ROLE OF PROTEIN-KINASE C-MEDIATED PATHWAY IN THE PATHOGENESIS OF CORONARY-ARTERY SPASM IN A SWINE MODEL

Article

关键词: INTRACELLULAR CALCIUM LEVELS;    SMOOTH-MUSCLE CONTRACTION;    MINIATURE SWINE;    PHORBOL ESTER;    BAY K-8644;    HISTAMINE;    PIGS;    MECHANISMS;    INCREASES;    RESPONSES;   

DOI  :  10.1161/01.CIR.90.5.2425

来源: SCIE

【 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 mu g/kg) or histamine (3 mu g/kg) repeatedly induced coronary artery spasm at the atherosclerotic site. At the spastic site, intracoronary administration of phorbol-12,13-dibutyrate (PDBu) (10(-9) mol/kg), a PKC-activating phorbol ester, also induced coronary artery spasm, which was completely blocked by pretreatment with intracoronary staurosporine (10 mu g/kg), a PKC inhibitor. Intracoronary administration of an inactive phorbol ester, phorbol-12,13-didecanoate (10(-9) mol/kg), did not induce coronary vasoconstriction. Coronary artery spasm induced by the autacoids was significantly augmented by pre treatment with intracoronary PDBu and partially inhibited by staurosporine. Intracoronary administration of Bay K 8644 (10 mu g/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.

【 授权许可】

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