title: 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-1 beta in vivo.
abstract: 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.
  
  
  RESULTS
  In 25 pigs, interleukin-1 beta (IL-1 beta) 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-1 beta-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 Ca(2+)-induced Ca2+ release from SR) or thapsigargin (an inhibitor of Ca(2+)-ATPase of SR). Bay K 8644 (an L-type Ca2+ channel agonist) also induced coronary spasm at the IL-1 beta-treated site, which was significantly inhibited by pretreatment with staurosporine, sphingosine, and nifedipine. In contrast, coronary vasoconstriction induced by prostaglandin F2 alpha 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.
authors.affiliation: Research Institute of Angiocardiology, Kyushu University School of Medicine, Fuknoka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kadokami
authors.forename: H
authors.initials: H
authors.lastname: Shimokawa
authors.forename: Y
authors.initials: Y
authors.lastname: Fukumoto
authors.forename: A
authors.initials: A
authors.lastname: Ito
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; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D003329:Coronary Vasospasm / Q000139:chemically induced / Q000209:etiology*; D003600:Cytosol / Q000378:metabolism; D004789:Enzyme Activation; D006632:Histamine; D007375:Interleukin-1 / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012433:Ryanodine / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D012701:Serotonin; D013110:Sphingosine / Q000494:pharmacology; D019311:Staurosporine; D013552:Swine; D013729:Terpenes / Q000494:pharmacology; D019284:Thapsigargin
chemical_list: D000470:Alkaloids; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D007375:Interleukin-1; D013729:Terpenes; D012433:Ryanodine; D012701:Serotonin; D015240:Phorbol 12,13-Dibutyrate; D019284:Thapsigargin; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D006632:Histamine; D011493:Protein Kinase C; D000252:Calcium-Transporting ATPases; D019311:Staurosporine; D009543:Nifedipine; D013110:Sphingosine; D002118:Calcium