title: 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 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.
authors.affiliation: Laboratoire de Physiologie Cellulaire et Moléculaire, CNRS UMR6548, Université de Nice-Sophia Antipolis, Faculté des Sciences, Parc Valrose, 06108 cedex 2, Nice, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Touret
authors.forename: Valérie
authors.initials: V
authors.lastname: Tanneur
authors.forename: Hélène
authors.initials: H
authors.lastname: Godart
authors.forename: Randolph
authors.initials: R
authors.lastname: Seidler
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Taki
authors.forename: Erich
authors.initials: E
authors.lastname: Bürger
authors.forename: Jürgen
authors.initials: J
authors.lastname: Dämmgen
authors.forename: Laurent
authors.initials: L
authors.lastname: Counillon
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002460:Cell Line; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005260:Female; D006146:Guanidines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D002316:Cardiotonic Agents; D006146:Guanidines; D020033:Protein Isoforms; D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1; C476560:sabiporide