Background: Endothelium-dependent, pertussis toxin-sensitive relaxation to 5-hydroxytryptamine (5-HT) is impaired selectively after balloon injury of porcine coronary artery, followed by regeneration of the endothelial cells. The present study was designed to test the hypothesis that 5-HT, released from aggregating platelets, affects the progression of the endothelial dysfunction.
Methods and results: Yorkshire pigs were assigned randomly to three groups: control group (standard diet), denudation group (high-cholesterol diet plus balloon denudation of the endothelium of coronary artery under fluoroscopy), and DV-7028-treated group (denudation group plus chronic treatment with the selective 5-HT2 receptor antagonist DV-7028, given from the first day on after balloon denudation). Four weeks after the denudation, quantitative angiography revealed that 5-HT injected into the coronary artery decreased the luminal diameter of the left anterior descending coronary artery at the denuded site in the denudation group but not in the control or the DV-7028-treated group. Then, animals were killed so we could study the endothelium-dependent responses of their coronary arteries in conventional organ chambers. The arteries from the denudation group exhibited less relaxation to 5-HT and sodium fluoride (a stimulant of G proteins) than those of the control group. Relaxations to 5-HT and sodium fluoride were greater in arteries from the DV-7028-treated group than in those from the denudation group. In contrast, the endothelium-dependent, pertussis toxin-insensitive relaxations to bradykinin and thrombin and the endothelium-independent relaxations to sodium nitroprusside and isoproterenol were not affected significantly by chronic treatment with DV-7028.
Conclusions: These results suggest that 5-HT2 receptors are involved in the chronic progression of endothelial dysfunction after balloon denudation in the porcine coronary artery.