title: Role of protein kinase C-mediated pathway in the pathogenesis of coronary artery spasm in a swine model.
abstract: 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.
  
  
  RESULTS
  Seven Göttingen 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(-9) mol/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(-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 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.
authors.affiliation: Research Institute of Angiocardiology and Cardiovascular Clinic, Kyushu University School of Medicine, Fukuoka, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Ito
authors.forename: H
authors.initials: H
authors.lastname: Shimokawa
authors.forename: R
authors.initials: R
authors.lastname: Nakaike
authors.forename: T
authors.initials: T
authors.lastname: Fukai
authors.forename: M
authors.initials: M
authors.lastname: Sakata
authors.forename: T
authors.initials: T
authors.lastname: Takayanagi
authors.forename: K
authors.initials: K
authors.lastname: Egashira
authors.forename: A
authors.initials: A
authors.lastname: Takeshita
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003329:Coronary Vasospasm / Q000209:etiology*; D004195:Disease Models, Animal; D006632:Histamine / Q000494:pharmacology; D008297:Male; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D019311:Staurosporine; D013552:Swine; D013556:Swine, Miniature
chemical_list: D000470:Alkaloids; D012701:Serotonin; D015240:Phorbol 12,13-Dibutyrate; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D006632:Histamine; D011493:Protein Kinase C; D019311:Staurosporine; D002118:Calcium