Abstract
We evaluated the cardioprotective effects of 4-cyano (benzo[ b]thiophene-2-carbonyl)guanidine (KR-33028), a recently developed inhibitor of the Na +/H + exchanger (NHE), on hypoxia-induced H9c2 cell death and on perfused rat hearts subjected to ischemia/reperfusion. KR-33028 inhibited in a concentration-dependent manner the recovery from acidosis induced by an NH 4Cl prepulse in PS120 fibroblast cells expressing the human NHE-1 isoform (IC 50: 2.59 μM). Treatment with KR-33028 (1–10 μM) significantly decreased hypoxia-induced necrotic cell death and apoptotic cell death in H9c2 cells. KR-33028 significantly inhibited hypoxia-induced increases in cytosolic and mitochondrial Ca 2+ level and cytochrome c release, and recovered hypoxia-induced Δ ψ m reduction. In the perfused rat hearts subjected to 30 min of ischemia and 30 min of reperfusion, KR-33028 (1–10 μM) improved cardiac contractility, decreased lactate dehydrogenase release, and increased content of tissue ATP, creatine phosphate and glycogen in a concentration-dependent manner. In addition, KR-33028 did not produce significant acute or subacute toxicity in the rats at doses tested. Our results suggest that a novel NHE-1 inhibitor KR-33028 possesses potent cardioprotective effects with minimal toxicity and that the effects may be mediated by inhibition of intracellular Ca 2+ overload and mitochondrial cell death pathway.
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