Zoniporide: a potent and highly selective inhibitor of human Na+/H+ exchanger-1

Cardioprotective efficacy of zoniporide, a potent and selective inhibitor of Na+/H+ exchanger isoform 1, in an experimental model of cardiopulmonary bypass

“…The IC 50 value that we obtained (67 nM) is very similar to the IC 50 value reported previously in human platelets (59 nM), using an identical assay (Marala et al, 2002). This observation suggests that zoniporide does indeed inhibit NHE1 activity with similar potency in rats and humans.…”

“…Comparison of the IC 50 values obtained in the present study and in our previous work with cariporide (Hoshino & Avkiran, 2001) under similar assay conditions reveals that zoniporide (IC 50 73 nM at 251C) is more potent than cariporide (IC 50 130 nM at 251C) as an inhibitor of native sarcolemmal NHE activity in rat ventricular myocytes. Notably, the IC 50 value for zoniporide that we have obtained in the present study is markedly greater than the IC 50 value of 14 nM previously reported for the inhibition of human NHE1, expressed exogenously in transfected hamster fibroblasts (Marala et al, 2002). This difference is likely to have arisen from differences in assay conditions, in particular the extracellular Na þ concentration, rather than a species difference in the affinity of zoniporide for NHE1.…”

“…This difference is likely to have arisen from differences in assay conditions, in particular the extracellular Na þ concentration, rather than a species difference in the affinity of zoniporide for NHE1. In this context, it is worth noting that (1) the rate of 22 Na þ uptake, the index of NHE activity in the fibroblast assay, is commonly measured in the presence of a trace amount of extracellular Na þ (Marala et al, 2002), and (2) extracellular Na þ is known to antagonize competitively the binding of benzoylguanidine inhibitors, such as HOE-694, cariporide and eniporide, to NHE1 (Baumgarth et al, 1998). Indeed, in guinea pig ventricular myocytes, the IC 50 for HOE-694 has been estimated to be approximately 16-fold greater in the presence of an extracellular Na þ concentration of 150 mM, relative to the value obtained in the virtual absence of extracellular Na þ (Loh et al, 1996).…”

“…Zoniporide is a newer pyrazolylguanidine NHE inhibitor; relative to cariporide, it possesses (1) greater potency in inhibiting human NHE1, when expressed exogenously in transfected hamster fibroblasts; and (2) greater selectivity for NHE1 over the NHE2 and NHE3 isoforms (Marala et al, 2002). However, while the potency of cariporide as an inhibitor of the native sarcolemmal NHE that is expressed in myocardial cells has been established under both normothermic and hypothermic conditions (Hoshino & Avkiran, 2001), comparable information is not available for zoniporide.…”

Effect of NSAIDs on Na+/H+ exchanger activity in rat colonic crypts

“…Activity of the Na ϩ /H ϩ exchangers NHE-1, NHE-2, NHE-3, and NHE-4 in crypt cells of the distal colon of Sprague-Dawley rats was evaluated in response to NSAID exposure, with a focus on apical NHE isoforms 2 and 3, which are involved in pH maintenance of the colonic lumen (58). Through inhibition of NHE 1-4 using high-dose amiloride (39), preferential inhibition of NHE-3 using 2.4 M EIPA (39), selective inhibition of NHE-1 using 60 nM zoniporide dihydrochloride (38), and inhibition of both NHE-1 and NHE-2 using 12 M zoniporide dihydrochloride (38), we were able to characterize average NHE activity in crypt cells following treatment with indomethacin. We were also able to investigate a possible increase in hydrogen ion extrusion in colonic crypts following exposure to high-dose aspirin.…”