31 248

Cited 16 times in

Pharmacodynamic characteristics and cardioprotective effects of new NHE1 inhibitors.

Authors
Kim, J; Jung, YS; Han, W; Kim, MY; Namkung, W; Lee, BH; Yi, KY; Yoo, SE; Lee, MG; Kim, KH
Citation
European journal of pharmacology, 567(1-2):131-138, 2007
Journal Title
European journal of pharmacology
ISSN
0014-29991879-0712
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.
MeSH terms
AnimalsAnimals, NewbornCardiotonic Agents/pharmacology*Cell HypoxiaCell Survival/drug effectsCells, CulturedFurans/pharmacologyGuanidines/pharmacology*HumansKineticsMyocytes, Cardiac/drug effectsRatsRats, Sprague-DawleySodium-Hydrogen Antiporter/antagonists & inhibitors*Structure-Activity RelationshipSubmandibular Gland/cytologySulfones/pharmacologyThiophenes/pharmacology
DOI
10.1016/j.ejphar.2007.03.056
PMID
17482160
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Physiology
AJOU Authors
정이숙
Full Text Link
Export
RIS (EndNote)
XLS (Excel)
XML

qrcode

해당 아이템을 이메일로 공유하기 원하시면 인증을 거치시기 바랍니다.

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse