Serotonin-induced hypercontraction through 5-hydroxytryptamine 1B receptors in atherosclerotic rabbit coronary arteries

Background-Augmented vasoconstriction to serotonin (5-hydroxytryptamine [5- HT]) in atherosclerotic vessels plays a crucial role in the development of myocardial ischemia. We investigated mechanisms for serotonin-evoked hyperc ontraction in atherosclerotic rabbit coronary arteries. Methods and Results-Contractile responses to serotonergic agents of endothe lium-denuded coronary arteries from control and Watanabe heritable hyperlip idemic rabbits (WHHL) were examined. WHHL coronary arteries exhibited hyper contraction to 5-HT1-receptor agonists, the constrictor threshold concentra tions and ED50 to serotonin, 5-carboxamidotryptamine, and sumatriptan in WH HL were significantly lower, and the E-max in WHHL to these agents were inc reased 55% to 59% above those of the control. Serotonin-evoked contractions in both groups were inhibited by GR127935 (5-HT1B/1D antagonist; 0.1 to 1 nmol/L) and pertussis toxin but not by ketanserin (5-HT2 antagonist; 0.01 t o 1 mu mol/L), suggesting that the hypercontraction is most likely mediated by 5-HT1B/1D receptors through a pertussis toxin-sensitive pathway. Furthe rmore, simultaneous measurements of [Ca2+](i) and isometric tension of fura -2-loaded arteries revealed that the hypercontraction was concomitant with the augmented elevation of [Ca2+](i) in the smooth muscle. The 5-HT1B mRNA levels in WHHL coronary arteries increased to 2.5-fold over those in contro l arteries, whereas neither 5-HT1D nor 5-HT2A mRNA was detected in either g roup. Conclusions-Atherosclerotic rabbit coronary arteries exhibited the enhancem ent in contraction and Ca2+ mobilization in response to serotonin. The 5-HT 1B receptor, which is upregulated by atherosclerosis, most likely mediates the augmenting effects of serotonin.