HOE 694 affords protection versus veratrine contractures in rat atria by Na+ channel blockade.
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.
Le Grand
B
B
Centre de Recherche Pierre Fabre, Division of Cardiovascular Diseases, Castres, France.
Marty
A
A
Talmant
J M
JM
John
G W
GW
D000200:Action Potentials / Q000187:drug effects; D000465:Algorithms; D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D004232:Diuretics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000494:pharmacology*; D006325:Heart Atria / Q000187:drug effects* / Q000378:metabolism; D007928:Lethal Dose 50; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D015222:Sodium Channels / Q000187:drug effects*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000494:pharmacology*; D014702:Veratrine / Q000633:toxicity*
D004232:Diuretics; D006146:Guanidines; D015222:Sodium Channels; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C074107:3-methylsulfonyl-4-piperidinobenzoyl guanidine; D000584:Amiloride; D014702:Veratrine