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

• Published in: European journal of pharmacology 2003-01, Vol.459 (2), p.151-158
• Main Authors: Touret, Nicolas, Tanneur, Valérie, Godart, Hélène, Seidler, Randolph, Taki, Naoyuki, Bürger, Erich, Dämmgen, Jürgen, Counillon, Laurent
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cardioprotective effect; Cardiotonic Agents - chemistry; Cardiotonic Agents - pharmacokinetics; Cardiotonic Agents - therapeutic use; Cardiovascular system; Cell Line; Cricetinae; Dose-Response Relationship, Drug; Female; Guanidines - chemistry; Guanidines - pharmacokinetics; Guanidines - therapeutic use; Humans; Male; Medical sciences; Miscellaneous; Myocytes, Cardiac - metabolism; Pharmacology. Drug treatments; Protein Isoforms - antagonists & inhibitors; Protein Isoforms - metabolism; Rabbits; Rats; Rats, Wistar; Reperfusion Injury - drug therapy; Reperfusion Injury - metabolism; Sabiporide; Slow dissociation kinetics; Sodium-Hydrogen Exchangers - antagonists & inhibitors; Sodium-Hydrogen Exchangers - metabolism
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(02)02824-8

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.