title: Pharmacodynamic characteristics and cardioprotective effects of new NHE1 inhibitors.
abstract: Inhibitors of Na(+)/H(+) exchanger (NHE) 1 have been shown to exert protective effects on various myocardial injuries. In this study, we characterized the pharmacodynamic properties of new guanidine NHE1 inhibitors (cariporide, sabiporide, KR-32511, KR-32570, and KR-33028) to analyze their myocardial protective effects. Although NHE1 is the major NHE isoform in cardiomyocytes, IC(50)values of these chemicals tested in rat cardiomyocytes were significantly different from those in PS120/hNHE1 cells where human NHE1 is heterologously expressed. In rat cardiomyocytes, KR-32570 and KR-33028 exhibited the highest potencies and their IC(50)values were 7+/-2 nM and 9+/-3 nM, respectively. The IC(50)values of all the chemicals tested on rat submandibular gland NHE2 were in the micromolar range, and they showed no inhibitory effects on hNHE3 and epithelial Na(+) channels up to 30 microM, suggesting a high selectivity toward NHE1. Sabiporide and KR-32570 exhibited slow dissociation kinetics with NHE1 inhibition persisting even after rinsing-out. When the cytoprotective effects of chemicals against hypoxic damage of rat cardiomyocytes were examined, the order of potency was KR-32570>or=KR-33028>sabiporide>cariporide>KR-32511. This order was exactly the same as that for the NHE1 inhibition in rat cardiomyocytes and did not correlate with any other properties, including the slow dissociation kinetics. Taken together, these results suggest that KR-32570 and KR-33028 are potent candidates for cardioprotective agents, and that the IC(50) in the target organ is the most critical factor governing the cytoprotective effects of NHE1 inhibitors.
authors.affiliation: Department of Pharmacology, Yonsei University College of Medicine, Sinchon-Dong, Seoul 120-752, Republic of Korea.
authors.forename: Juno
authors.initials: J
authors.lastname: Kim
authors.forename: Yi-Sook
authors.initials: YS
authors.lastname: Jung
authors.forename: Wonsun
authors.initials: W
authors.lastname: Han
authors.forename: Mi-Young
authors.initials: MY
authors.lastname: Kim
authors.forename: Wan
authors.initials: W
authors.lastname: Namkung
authors.forename: Byung Ho
authors.initials: BH
authors.lastname: Lee
authors.forename: Kyu Yang
authors.initials: KY
authors.lastname: Yi
authors.forename: Sung-eun
authors.initials: SE
authors.lastname: Yoo
authors.forename: Min Goo
authors.initials: MG
authors.lastname: Lee
authors.forename: Kyung Hwan
authors.initials: KH
authors.lastname: Kim
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002316:Cardiotonic Agents / Q000494:pharmacology*; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005663:Furans / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D032383:Myocytes, Cardiac / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013363:Submandibular Gland / Q000166:cytology; D013450:Sulfones / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology
chemical_list: C521402:(5-(4-fluorophenyl)furan-2-ylcarbonyl)guanidine; D002316:Cardiotonic Agents; D005663:Furans; D006146:Guanidines; C507425:N-(4-cyano-benzo(b)thiophene-2-carbonyl)guanidine; C452850:Slc9a1 protein, rat; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; D013876:Thiophenes; C502305:(5-(2-methoxy-5-chloro-5-phenyl)furan-2-ylcarbonyl)guanidine; C093373:cariporide; C476560:sabiporide