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

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

Author information

1
Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, Division of Medical Sciences, Oxford University, Oxford, UK.

Abstract

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.

PMID:
18204485
PMCID:
PMC2267275
DOI:
10.1038/sj.bjp.0707667
[Indexed for MEDLINE]
Free PMC Article

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