cinanserin and Myocardial-Ischemia

Previous studies have indicated that structurally dissimilar serotonin2 (5HT2) antagonists can protect globally ischemic/reperfused reperfused rat hearts. We therefore determined if the 5HT2 antagonist cinanserin can protect the ischemic myocardium in two models of pacing-induced ischemia in anesthetized dogs. In one model, dogs were subjected to repeated 5-min episodes of pacing superimposed upon left anterior descending coronary artery stenosis such that an ST segment elevation of 10-11 mV was obtained and upon cessation of pacing, a return of ST segment elevation to baseline. In vehicle-treated animals, this ST segment elevation to baseline. In vehicle-treated animals, this ST segment elevation was constant for all pacing-induced ischemic episodes. After infusion of 20 micrograms/kg/min cinanserin (intracoronary, i.c.), ST segment elevation was significantly reduced during pacing-induced ischemia at all times measured postdrug. In the second model, animals were subjected to pacing-induced ischemia for 15 min such that segmental shortening was reduced to zero. Upon cessation of pacing-induced ischemia, recovery of shortening was assessed. In vehicle-treated dogs, function recovered to only 40% of baseline at 3 h into recovery. Pretreatment with 5 micrograms/kg/min cinanserin i.c. significantly improved recovery of postischemic function. In both protocols, cinanserin had no effect on ischemic regional blood flow or peripheral hemodynamics. Thus, cinanserin appears to exert profound protective effects in two models of effort-induced ischemia.

Topics: Analysis of Variance; Animals; Blood Platelets; Cardiac Pacing, Artificial; Cinanserin; Dogs; Electrocardiography; Female; Heart; Hemodynamics; Male; Myocardial Contraction; Myocardial Ischemia

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 microM), ketanserin (0.3-10 microM), and LY 53857 (1-10 microM) 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 microM for cinanserin, ketanserin, and LY 53857, respectively). These compounds also significantly reduced LDH release and improved recovery of contractile function during reperfusion. 5-HT > or = 30 microM 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 cardioprotection, further indicating the involvement of 5-HT in the pathogenesis of ischemia in this model. Although cinanserin and ketanserin had alpha 1-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.

Topics: Animals; Cinanserin; Disease Models, Animal; Ergolines; Heart; Hemodynamics; Ketanserin; L-Lactate Dehydrogenase; Male; Muscle, Smooth, Vascular; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha; Serotonin Antagonists