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 hypercontraction in atherosclerotic rabbit coronary arteries. METHODS AND RESULTS: Contractile responses to serotonergic agents of endothelium-denuded coronary arteries from control and Watanabe heritable hyperlipidemic rabbits (WHHL) were examined. WHHL coronary arteries exhibited hypercontraction to 5-HT(1)-receptor agonists; the constrictor threshold concentrations and E:D(50) to serotonin, 5-carboxamidotryptamine, and sumatriptan in WHHL were significantly lower, and the E:(max) in WHHL to these agents were increased 55% to 59% above those of the control. Serotonin-evoked contractions in both groups were inhibited by GR127935 (5-HT(1B/1D) antagonist; 0.1 to 1 nmol/L) and pertussis toxin but not by ketanserin (5-HT(2) antagonist; 0.01 to 1 micromol/L), suggesting that the hypercontraction is most likely mediated by 5-HT(1B/1D) receptors through a pertussis toxin-sensitive pathway. Furthermore, simultaneous measurements of Ca(2+)(i) and isometric tension of fura-2-loaded arteries revealed that the hypercontraction was concomitant with the augmented elevation of Ca(2+)(i) in the smooth muscle. The 5-HT(1B) mRNA levels in WHHL coronary arteries increased to 2.5-fold over those in control arteries, whereas neither 5-HT(1D) nor 5-HT(2A) mRNA was detected in either group. CONCLUSIONS: Atherosclerotic rabbit coronary arteries exhibited the enhancement in contraction and Ca(2+) mobilization in response to serotonin. The 5-HT(1B) receptor, which is upregulated by atherosclerosis, most likely mediates the augmenting effects of serotonin.