia/reperfusion injury without changing hemodynamic indices.