Relative electrophysiological potencies of quinidine, 3-OH quinidine and quinidine-N-oxide in guinea-pig heart.
The relative potencies of the quinidine metabolites, 3-OH quinidine (3OHQ) and quinidine-N-oxide (QNO), to their parent drug, quinidine, were obtained electrophysiologically using guinea-pig hearts. The items examined were QT interval of local extracellular electrogram in a Langendorff's perfused heart, effective refractory period (ERP) and action potential duration at 90% repolarization (APD90) in the right papillary muscle. Quinidine (0.125-1 mg/l) and 3OHQ (0.5-4 mg/l) prolonged QT interval in a concentration-dependent manner and the relative potency of 3OHQ to quinidine was 0.25. The effect of QNO on QT interval within the range of concentration used (up to 8 mg/l) was small and the relative potency was 0.04 at the most. An apparent additive effect of 3OHQ to that of quinidine was revealed, but QNO of 4 mg/l has no effect on the concentration-effect relationship of quinidine for prolonging QT interval. These results were quite similar to those in humans reported previously. Quinidine (0.5-4 mg/l), 3OHQ (1-8 mg/l) and QNO (2-8 mg/l) prolonged APD90 in a concentration-dependent manner. These effects were accompanied by the prolongation of ERP in similar degrees. The relative potencies of 3OHQ to Q were 0.22 for APD90 and 0.27 for ERP and those of QNO were 0.087 for APD90 and 0.084 for ERP. Quinidine (10(-5) M) depressed the maximum upstroke of action potential (Vmax) in a frequency-dependent manner. 3OHQ of the same concentration also depressed it in the same manner to a much lesser extent and QNO had no effect. In conclusion, relative potencies of quinidine metabolites to quinidine for prolonging QT interval of local extracellular electrogram represent those to prolong APD90 and ERP, suggesting the relative potencies for antiarrhythmic activity in the same order. In the physiological range of concentrations of metabolites, 3OHQ may contribute to the antiarrhythmic effect of quinidine in an additive way, but QNO may have little effect when we take into account the fact that the free fraction of 3OHQ is 2.5 times that of quinidine.
Uematsu
T
T
Department of Pharmacology, Hamamatsu University School of Medicine, Japan.
Sato
R
R
Vozeh
S
S
Follath
F
F
Nakashima
M
M
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004562:Electrocardiography; D004594:Electrophysiology; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D010210:Papillary Muscles / Q000187:drug effects; D011802:Quinidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D012032:Refractory Period, Electrophysiological / Q000187:drug effects
D003497:Cyclic N-Oxides; C013569:3-hydroxyquinidine; C045112:quinidine-N-oxide; D011802:Quinidine