PROTECTIVE EFFECT OF SEROTONIN (5-HT(2)) RECEPTOR ANTAGONISTS IN ISCHEMIC RAT HEARTS

Serotonin (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 muM), ketanserin (0.3-10 muM), and LY 53857 (1-10 muM) 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 muM for cinansefin, ketanserin, and LY 53857, respectively). These compounds also significantly reduced LDH release and improved recovery of contractile function during reperfusion. 5-HT greater-than-or-equal-to 30 muM significantly reduced time to contracture, indicating a proischemic effect. The proischemic effect of 5-HT was abolished by ketanserin and cinansefin. 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 cinansefin and ketanserin had alpha1-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-HT, receptors.