Pharmacodynamic characteristics and cardioprotective effects of new NHE1 inhibitors

Juno Kim, Yi Sook Jung, Won Sun Han, Mi Young Kim, Wan Namkung, Byung Ho Lee, Kyu Yang Yi, Sung eun Yoo, Min Goo Lee, Kyung Hwan Kim

Research output: Contribution to journalArticle

18 Citations (Scopus)

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, IC50values 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 IC50values were 7 ± 2 nM and 9 ± 3 nM, respectively. The IC50values 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 μM, 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 ≥ 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 IC50 in the target organ is the most critical factor governing the cytoprotective effects of NHE1 inhibitors.

Original languageEnglish
Pages (from-to)131-138
Number of pages8
JournalEuropean Journal of Pharmacology
Volume567
Issue number1-2
DOIs
Publication statusPublished - 2007 Jul 12

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Cardiac Myocytes
Sodium-Hydrogen Antiporter
Epithelial Sodium Channels
Cardiotonic Agents
Submandibular Gland
Guanidine
Inhibitory Concentration 50
Protein Isoforms
(5-(2-methoxy-5-chloro-5-phenyl)furan-2-ylcarbonyl)guanidine
N-(4-cyano-benzo(b)thiophene-2-carbonyl)guanidine
Wounds and Injuries
sabiporide
cariporide
(5-(4-fluorophenyl)furan-2-ylcarbonyl)guanidine

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Kim, Juno ; Jung, Yi Sook ; Han, Won Sun ; Kim, Mi Young ; Namkung, Wan ; Lee, Byung Ho ; Yi, Kyu Yang ; Yoo, Sung eun ; Lee, Min Goo ; Kim, Kyung Hwan. / Pharmacodynamic characteristics and cardioprotective effects of new NHE1 inhibitors. In: European Journal of Pharmacology. 2007 ; Vol. 567, No. 1-2. pp. 131-138.
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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, IC50values 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 IC50values were 7 ± 2 nM and 9 ± 3 nM, respectively. The IC50values 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 μM, 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 ≥ 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 IC50 in the target organ is the most critical factor governing the cytoprotective effects of NHE1 inhibitors.",
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Kim, J, Jung, YS, Han, WS, Kim, MY, Namkung, W, Lee, BH, Yi, KY, Yoo, SE, Lee, MG & Kim, KH 2007, 'Pharmacodynamic characteristics and cardioprotective effects of new NHE1 inhibitors', European Journal of Pharmacology, vol. 567, no. 1-2, pp. 131-138. https://doi.org/10.1016/j.ejphar.2007.03.056

Pharmacodynamic characteristics and cardioprotective effects of new NHE1 inhibitors. / Kim, Juno; Jung, Yi Sook; Han, Won Sun; Kim, Mi Young; Namkung, Wan; Lee, Byung Ho; Yi, Kyu Yang; Yoo, Sung eun; Lee, Min Goo; Kim, Kyung Hwan.

In: European Journal of Pharmacology, Vol. 567, No. 1-2, 12.07.2007, p. 131-138.

Research output: Contribution to journalArticle

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AU - Kim, Juno

AU - Jung, Yi Sook

AU - Han, Won Sun

AU - Kim, Mi Young

AU - Namkung, Wan

AU - Lee, Byung Ho

AU - Yi, Kyu Yang

AU - Yoo, Sung eun

AU - Lee, Min Goo

AU - Kim, Kyung Hwan

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