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(Circulation. 1996;94:190-196.)
© 1996 American Heart Association, Inc.

Articles

Coronary Artery Spasm Does Not Depend on the Intracellular Calcium Store but Is Substantially Mediated by the Protein Kinase C–Mediated Pathway in a Swine Model With Interleukin-1ß In Vivo

Toshiaki Kadokami, MD; Hiroaki Shimokawa, MD; Yoshihiro Fukumoto, MD; Akira Ito, MD; Tsuneo Takayanagi, MS; Kensuke Egashira, MD; Akira Takeshita, MD

the Research Institute of Angiocardiology and Cardiovascular Clinic, Kyushu University School of Medicine, Fukuoka, Japan.

Correspondence to Hiroaki Shimokawa, MD, Research Institute of Angiocardiology and Cardiovascular Clinic, Kyushu University School of Medicine, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-82, Japan.

Background The intracellular mechanism for coronary artery spasm is still unknown. Since the protein kinase C (PKC)–mediated pathway and Ca²⁺ release from sarcoplasmic reticulum (SR) are important intracellular mechanisms of vascular smooth muscle contraction, we examined the possible role of these two mechanisms in the pathogenesis of coronary spasm in our swine model in vivo.

Methods and Results In 25 pigs, interleukin-1ß (IL-1ß) was applied chronically to the coronary arteries from the adventitia to induce an inflammatory/proliferative lesion. Two weeks after the operation, either intracoronary serotonin or histamine repeatedly induced coronary spasm at the IL-1ß–treated site. At those spastic sites, phorbol-12,13-dibutyrate, a PKC-activating phorbol ester, also induced coronary spasm, which was blocked by pretreatment with the PKC inhibitors staurosporine and sphingosine. Serotonin- and histamine-induced coronary spasm was also significantly inhibited by pretreatment with staurosporine, sphingosine, or nifedipine (an L-type Ca²⁺ channel antagonist) but not by ryanodine (an inhibitor of Ca²⁺-induced Ca²⁺ release from SR) or thapsigargin (an inhibitor of Ca²⁺-ATPase of SR). Bay K 8644 (an L-type Ca²⁺ channel agonist) also induced coronary spasm at the IL-1ß–treated site, which was significantly inhibited by pretreatment with staurosporine, sphingosine, and nifedipine. In contrast, coronary vasoconstriction induced by prostaglandin F₂ was not affected by pretreatment with staurosporine or sphingosine but was significantly inhibited by pretreatment with ryanodine, thapsigargin, or nifedipine.

Conclusions These results suggest that (1) PKC activation largely accounts for the serotonin- and histamine-induced coronary spasm; (2) at the spastic site, the calcium influx through L-type Ca²⁺ channels may be augmented via the PKC-mediated pathway; and (3) the Ca²⁺ release from the SR into the cytosol may not play a primary role in coronary spasm.

Key Words: vasospasm • cytokines • protein kinase C • calcium channels • signal transduction

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