S0859, an N-cyanosulphonamide inhibitor of sodium-bicarbonate cotransport in the heart

Br J Pharmacol. 2008 Mar;153(5):972-82. doi: 10.1038/sj.bjp.0707667. Epub 2008 Jan 21.


Background and purpose: Intracellular pH (pH(i)) in heart is regulated by sarcolemmal H(+)-equivalent transporters such as Na(+)-H(+) exchange (NHE) and Na(+)-HCO(3) (-) 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 (SNARF-fluorophore) in guinea pig, rat and rabbit isolated ventricular myocytes. Electrically evoked cell shortening (contraction) was measured optically. With CO(2)/HCO(3) (-)-buffered superfusates containing 30 muM 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)=1.7 microM, full inhibition at approximately 30 microM). In HEPES-buffered superfusates, NHE-mediated pH(i) recovery was unaffected by 30 microM S0859. With CO(2)/HCO(3) (-) buffer, pH(i) recovery from intracellular alkalosis (mediated by Cl(-)/HCO(3) (-) and Cl(-)/OH(-) exchange) was also unaffected. Selective NBC-inhibition was not due to action on carbonic anhydrase (CA) enzymes, as 100 microM 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acidosis / metabolism
  • Animals
  • Benzamides / pharmacology*
  • Benzopyrans
  • Biological Transport
  • Carbonic Anhydrases / metabolism
  • Electric Stimulation
  • Guinea Pigs
  • Heart Ventricles / cytology
  • Heart Ventricles / metabolism
  • Hydrogen-Ion Concentration
  • In Vitro Techniques
  • Myocardial Contraction / drug effects
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism
  • Naphthols
  • Rabbits
  • Rats
  • Rats, Sprague-Dawley
  • Rhodamines
  • Sodium-Bicarbonate Symporters / antagonists & inhibitors*
  • Sodium-Bicarbonate Symporters / physiology
  • Sulfonamides / pharmacology*


  • Benzamides
  • Benzopyrans
  • Naphthols
  • Rhodamines
  • S 0859 compound
  • Sodium-Bicarbonate Symporters
  • Sulfonamides
  • seminaphthorhodaminefluoride
  • Carbonic Anhydrases