HOE 694 affords protection versus veratrine contractures in rat atria by Na+ channel blockade

Abstract

We examined the effects of the benzoylguanidine derivative HOE 694, an inhibitor of Na(+)-H+ exchange, against veratrine-induced diastolic contractures and action potentials recorded in rat isolated left atria. Concentration-dependent protective effects against veratrine-contractures, in the absence of negative inotropic responses, were observed with HOE 694 (IC50 = 20.1(7.6-27.0) microM, n = 24) and with the chemically related amiloride derivatives DMA, EIPA, HMA and MIA, but not with amiloride itself. Concomitant Na(+)-H+ exchange blockade by a high concentration of amiloride (100 microM) failed to significantly modify the protective effects of HOE 694. HOE 694 decreased Vmax significantly at 10 microM (166.7 +/- 21 vs 154.7 +/- 20 V/s, P < 0.05, n = 6) without any effect on resting potential or action potential duration. High concentrations (100 microM) of HOE 694 further decreased Vmax and increased action potential duration. The protective effects of HOE 694 were compared with three of the class 1 antiarrhythmic agents, quinidine, lidocaine and flecainide against veratrine contracture. These Na+ channel blockers exerted protective effects in the same range of concentrations as HOE 694. Our findings demonstrate that HOE 694 prevents veratrine contractures at concentrations which presumably affect Na(+)-H+ exchange. However, the mechanism by which HOE 694 affords protection is apparently mediated by class 1-type Na+ channel blockade.

Localization and characterization of phenamil-sensitive Na+influx in isolated rainbow trout gill epithelial cells

“…Amiloride and other amiloride analogues could not be used to block the NHE due to their efficacy at also blocking eNaC family members. HOE-694 (10 µmol l -1 ) is a selective NHE-1 inhibitor without effect on eNaC in mammalian systems (Scholtz et al, 1993;Woll et al, 1993;Le Grand et al, 1996;Loh et al, 1996). We demonstrate that HOE-694 is also effective in inhibiting NHE activity in epithelial cells isolated for trout gills.…”

“…HOE-694 is an Na + /H + exchange (NHE) inhibitor that has been shown to be specific for NHE isoform 1 (NHE-1) in a variety of vertebrate tissues and cells (Scholtz et al, 1993;Woll et al, 1993;Le Grand et al, 1996;Loh et al, 1996;Bleich et al, 1998). Half-maximal inhibition of NHE activity is 10 µmol l -1 and 20 µmol l -1 in fibroblasts (Woll et al, 1993) and isolated rat atria (Le Grand et al, 1996), respectively. The present study represents the first application of HOE-694 in the study of ion transport in branchial epithelium of freshwater fish.…”