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Cellular and Molecular CardiologyRole of Protein Kinase C-Mediated Pathway in the Patho...
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Cellular and Molecular CardiologyRole of Protein Kinase C-Mediated Pathway in the Pathogenesis of Coronary Artery Spasm in a Swine Model
作者:
Akira Ito,
Hiroaki Shimokawa,
Ryuichi Nakaike,
Tohru Fukai,
Makoto Sakata,
Tsuneo Takayanagi,
Kensuke Egashira,
Akira Takeshita,
期刊:
Circulation
(OVID Available online 1994)
卷期:
Volume 90,
issue 5
页码: 2425-2431
ISSN:0009-7322
年代: 1994
出版商: OVID
数据来源: OVID
摘要:
Background The intracellular mechanism of coronary artery spasm is still unknown.The pathway mediated by protein kinase C (PKC) is an important intracellular process of various cellular responses, including vascular smooth muscle contraction. Thus, we examined the role of the PKC-mediated pathway in the pathogenesis of coronary artery spasm in our in vivo swine model.Methods and Results Seven Gottingen miniature pigs underwent coronary balloon injury and x-ray irradiation to induce atherosclerotic lesion. After 6 to 18 months, intracoronary serotonin (3 micrograms/kg) or histamine (3 micrograms/kg) repeatedly induced coronary artery spasm at the atherosclerotic site. At the spastic site, intracoronary administration of phorbol-12,13-dibutyrate (PDBu) (10-9mol/kg), a PKC-activating phorbol ester, also induced coronary artery spasm, which was completely blocked by pretreatment with intracoronary staurosporine (10 micrograms/kg), a PKC inhibitor. Intracoronary administration of an inactive phorbol ester, phorbol-12,13-didecanoate (10-9mol/kg), did not induce coronary vasoconstriction. Coronary artery spasm induced by the autacoids was significantly augmented by pretreatment with intracoronary PDBu and partially inhibited by staurosporine. Intracoronary administration of Bay K 8644 (10 micrograms/kg), a dihydropyridine-sensitive L-type calcium channel agonist, also induced coronary artery spasm at the spastic site, which was significantly inhibited by pretreatment with intracoronary staurosporine or nifedipine (0.1 mg/kg).Conclusions These results suggest (1) the PKC-mediated pathway is importantly involved in the pathogenesis of coronary artery spasm, (2) activation of the PKC-mediated pathway partially accounts for serotonin- and histamine-induced coronary artery spasm, and (3) at the spastic site, calcium influx through dihydropyridine-sensitive L-type calcium channel and/or calcium sensitivity of the contractile proteins may be augmented by the PKC-mediated pathway. (Circulation. 1994;90:2425-2431.)
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