Effects of 5-(N,N-hexamethylene)amiloride on action potentials, intracellular Na, and pH of guinea pig ventricular muscle in vitro.
We examined the effects of 5-(N,N-hexamethylene)amiloride (one of the Na(+)-H+ exchange blockers, HMA) and amiloride (AM) on action potentials (APs), intracellular Na+ activity, and pH using conventional and double-barreled ion-selective microelectrodes in guinea pig papillary muscle in vitro. Papillary muscle preparations were superfused with HEPES-buffered solution, and intracellular Na+ (aiNa+) and H+ (intracellular pH, pHi) activities were measured in quiescent preparations without stimulation. HMA at a concentration of 1 microM began to induce prolongation of action potential duration (APD) and at concentrations > 10 microM induced a decrease in action potential amplitude (APA), depolarization of resting membrane potential (RMP), prolongation of APD and depression of the maximum upstroke velocity (Vmax). HMA exerted dose-, time-, and rate-dependent reduction in Vmax. AM began to prolong APD at a concentration of 10 microM and at 1 mM induced depolarization of RMP, decreased Vmax and induced significant prolongation of APD. HMA (100 microM) induced a decrease in aiNa+ by 2-3 mM, but exerted no effects on pHi in normal Tyrode's solution. Under conditions of intracellular acidosis induced by exposure to K(+)-free solution, HMA produced a further decrease in pHi. Our results provide direct evidence that HMA has a depressant action on cardiac Na+ channels and prolongs AP at concentrations that presumably affect Na(+)-H+ exchange in cardiac muscle.
Lai
Z F
ZF
Department of Pharmacology, Kumamoto University School of Medicine, Japan.
Hotokebuchi
N
N
Cragoe
E J
EJ
Nishi
K
K
D000138:Acidosis / Q000139:chemically induced / Q000503:physiopathology; D000200:Action Potentials / Q000187:drug effects; D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology; D000643:Ammonium Chloride / Q000494:pharmacology; D000818:Animals; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D017736:Ion-Selective Electrodes; D007700:Kinetics; D008297:Male; D008839:Microelectrodes; D009206:Myocardium / Q000378:metabolism*; D010210:Papillary Muscles / Q000187:drug effects; D012964:Sodium / Q000378:metabolism*
D000643:Ammonium Chloride; C057360:5-(N,N-hexamethylene)amiloride; D000584:Amiloride; D012964:Sodium