Jürgen Dr. Dämmgen

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

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 x 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 x 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 x 10(-9) and 2.7+/-0.4 x 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.