Effect of probucol on intracellular pH and proliferation of human vascularendothelial cells

We investigated the effect of probucol on the intracellular pH ([pH]i) and proliferation of human umbilical vein endothelial cells (HUVEC). as well as their production of prostacyclin (PGI(2)). The addition of probucol produc ed a biphasic shift in [pH]i, with a brief initial acidification followed b y a rapid alkaline shift. After pretreatment with EGTA. the initial decreas e in [pH]i was abolished, and the subsequent increase was inhibited. After pretreatment with amiloride. only the increase of [pH]i was abolished. Thes e results suggest that the probucol-induced increase of [pH]i was mainly de pendent on Na+/H+ exchange and partly on extracellular Ca2+. In contrast, t he addition of LDL produced a decrease of [pH]i. Under Ca2+-free condition. [pH]i was further decreased by LDL. In cells pretreated with amiloride, ho wever, [pH]i was not further decreased by LDL. It was found that probucol p romoted cell proliferation, and LDL inhibited cell proliferation. Addition of probucol also enhanced prostacyclin generation by HUVEC. This enhancemen t of PGI(2) generation resulted from increased release of Ca2+ from the sto rage sites. due not only to increased production of inositol 1,4,5-triphosp hate (IP3) but also to the increase of [pH]i. These findings may help to ex plain the antiatheroselerotic action of probucol. (C) 1999 Elsevier Science Inc.