Background: 5-Hydroxytryptamine (5-HT) has been shown to be involved in exacerbating cardiac ischemia-reperfusion injury; however, the role of 5-HT in the injury has yet to be established. This study demonstrates that 5-HT has dual roles in ischemia-reperfusion injury.

Methods and Results: The role of 5-HT in cardiac ischemia-reperfusion injury was examined in isolated rat hearts perfused with oxygenated Krebs-Henseleit solution. A 30-minute global ischemia and 30-minute reperfusion exacerbated functional cardiac parameters such as left ventricular end-diastolic pressure, coronary flow, heart rate, and total lactate dehydrogenase release. The 5-HT₂A receptor antagonist sarpogrelate (0.3-1.0 μM) improved cardiac function during ischemia-reperfusion. High-performance liquid chromatography analysis revealed an elevation in the level of 5-HT in the coronary effluent immediately after ischemia, suggesting that 5-HT is released from the ischemic heart and that sarpogrelate protects the heart from ischemia-reperfusion injury by blocking 5-HT₂A receptors. However, 5-HT (0.3-1.0,μM) applied exogenously unexpectedly improved the cardiac mechanical parameters during ischemia-reperfusion, increased coronary flow, and increased the level of NO in the effluent, which was inhibited by L-N^G-nitro-arginine methyl ester, a NO synthase blocker.

Conclusions: Present results suggest dual roles of 5-HT in ischemia-reperfusion injury. During ischemia, 5HT is released endogenously, constricts coronary smooth muscles via 5-HT2A receptors, and aggravates cardiac function. In contrast, 5-HT applied exogenously affects predominantly non-5HT₂A receptors on the endothelium and induces coronary vasodilatation via endothelial NO production, which is protective against ischemia-reperfusion injury.