Background and purpose: Intracellular pH (pH i ) in heart is regulated by sarcolemmal H þ -equivalent transporters such as Na þ -H þ exchange (NHE) and Na þ -HCO 3 À cotransport (NBC). Inhibition of NBC influences pH i and can be cardioprotective in animal models of post-ischaemic reperfusion. Apart from a rabbit polyclonal NBC-antibody, a selective NBC inhibitor compound has not been studied. Compound S0859 (C 29 H 24 ClN 3 O 3 S) is a putative NBC inhibitor. Here, we provide the drug's chemical structure, test its potency and selectivity in ventricular cells and assess its suitability for experiments on cardiac contraction. Experimental approach: pH i recovery from intracellular acidosis was monitored using pH-epifluorescence (SNARFfluorophore) in guinea pig, rat and rabbit isolated ventricular myocytes. Electrically evoked cell shortening (contraction) was measured optically. With CO 2 /HCO 3 À -buffered superfusates containing 30 mM cariporide (to inhibit NHE), pH i recovery is mediated by NBC. Key results: S0859, an N-cyanosulphonamide compound, reversibly inhibited NBC-mediated pH i recovery (K i ¼ 1.7 mM, full inhibition at B30 mM). In HEPES-buffered superfusates, NHE-mediated pH i recovery was unaffected by 30 mM S0859. With CO 2 /HCO 3 À buffer, pH i recovery from intracellular alkalosis (mediated by Cl À /HCO 3 À and Cl À /OH À exchange) was also unaffected. Selective NBC-inhibition was not due to action on carbonic anhydrase (CA) enzymes, as 100 mM acetazolamide (a membrane-permeant CA-inhibitor) had no significant effect on NBC activity. pH i recovery from acidosis was associated with increased contractile-amplitude. The time course of recovery of pH i and contraction was slowed by S0859, confirming that NBC is a significant controller of contractility during acidosis. Conclusions and implications: Compound S0859 is a selective, high-affinity generic NBC inhibitor, potentially important for probing the transporter's functional role in heart and other tissues.
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