INHIBITION BY XIPAMIDE OF AMILORIDE-INDUCED ACIDIFICATION IN CULTUREDRAT CARDIOCYTES

The diuretic drug xipamide improves myocardial relaxation in hypertens ive patients with left ventricular hypertrophy, but its mechanism of a ction is unknown. Here, xipamide was tested in cultured rat heart myog enic H9c2 cells and newborn cardiomyocytes for its effects on cell aci dification (and Ca2+ mobilization). In H9c2 cells, blocking Na+/H+ exc hange with amiloride (2 mM) provoked cell acidification with rate = 0. 82 +/- 0.17 pH units/h (n = 6). Xipamide 1 mu M maximally inhibited 50 +/- 7% (n = 9) of cell acidification. The action of xipamide required the presence of HCO3- and was antagonized by the HCO3--transport bloc ker DIDS (4,4'-diisothiocyanostilbene-2,2'-disulfonic acid). Conversel y, the carbonic anhydrase (EC 4.2.1.1) inhibitor acetazolamide failed to prevent xipamide action. Finally, xipamide was without significant effect on the Ca2+ signals induced by endothelin-1, vasopressin or the Ca2+ ionophore ionomycin. In newborn rat cardiomyocytes, xipamide red uced amiloride-induced cell acidification at similar concentrations as in H9c2 cardiocytes, but with a slightly higher extent of maximal inh ibition (70-80%). In conclusion, xipamide reduced amiloride-dependent cell acidification in the rat heart myogenic H9c2 cell line and in new born rat cultured cardiomyocytes. This action of xipamide seems to be related to a complex interaction with DIDS-sensitive HCO3- movements. Prevention of cell acidification by xipamide could be involved in the beneficial effects of this compound in myocardial relaxation and left ventricle filling in hypertensive patients with left ventricular hyper trophy. (C) 1997 Elsevier Science B.V.