Characterization of sabiporide, a new specific NHE-1 inhibitor exhibiting slow dissociation kinetics and cardioprotective effects

Abstract

Sabiporide, a new benzoguanidine, was characterized on fibroblasts stably expressing the Na +/H + exchanger isoforms NHE-1, NHE-2 and NHE-3. 22Na + uptake experiments show that this compound possesses a K i of 5±1.2×10 −8 M for NHE-1, and discriminates efficiently between the NHE-1, -2 and -3 isoforms ( K i for NHE-2: 3±0.9×10 −6 M, and K i>1 mM for NHE-3). Similar K i values are obtained on rat cardiomyocytes and human platelets expressing NHE-1 ( K i's of 7±1×10 −9 and 2.7±0.4×10 −8 M respectively). Interestingly, when compared with amiloride and cariporide, sabiporide inhibition persists even after this molecule had been rinsed out (half time of 7 h for sabiporide, and of 1 and 2.5 min for amiloride and cariporide, respectively), the decay of all these molecules exhibiting a complex multiexponential behavior. Thus, sabiporide, which possesses remarkable cardioprotective properties, is a specific NHE-1 inhibitor possessing unique binding kinetics.