Cardiac effects of quinidine on guinea‐pig isolated perfused hearts after in vivo quinidine pretreatment

Abstract

1 Experimental and clinical studies suggest that class I and class III antiarrhythmic drugs may be subject to pharmacological tolerance during long term treatment, leading to loss of therapeutic e ectiveness. 2 The aim of this study was to ascertain whether prolonged in vivo treatment with the Class Ia agent quinidine can modify cardiac (electrical and mechanical) responses to the drug. 3 A group of guinea-pigs (n=7) were treated intraperitoneally (q.d.) for 6 days with 75 mg kg 71 quinidine sulphate. Preliminary pharmacokinetic experiments indicated that this dose could attain plasma concentrations similar to those that are therapeutic in man (2 ± 5 mg l 71 ). A control group (n=7) received a saline solution for the same period. 4 Twenty-four hours after the last administration hearts were removed and retrogradely perfused at constant¯ow (stimulation frequency: 2.5 Hz). The following parameters were measured: maximal derivative of intraventricular pressure (dP/dt max ); coronary perfusion pressure (Cp); PR, QRS and JT intervals, on surface ECG. The e ects of quinidine on these parameters were measured at di erent concentrations (2, 4, 8, 12, 16, 20 mM) and compared in the two experimental groups. 5 In the control group quinidine decreased in a dose-dependent manner dP/dt and increased PR and QRS intervals. JT interval was increased at the lowest concentrations and decreased at the highest (biphasic e ect). Cp did not change signi®cantly. 6 In the pretreated group quinidine qualitatively produced the same e ects on dP/dt and ECG intervals as in control group. Also the magnitude of these e ects was not signi®cantly di erent between the two groups. In contrast with ®ndings in control experiments, Cp was signi®cantly decreased by increasing quinidine concentration. Mean baseline Cp was higher in pretreated than in the control group (though not signi®cantly, P=0.072) and quinidine addition abolished this di erence. Thus, it is suggested that quinidine withdrawal induced a rebound increase in coronary tone, due to the unmasking of vasoconstrictor homeostatic mechanisms elicited by the in vivo vasodilating e ect of the drug. 7 In conclusion, our data do not support the possibility that tolerance ensues during long term quinidine treatment, at least as far as electrophysiological and contractility e ects are concerned. Further experimental work is needed to explain the appearance of a coronary vasodilating e ect in pretreated hearts.

Acute isoproterenol leads to age-dependent arrhythmogenesis in guinea pigs

“…In the present study, administration of flecainide lowered the number of PVCs induced by exposure to ISO in both adult and young guinea pigs (Fig. 3) (21,67,73). In contrast, quinidine (a class I antiarrhythmic that blocks Na ϩ channels but not RyR2 channels) did not lower the number of PVCs in ISO-treated guinea pigs.…”

Risk Factors for Recurrence of Atrial Fibrillation in Horses After Cardioversion to Sinus Rhythm

“…QS plasma levels at the time of echocardiography were available in only 6 horses, in which low concentrations were found. The negative inotropic properties of QS have been documented in vivo in several species and are dose‐dependent . The potential influence of occurrence and severity of adverse quinidine effects was not considered within the scope of this study.…”