Protective effect of serotonin (5-HT2) 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 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.
Grover
G J
GJ
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543.
Sargent
C A
CA
Dzwonczyk
S
S
Normandin
D E
DE
Antonaccio
M J
MJ
D000818:Animals; D002928:Cinanserin / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004873:Ergolines / Q000494:pharmacology; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D007650:Ketanserin / Q000494:pharmacology / Q000627:therapeutic use; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects*; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy*; D009206:Myocardium / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology* / Q000627:therapeutic use
D004873:Ergolines; D011942:Receptors, Adrenergic, alpha; D012702:Serotonin Antagonists; D007650:Ketanserin; D007770:L-Lactate Dehydrogenase; D002928:Cinanserin; C032663:LY 53857