S0859, an N-cyanosulphonamide Inhibitor of Sodium-bicarbonate Cotransport in the Heart

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2008 Jan 22

PMID 18204485

Citations 62

Authors

F F-T Chen

F C Villafuerte

P Swietach

P M Cobden

R D Vaughan-Jones

Affiliations

Soon will be listed here.

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.

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References

Choi I, Romero M, Khandoudi N, Bril A, Boron W . Cloning and characterization of a human electrogenic Na+-HCO-3 cotransporter isoform (hhNBC). Am J Physiol. 1999; 276(3):C576-84. DOI: 10.1152/ajpcell.1999.276.3.C576. View

Masereel B, Pochet L, Laeckmann D . An overview of inhibitors of Na(+)/H(+) exchanger. Eur J Med Chem. 2003; 38(6):547-54. DOI: 10.1016/s0223-5234(03)00100-4. View

Aiello E, Petroff M, Mattiazzi A, Cingolani H . Evidence for an electrogenic Na+-HCO3- symport in rat cardiac myocytes. J Physiol. 1998; 512 ( Pt 1):137-48. PMC: 2231183. DOI: 10.1111/j.1469-7793.1998.137bf.x. View

Clements-Jewery H, Sutherland F, Allen M, Tracey W, Avkiran M . Cardioprotective efficacy of zoniporide, a potent and selective inhibitor of Na+/H+ exchanger isoform 1, in an experimental model of cardiopulmonary bypass. Br J Pharmacol. 2004; 142(1):57-66. PMC: 1574931. DOI: 10.1038/sj.bjp.0705749. View

Alvarez B, Loiselle F, Supuran C, Schwartz G, Casey J . Direct extracellular interaction between carbonic anhydrase IV and the human NBC1 sodium/bicarbonate co-transporter. Biochemistry. 2003; 42(42):12321-9. DOI: 10.1021/bi0353124. View

Avkiran M, Marber M . Na(+)/H(+) exchange inhibitors for cardioprotective therapy: progress, problems and prospects. J Am Coll Cardiol. 2002; 39(5):747-53. DOI: 10.1016/s0735-1097(02)01693-5. View

Supuran C, Scozzafava A, Casini A . Carbonic anhydrase inhibitors. Med Res Rev. 2002; 23(2):146-89. DOI: 10.1002/med.10025. View

Schwab A, Rossmann H, Klein M, Dieterich P, Gassner B, Neff C . Functional role of Na+-HCO3- cotransport in migration of transformed renal epithelial cells. J Physiol. 2005; 568(Pt 2):445-58. PMC: 1474735. DOI: 10.1113/jphysiol.2005.092957. View

Choi I, Aalkjaer C, Boulpaep E, Boron W . An electroneutral sodium/bicarbonate cotransporter NBCn1 and associated sodium channel. Nature. 2000; 405(6786):571-5. DOI: 10.1038/35014615. View

10.

Lagadic-Gossmann D, Buckler K, Vaughan-Jones R . Role of bicarbonate in pH recovery from intracellular acidosis in the guinea-pig ventricular myocyte. J Physiol. 1992; 458:361-84. PMC: 1175160. DOI: 10.1113/jphysiol.1992.sp019422. View

11.

Blanchard E, Solaro R . Inhibition of the activation and troponin calcium binding of dog cardiac myofibrils by acidic pH. Circ Res. 1984; 55(3):382-91. DOI: 10.1161/01.res.55.3.382. View

12.

Leem C, Vaughan-Jones R . Sarcolemmal mechanisms for pHi recovery from alkalosis in the guinea-pig ventricular myocyte. J Physiol. 1998; 509 ( Pt 2):487-96. PMC: 2230980. DOI: 10.1111/j.1469-7793.1998.487bn.x. View

13.

Lazdunski M, Frelin C, VIGNE P . The sodium/hydrogen exchange system in cardiac cells: its biochemical and pharmacological properties and its role in regulating internal concentrations of sodium and internal pH. J Mol Cell Cardiol. 1985; 17(11):1029-42. DOI: 10.1016/s0022-2828(85)80119-x. View

14.

Schafer C, Ladilov Y, Siegmund B, Piper H . Importance of bicarbonate transport for protection of cardiomyocytes against reoxygenation injury. Am J Physiol Heart Circ Physiol. 2000; 278(5):H1457-63. DOI: 10.1152/ajpheart.2000.278.5.H1457. View

15.

POOLE R, Halestrap A, Price S, Levi A . The kinetics of transport of lactate and pyruvate into isolated cardiac myocytes from guinea pig. Kinetic evidence for the presence of a carrier distinct from that in erythrocytes and hepatocytes. Biochem J. 1989; 264(2):409-18. PMC: 1133596. DOI: 10.1042/bj2640409. View

16.

Orchard C, Cingolani H . Acidosis and arrhythmias in cardiac muscle. Cardiovasc Res. 1994; 28(9):1312-9. DOI: 10.1093/cvr/28.9.1312. View

17.

Xiao X, Allen D . Role of Na(+)/H(+) exchanger during ischemia and preconditioning in the isolated rat heart. Circ Res. 1999; 85(8):723-30. DOI: 10.1161/01.res.85.8.723. View

18.

Cingolani H, Ennis I . Sodium-hydrogen exchanger, cardiac overload, and myocardial hypertrophy. Circulation. 2007; 115(9):1090-100. DOI: 10.1161/CIRCULATIONAHA.106.626929. View

19.

Damkier H, Nielsen S, Praetorius J . An anti-NH2-terminal antibody localizes NBCn1 to heart endothelia and skeletal and vascular smooth muscle cells. Am J Physiol Heart Circ Physiol. 2005; 290(1):H172-80. DOI: 10.1152/ajpheart.00713.2005. View

20.

Sun B, Leem C, Vaughan-Jones R . Novel chloride-dependent acid loader in the guinea-pig ventricular myocyte: part of a dual acid-loading mechanism. J Physiol. 1996; 495 ( Pt 1):65-82. PMC: 1160725. DOI: 10.1113/jphysiol.1996.sp021574. View