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 exchange (AE) inhibitor in rat cardiomyocytes. The AE transporter mediates sarcolemmal acid influx but is only one part of the cardiac cell's dual acid loading mechanism, the other part being a sarcolemmal Cl--OH- exchanger (CHE). We 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 transporters by monitoring its effect on intracellular pH (pH(i)) recovery from alkali or acid loads. The pH(i) was measured using microspectrofluorimetry (carboxy-SNARF-1). The results indicate that CHE activity was unaffected by the drug (1-20 microM), whereas up to 78% of AE activity was blocked (K(i) = 3.9 microM). Thus, S20787 targets only the AE component of the dual acid influx system. Activities of other acid-transporting carriers, such as Na+-H+ exchange, Na+-HCO3- co-transport and the monocarboxylic acid transporter, were unaffected by the drug. The inhibitory efficacy of S20787 for AE in guinea pig cardiomyocytes appears to be considerably higher (approximately 78%) than proposed 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 allowance for the CHE component, which would result in an underestimation. S20787 is thus a highly selective AE inhibitor which may be useful as an experimental tool and a potential cardiac protective agent in the heart.
Loh
S H
SH
Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan, ROC. shloh@ndmctsgh.edu.tw
Tsai
C S
CS
Lin
C I
CI
Jin
J S
JS
Vaughan-Jones
R D
RD
D000818:Animals; D001457:Anion Exchange Protein 1, Erythrocyte / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D027321:Anion Transport Proteins / Q000187:drug effects / Q000378:metabolism; D017920:Antiporters / Q000187:drug effects / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D026901:Membrane Transport Proteins; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism; D013050:Spectrometry, Fluorescence / Q000379:methods; D016276:Ventricular Function
D001457:Anion Exchange Protein 1, Erythrocyte; D027321:Anion Transport Proteins; D017920:Antiporters; D002352:Carrier Proteins; C491393:Mct3 protein, rat; D026901:Membrane Transport Proteins; C093920:chloride-base exchanger