抄録
Ca antagonists, Nifedipine, Diltiazem and Verapamil enhanced PGI2 production human vascular endothelial cells derived from umbilical veins via activation of phospholipases. Their mode of action was analyzed with reference to Ca++ mobilization and cyclic nucleotides. PGI2 pioduction by Diltiazem, A23187, arachidonic acid (AA) or PGH2 was remarkably decreased by the pretreatment with TMB-8. And its inhibition rate was increased in addition of Diltiazem or A23187. The enhancement of PGI2 production by Diltiazem or A23187 was almost diminished in Ca++ free medium. When the endothelial cells were pretreated with MIX, intracellular cAMP and cGMP concentration was increased, and PGI2 producton was decreased. Addition of dibutyryl cAMP or 8-bromo cGMP increased intracellular cAMP or cGMP concentration, respectively, and simultaneously suppressed PGI2 production. Addition of PGI2 or AA increased the concentration of PGI2 of the medium and intracellular cAMP concentration, but had no effect on cGMP concentration. While in the presence of 1mM MIX, Diltiazem had no effect on intracelluler cAMP concentration but decreased cGMP concentration. Through these results, it is speculated that 1) PGI2 production is depend upon mainly intracellular Ca++, 2) and this dependency is dominant in the early step of AA cascade. 3) The enhancemt of PGI2 production by Diltiazem or A23187 was also depend upon extracellular Ca++. 4) The enhanced PGI2 production is suppressed by increased cAMP due to increased PGI2 production, as an autoregulation mechanism. 5) PGI2 production is regulated by not only cAMP but also cGMP concentration. 6) Enhancement of PGI2 production induced by Diltiazem may be derived from extra to intracellular mobilization of Ca++ or decreased cGMP concentration.
