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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