Combined effect of disopyramide and bethanechol: use of bethanechol to prevent anticholinergic side effects of disopyramide without reduction of antiarrhythmic efficacy.

Because bethanechol chloride (B) relieves the anticholinergic side effects of disopyramide (D), we examined the combined effects of D and B on the heart and urinary bladder. B was confirmed to counteract dose dependently the effect of D on the dog bladder. In the ventricular muscle, the combined electrophysiological effects (D + B) were additive, with no reduction in the effect of D. With the control value set as 100%, the decrease in the maximum rate of depolarization with 5 X 10(-6) g/ml D (90 +/- 6%) was not affected by the same dose of B (D + B: 84 +/- 14%). Moreover, the effective refractory period (ERP) was larger with D + B (128 +/- 12%) than with either B (109 +/- 9%, p less than 0.01) or D (115 +/- 11%, p less than 0.05). In contrast, in the atrial muscle and AV and SA nodes, B had marked acetylcholine-like effects. These were completely suppressed by the addition of D except for the atrial ERP with the highest tested concentration of B (5 X 10(-6) g/ml). In the latter case, the prolongation of ERP was minimal (B + D: 105 +/- 14%) as compared with D alone (130 +/- 15%). Since the plasma concentration of B after oral administration of a clinical dose is expected to be on the order of 10(-7) g/ml, no practical effect is anticipated. We conclude that B can be expected to counteract urination disorders caused by D without reducing D's antiarrhythmic efficacy.

Evaluation of the vasodilator vs inotropic effect of milrinone using an animal model of left ventricular failure: reversal of disopyramide depression of the myocardium with milrinone.

Milrinone (M) has been shown to improve left ventricular (LV) performance in animal and human studies. M has strong vasodilator action, and whether increased LV performance is due primarily to vasodilation or to a direct positive inotropic effect is unclear. Ten mongrel dogs were studied. Disopyramide caused a significant and sustained decrease in LV function and was a good model for myocardial depression. At equal reduction in systemic vascular resistance (SVR), M reversed this LV depression to a significantly greater degree than nitroprusside (NP) did. At equal levels of vasodilation, M produced significantly greater improvement in indices of LV function than NP did in our model of disopyramide-induced LV failure. This suggest that its effect on LV function is not due entirely to afterload reduction, or to reflex sympathetic stimulation, but has a substantial component of direct inotropic stimulation. This study also demonstrated a reversal of disopyramide-induced LV dysfunction by M, which may be clinically useful since, as in many antiarrhythmics, myocardial depression may be a limiting factor in its use.

Disopyramide-pyridostigmine interaction: selective reversal of anticholinergic symptoms with preservation of antiarrhythmic effect.

This double-blind, randomized, placebo crossover study was used to evaluate the effects of a cholinesterase inhibitor--slow-release pyridostigmine (180 mg orally every 12 hours)--on the anticholinergic and antiarrhythmic properties of disopyramide. Quantitative side effects questionnaire scores were used to guide disopyramide administration in 20 men with ventricular tachycardia. Disopyramide was given to each patient both with placebo and with active pyridostigmine. The maximal administered dose for each regimen was used in conjunction with corresponding questionnaire scores to calculate an index or estimate of the maximal tolerable dose of disopyramide. Additional evaluations performed at baseline and at each maximal administered dose regimen included tear and saliva quantitation, 24 hour electrocardiogram (ECG), exercise testing and programmed ventricular stimulation. Results showed that the maximal administered dose of disopyramide was greater with active pyridostigmine than with placebo: 295 +/- 75 versus 245 +/- 100 mg every 6 hours (p less than 0.05). The calculated maximal tolerable dose was substantially greater in the presence of pyridostigmine: 355 +/- 90 versus 260 +/- 115 mg every 6 hours (p less than 0.001). Maximal side effects questionnaire scores also reflected decreased anticholinergic activity in the presence of pyridostigmine compared with placebo: 101.9 +/- 2.2 versus 104.6 +/- 2.8, respectively (p less than 0.005). Baseline tear and saliva production was significantly reduced during disopyramide therapy, but was restored toward normal by the addition of pyridostigmine.(ABSTRACT TRUNCATED AT 250 WORDS)

Supresión del efecto inotrópico negativo de la disopiramida por el prazosín / Suppression of the negative inotropic effect of disopyramide by prasozine

A catorce perros, divididos en 2 grupos, se les realizó una oclusión coronaria experimental. A un grupo se le administró disopiramida por vía intravenosa en el minuto 11 después de la oclusión total, mientras que al otro grupo se le realizó la operación anterior y se le administró prazosín por vía intravenosa en el minuto 21 después de la oclusión total. La disopiramida prolongó los intervalos electrocardiográficos RR, PR, QRS y QTc. Hubo un aumento máximo de la presión arterial media a los 20 minutos de la oclusión total y la dP/dt del ventrículo izquierdo disminuyó significativamente a los 15 y 20 minutos de la misma. En presencia de prazosín hubo una reducción de la presión arterial media y un incremento de la dP/dt del ventrículo izquierdo hasta valores que no difieren del control

Supresión del efecto inotrópico negativo de la disopiramida por el prazosín / Suppression of the negative inotropic effect of disopyramide by prasozine

A catorce perros, divididos en 2 grupos, se les realizó una oclusión coronaria experimental. A un grupo se le administró disopiramida por vía intravenosa en el minuto 11 después de la oclusión total, mientras que al otro grupo se le realizó la operación anterior y se le administró prazosín por vía intravenosa en el minuto 21 después de la oclusión total. La disopiramida prolongó los intervalos electrocardiográficos RR, PR, QRS y QTc. Hubo un aumento máximo de la presión arterial media a los 20 minutos de la oclusión total y la dP/dt del ventrículo izquierdo disminuyó significativamente a los 15 y 20 minutos de la misma. En presencia de prazosín hubo una reducción de la presión arterial media y un incremento de la dP/dt del ventrículo izquierdo hasta valores que no difieren del control

Effects of disopyramide on the isolated rabbit aorta and pulmonary artery.

1. Disopyramide (8 X 10(-5)-4 X 10(-4) M) contracted the rabbit aortic strips and this could be prevented by verapamil or by omitting Ca2+ from Krebs solution. 2. Disopyramide (1.5-6 X 10(-5) M) significantly potentiated the contractile response of the rabbit aortic strips to noradrenaline, clonidine and methoxamine but not that of potassium chloride. 3. Disopyramide (2-6 X 10(-5) M) attenuated the contractile response of the rabbit pulmonary artery to transmural electrical stimulation but potentiated response to noradrenaline. Similar results were observed with the portal vein. 4. The relaxant effect of acetylcholine, on the rabbit aortic ring precontracted with noradrenaline, was blocked by disopyramide while the relaxant effect of adenosine-5'-triphosphate (ATP) was not blocked.