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

被引:49
作者
Kadokami, T
Shimokawa, H
Fukumoto, Y
Ito, A
Takayanagi, T
Egashira, K
Takeshita, A
机构
[1] KYUSHU UNIV,SCH MED,ANGIOCARDIOL RES INST,HIGASHI KU,FUKUOKA 81282,JAPAN
[2] KYUSHU UNIV,SCH MED,CARDIOVASC CLIN,HIGASHI KU,FUKUOKA 81282,JAPAN
关键词
vasospasm; cytokines; protein kinase C; calcium channels; signal transduction;
D O I
10.1161/01.CIR.94.2.190
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 contration, we examined the possible role of these two mechanisms in the pathogenesis of coronary spasm in our swine model in vivo. Method and 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 Ca2+-induced Ca2+ release from SR) or thapsigargin (an inhibitor of Ca2+-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 F-2 alpha was not affected by pretreatment with staurosporine of 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.
引用
收藏
页码:190 / 196
页数:7
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