Effect of S20787, a novel Cl--HCO3- exchange inhibitor, on intracellular pH regulation in guinea pig ventricular myocytes

S20787 has recently been proposed to be a selective Cl--HCO3- anion exchang e (AE) inhibitor in rat cardiomyocytes. The AE transporter mediates sarcole mmal acid influx but is only one part of the cardiac cell's dual acid loadi ng mechanism, the other part being a sarcolemmal Cl--OH- exchanger (CHE). W e have therefore (1) investigated the differential effects of S20787 on the AE and CHE transporters in isolated guinea pig ventricular myocytes and (2 ) re-examined the influence of the drug on other sarcolemmal acid transport ers by monitoring its effect on intracellular pH (pH(i)) recovery from alka li or acid loads. The pHi was measured using microspectrofluorimetry (carbo xy-SNARF-1). The results indicate that CHE activity was unaffected by the d rug (1-20 muM), whereas up to 78% of AE activity was blocked (K-i = 3.9 muM ). Thus, S20787 targets only the AE component of the dual acid influx syste m. Activities of other acid-transporting carriers, such as Na+-H+ exchange, Na+-HCO3- cotransport and the monocarboxylic acid transporter, were unaffe cted by the drug. The inhibitory efficacy of S20787 for AE in guinea pig ca rdiomyocytes appears to be considerably higher (approximately 78%) than pro posed previously for rat cardiomyocytes (50%). This is most likely because, in both cells, a significant fraction (20-30%) of acid influx is mediated through the S20787-insensitive CHE transporter. Previous studies made no al lowance for the CHE component, which would result in an underestimation. S2 0787 is thus a highly selective AE inhibitor which may be useful as an expe rimental tool and a potential cardiac protective agent in the heart. Copyri ght (C) 2001 National Science Council, ROC and S. Karger AG, Basel.