Background and purpose: Hydrogen sulphide (H 2 S) is an endogenous gaseous mediator active in the multilevel regulation of pathophysiological functions in mammalian cardiovascular tissues. Experimental approach: This study investigated the pharmacological activity of a new H 2 S-releasing derivative of diclofenac, S-diclofenac (2-[(2,6-dichlorophenyl)amino]benzeneacetic acid 4-(3H-1,2-dithiole-3-thione-5-yl)-phenyl ester) in the isolated rabbit heart submitted to low-flow ischaemia-reperfusion damage. Key results: S-diclofenac (3, 10 and 30 mM), despite inhibiting prostacyclin generation by cardiac tissues, achieved dosedependent normalization of coronary perfusion pressure, reducing left ventricular contracture during ischaemia and improving left ventricular developed pressure and ± dP/dt max at reperfusion. Creatine kinase and lactate dehydrogenase activities in heart perfusates were significantly reduced during reperfusion. These effects were accompanied by substantial release of reduced glutathione (GSH), indicating that the H 2 S moiety may have up-regulated cysteine transport. The anti-ischaemic activities of S-diclofenac and the H 2 S-donor sodium hydro sulphide (NaHS) were partially prevented by the K ATP channel antagonist glibenclamide, suggesting a mechanism similar to H 2 S-induced cardioprotection in metabolic ischaemic preconditioning. Perfusion with the nitric oxide (NO) synthase inhibitor N G -monomethyl-L-arginine worsened the myocardial ischaemiareperfusion damage, but this was dose-dependently prevented by S-diclofenac and NaHS, suggesting that the released H 2 S may have overcome NO deficiency.
Conclusion and implications:These data show that S-diclofenac had marked anti-ischaemic activity in ischaemic-reperfused rabbit hearts despite inhibition of prostaglandin generation. Increased GSH formation leading to activation of K ATP channels may have contributed to this beneficial effect. The pharmacological profile of S-diclofenac and its anti-inflammatory activity, with diminished gastrointestinal side effects, offer therapeutic applications in cardiovascular disease. (2008) Keywords: S-diclofenac; diclofenac; hydrogen sulphide; ischaemia-reperfusion; isolated rabbit heart; cardioprotection Abbreviations: 6-keto-PGF 1a , 6-keto-prostaglandin F 1a ; AUC, area under the curve; CBS, cystathionine b-synthase; CK, creatine kinase; CPP, coronary perfusion pressure; CSE, cystathionine g-lyase; ±dP/dt max , maximum rate of rise and fall of left ventricular pressure; DMSO, dimethylsulphoxide; GSH, reduced glutathione; KHS, Krebs Henseleit solution;
British Journal of Pharmacology-monomethyl-L-arginine; LVP, left ventricular pressure; LVDevP, left ventricular developed pressure; LVEDP, left ventricular end-diastolic pressure; LVSP, left ventricular systolic pressure; NaHS, sodium hydrosulphide; PGI 2 , prostacyclin; S-diclofenac, 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid 4-(3H-1,2-dithiole-3-thione-5-yl)-phenyl ester
