Role of protein kinase C-mediated pathway in the pathogenesis of coronary artery spasm in a swine model

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 μg/kg) or histamine (3 μg/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 slaurosporine (10 μg/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 pretreatment with intracoronary PDBu and partially inhibited by staurosporine. Intracoronary administration of Bay K 8644 (10 μg/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.