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Protective effect of serotonin (5-HT2) receptor antagonists in ischemic rat hearts
G J Grover1, C A Sargent, S Dzwonczyk
1Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543.
Abstract:
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.
Insights
Serotonin (5-HT) exacerbates heart damage during ischemia, but 5-HT2 receptor antagonists protect the heart. These findings suggest 5-HT2 receptors mediate ischemic injury in the rat heart.
Area of Science:
- Cardiology
- Pharmacology
- Biochemistry
Background:
- Serotonin (5-HT) involvement in myocardial ischemia is unclear.
- Potential role in thrombosis and coronary spasm.
- Direct mediation of myocardial damage needs clarification.
Purpose of the Study:
- Determine the effect of 5-HT2 receptor antagonists on ischemic myocardial injury.
- Investigate the role of 5-HT in exacerbating myocardial damage.
- Assess the specific receptor mediation of 5-HT's pro-ischemic effects.
Main Methods:
- Isolated rat heart model subjected to global ischemia and reperfusion.
- Administration of 5-HT2 receptor antagonists (cinanserin, ketanserin, LY 53857).
- Measurement of time to contracture, contractile function recovery, and lactate dehydrogenase (LDH) release.
Main Results:
- 5-HT2 antagonists significantly increased time to contracture and improved recovery of contractile function.
- These antagonists reduced LDH release, indicating reduced myocardial damage.
- Serotonin (5-HT) itself showed a pro-ischemic effect, which was blocked by antagonists.
- Inhibition of 5-HT synthesis provided cardioprotection.
Conclusions:
- Serotonin (5-HT) exacerbates ischemic injury in the rat heart.
- This exacerbation is specifically mediated by 5-HT2 receptors.
- 5-HT2 receptor antagonists demonstrate cardioprotective effects against ischemic damage.