Protective Effect of Serotonin (5-HT2) Receptor Antagonists in Ischemic Rat Hearts

SUMMARYSerotonin (5-HT) may play a role in exacerbating thrombosis and coronary spasm during myocardial ischemia, but its role in mediating myocardial damage directly is not clear. We determined the effect of the 5-HT2 receptor antagonists cinanserin (0.1–10 μM), ketanserin (0.3–10 μM), and LY 53857 (1–10 μM) on time to contracture, recovery of contractile function, and lactate dehydrogenase (LDH) release after 25-min global ischemia and 30-min reperfusion in isolated rat heart. All 5-HT2 antagonists significantly increased time to contracture in a concentration-dependent manner (EC25 = 1.6, 5.5, and 6.1 μM for cinanserin, ketanserin, and LY 53857, respectively). These compounds also significantly reduced LDH release and improved recovery of contractile function during reperfusion. 5-HT ±30 μM significantly reduced time to contracture, indicating a proischemic effect. The proischemic effect of 5-HT was abolished by ketanserin and cinanserin. Inhibition of 5-HT synthesis by parachlorophenylalanine resulted in significant cardio-protection, further indicating the involvement of 5-HT in the pathogenesis of ischemia in this model. Although cinanserin and ketanserin had α1-adrenoceptor blocking effects, LY 53857 was devoid of this activity at concentrations exhibiting cardioprotection. Therefore, 5-HT may exacerbate ischemic injury in rat heart, and this exacerbation appears to be mediated specifically by 5-HT2 receptors.