TY - JOUR T1 - Chloride dependent intracellular pH increase induced by bepridil in human red blood cells: a possible involvement in correction of ischemic acidosis. JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1509 LP - 1514 VL - 267 IS - 3 AU - H Kovacic AU - P Gallice AU - M Sarrazin AU - A Crevat Y1 - 1993/12/01 UR - http://jpet.aspetjournals.org/content/267/3/1509.abstract N2 - Inhibitors of Na+/H+ exchanger are reported to exert an anti-ischemic effect. Some calcium antagonists and particularly bepridil are commonly used as anti-ischemic agents. Therefore, in this study, we test the hypothesis that protective effect against ischemia may occur at least in part through an action on Na+/H+ exchanger. The effect of some calcium antagonists on Na+/H+ exchanger from acid-loaded and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid disodium salt (DIDS)-treated human red cells (RBC) has been studied with a pHstat technique. Doses above those required to affect calcium channel (10(-5) and 10(-4) M) of nifedipine, nicardipine, verapamil and diltiazem had no effect on Na+/H+ exchanger activity. Ethyl isoproply amiloride (10(-4) M) completely inhibited the exchanger. Among the calcium antagonists tested, bepridil exhibited a particular effect, dissipating the pH gradient independently from the Na+/H+ exchanger activity. Bepridil's effect on DIDS-treated RBC was compared with that of a well known protonophore, carbamyl cyanide p-(trifluoromethoxy)phenyl hydrazone, and with that of tributyltin, which mediates a Cl-/OH- exchange across the cell membrane. Bepridil (> 2 x 10(-6) M) acts like tributyltin by dissipating the pH gradient whatever the external cation (Na+ or K+) or the membrane potential, and its action depends on the ratio intracellular [Cl-]/extracellular [Cl-]. The dissipation seems to occur through an OH-/Cl- exchange but other mechanisms may intervene. Moreover, intraerythrocytic pH measurement by 31P nuclear magnetic resonance clearly showed that bepridil permits the cell to recover normal pH faster than control.(ABSTRACT TRUNCATED AT 250 WORDS) ER -