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(Circulation. 2001;103:1289.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Serotonin-Induced Hypercontraction Through 5-Hydroxytryptamine 1B Receptors in Atherosclerotic Rabbit Coronary Arteries

Tatsuro Ishida, MD, PhD; Seinosuke Kawashima, MD, PhD; Ken-ichi Hirata, MD, PhD; Tsuyoshi Sakoda, MD, PhD; Yasushi Shimokawa, MD; Yoichi Miwa, MD, PhD; Nobutaka Inoue, MD, PhD; Tomomi Ueyama, MD, PhD; Masashi Shiomi, PhD; Hozuka Akita, MD, PhD; Mitsuhiro Yokoyama, MD, PhD

From the First Department of Internal Medicine and Institute for Experimental Animals (M.S.), Kobe (Japan) University School of Medicine.

Correspondence to Mitsuhiro Yokoyama, MD, First Department of Internal Medicine, Kobe University School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. E-mail yokoyama{at}med.kobe-u.ac.jp

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-HT₁–receptor agonists; the constrictor threshold concentrations and ED₅₀ 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-HT₂ antagonist; 0.01 to 1 µmol/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 [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-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 Ca²⁺ mobilization in response to serotonin. The 5-HT_1B receptor, which is upregulated by atherosclerosis, most likely mediates the augmenting effects of serotonin.

Key Words: atherosclerosis • vasoconstriction • receptors • muscle, smooth

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