Serotonin is one of the most important vasoactive substances and has been implicated in the pathogenesis of coronary artery spasm and of acute coronary syndrome. We have recently demonstrated that local and long-term treatment with interleukin-1β (IL-1β) causes coronary arteriosclerotic changes and hyperconstrictive responses to serotonin in pigs in vivo. However, it remains to be examined which serotonergic (5-HT) receptor subtype mediates coronary spasm and whether alterations in serotonergic receptors are involved in the abnormality. In this study, we examined the inhibitory effect of sarpogrelate, a selective 5-HT(2A) serotonergic receptor antagonist, on the serotonin-induced coronary spasm as well as the possible alterations of serotonergic receptors in our porcine model. A segment of the porcine coronary artery was carefully dissected and aseptically wrapped with cotton mesh absorbing IL-β-bound microbeads from the adventitia. Two weeks after the procedure, angiographic study was performed, followed by binding assay for 5-HT(1B) and 5-HT(2A) serotonergic receptors and reverse transcription- polymerase chain reaction (RT-PCR) analysis for mRNA of those receptors. Angiographic study showed coronary vasospastic responses to serotonin at the IL-1β-treated site. Sarpogrelate dose-dependently inhibited the serotonin- induced coronary spasm, but it did not affect the prostaglandin F(2α)- induced vasoconstriction. Radiolabeled receptor-binding assay showed that receptor affinity or receptor number of the 5-HT(1B) or 5-HT(2A) receptors did not differ significantly between the spastic and the control sites. Furthermore, RT-PCR analysis showed that the expression of neither 5-HT(2A) nor 5-HT(1B) receptor mRNA was significantly altered at the spastic site. These results indicate that serotonin-induced coronary spasm is mediated primarily by 5-HT(2A) receptor in our porcine model, although the 5-HT(2A) receptor was not upregulated, suggesting that alteration in the signal- transduction pathway for vascular smooth muscle contraction beyond the 5- HT(2A) receptor plays a primary role in the pathogenesis of coronary spasm in our porcine model.
All Science Journal Classification (ASJC) codes
- Cardiology and Cardiovascular Medicine