| Co-Investigator(Kenkyū-buntansha) |
MICHAEL walsh University of Calgary, 医学部, 教授
WAYNE giles University of Calgary, 医学部, 教授
MURAKI Katsuhiko Nagoya City University, 薬学部, 助手 (20254310)
IMAIZUMI Yuji Nagoya City University, 薬学部, 助教授 (60117794)
ANTHONY Kana カルガリー大学, 医学部, 常勤博士研究員
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| Budget Amount *help |
¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 1993: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 1992: ¥2,500,000 (Direct Cost: ¥2,500,000)
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| Research Abstract |
1. Differences in regulation of early transient K (A-type) currents by arachidonic acid (AA) in cardiac and smooth muscle cells
A-type currents have been identified in smooth muscle cells isolated from portal vein, seminal vesicle, vas deferens, colon and stomach fundus. The activation and inactivation kinetics and the sensitivity to 4-aminopyridine of A-type current sin smooth muscle cells are similar to those in cardiac muscle cells, suggesting the same family of the channels in these muscles. The functional roles of the current in smooth muscle cells are suppressing AP or making a delay for AP firing during the early stage of depolarization and are, therefore, different from those in cardiac myocytes. We found that the application of 1muM AA reduced A-type current by about 50 % in these smooth muscle cells. In contract, substantial reduction of A-type current was observed in rabbit atrial myocytes only when much higher concentration of AA (>30muM) was applied, implying that physiolog
… More
ical significance of AA-induced reduction of A-type current is larger in smooth muscle cells. The AA-induced reduction of A-type current was not affected by inhibitors of cyclooxy-genase, lipoxygenase or superoxide dismutase. The reduction was partly decreased by proteinkinase C inhibitior.
2. Differences in modulation of delayed rectifier K current by Class III antiarrythmic drugs
Class III antiarrythmic drug prolongs AP duration and refractory period in cardiac myocytes. Although delayed rectifier K current is selectively suppressed by Class III anitiarrythmic drugs in cardiac myocytes, effects of the drugs on delayed rectifier K current in smooth muscle have not been clarified yet. The delayed rectifier K current in smooth muscle cells of the porcine coronary artery was much less sensitive to Class III antiarrythmic drugs, such as E-4031 and MS-551 but was equally sensitive to quinidine. The selectivity of Class III antiarrythmic drugs to cardiac delayed rectifier K current over that in vascular smooth muscle, especially that of coronary artery is quite important because suppression of delayed rectifier K current increases membrane excitability and contractility of the smooth muscle.
3. Increase in Ca sensitivity in smooth muscle by quaternary ammonium salt.
To examine the difference in Ca mobilization in cardiac and smooth muscle cells by inositol 1,4,5 trisphosphate (IP_3), effects of a putative blocker of K channels which couple with Ca release from sarcoplasmic reticulum by IP_3 were examined. Unexpectedly, tetrahexylammonium bromide, which has been reported as a potent K channel blocker in endoplasmic reticulum of central nervous system, markedly increased Ca sensitivity of smooth muscle strip skinned by beta-escin by separate mechanism. The mechanism underlying the increase in Ca sensitivity includes neither an increase in myosin light chain kinase activity nor a decrease in myosin dephosphatase activity. Less
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