Tomotsugu Konishi

Comparative effects of three calcium antagonists, diltiazem, verapamil and nifedipine, on the sinoatrial and atrioventricular nodes. Experimental and clinical studies.

Diltiazem, verapamil and nifedipine suppress sinoatrial (SA) nodal function in the excised rabbit heart. Clinically, however, their suppressive effect on the SA node is modified considerably by the reflex increase in sympathetic tone as a result of the fall in blood pressure caused by the vasodilating action of the calcium antagonists.Diltiazem, verapamil and nifedipine suppress atrioventricular (AV) nodal conduction and prolong refractory periods in the excised rabbit AV node. Clinically, diltiazem and verapamil exert a similar suppressive effect on the AV node and are useful for treating and preventing AV nodal reentrant tachycardia. Nifedipine, in clinically practical doses, has no antiarrhythmic properties, probably because of reflex activation of the sympathetic system secondary to its hypotensive effect, which is greater than that of the other two calcium antagonists.Diltiazem and verapamil may sometimes worsen AV conduction, especially in patients with conduction disturbances. Nifedipine, on the other hand, can be used as a coronary vasodilator with the least untoward effect on AV conduction.

Effects of pacing-induced ischemia on early left ventricular filling and regional myocardial dynamics and their modification by nifedipine.

The effect of pacing-induced ischemia on early left ventricular filling and regional myocardial lengthening was studied in 11 patients with coronary artery disease (CAD) and six control patients with normal coronary arteriograms. All of the 11 patients with CAD developed typical anginal pain during pacing tachycardia, and in the postpacing beat, the left ventricular end-diastolic pressure (LVEDP) rose from 13 +/- 4 to 26 +/- 4 mm Hg (mean +/- SD, p less than .01), the relaxation time constant increased from 43 +/- 9 to 59 +/- 7 msec (p less than .01), and the ejection fraction diminished from 62.1 +/- 6.7 to 51.6 +/- 10.6% (p less than .01). However, the peak rate of early left ventricular filling (LVPF) obtained from frame-by-frame analysis of left ventriculograms and the LVPF normalized for the stroke volume and for the end-diastolic volume did not change significantly. In the ischemic segment, the peak rate of lengthening (PL) decreased by 45% with ischemia, and the PL normalized for the end-diastolic segment length decreased by 42%. However, the PL normalized for the extent of systolic shortening did not change. In the control segment there was a tendency for these three variables to increase, but the changes were not statistically significant. The time difference from the PL to the LVPF increased significantly in the ischemic segment (31 +/- 28 vs 75 +/- 48 msec, p less than .05). Although the LVEDP rose slightly but significantly from 9 +/- 3 to 12 +/- 5 mm Hg (p less than .05) in the control patients in the postpacing beat, the other global hemodynamic variables and the variables of regional myocardial dynamics did not change. The administration of nifedipine in six patients with CAD resulted in the disappearance or diminution of anginal pain even with the same duration and rate of pacing and was associated with restoration of global systolic function and regional myocardial shortening and lengthening in the ischemic segment. In the control segment, the three variables of segmental lengthening increased with administration of nifedipine. Thus, the segmental myocardial lengthening rate decreased with ischemia due to a decrease in segmental shortening and impairment of myocardial distensibility. The LVPF did not decrease with ischemia despite impairment in isovolumetric relaxation, accentuation of asynchrony in left ventricular filling, and a decrease in the PL in the ischemic segment because of an increase in the PL in the nonischemic segment secondary to an increase in left ventricular filling pressure.(ABSTRACT TRUNCATED AT 400 WORDS)

Electrophysiological effects of amiodarone on isolated rabbit heart muscles.

We studied the electrophysiological effects of amiodarone on isolated rabbit heart muscles by conventional microelectrode techniques. It significantly suppressed not only sinus node functions (basic cycle length, sinus recovery time, and corrected sinus recovery time) but also atrioventricular node functions (AH interval, effective refractory period, and functional refractory period) by both superfusion (10 μg/ml amiodarone in Tyrode solution) and long-term oral administration (50 mg/day for 2 weeks, then 25 mg/day for 4–6 weeks). On the other hand, oral administration significantly lengthened the action potential duration and effective refractory period of the left atrium and the right ventricle, while superfusion did not. The maximum rate of depolarization, action potential amplitude, and diastolic resting potential were not changed by either route of administration. It is thought that the action of amiodarone on the sinus node and on the atrioventricular node is mainly due to its noncompetitive sympathetic inhibition, and that its action on the left atrium and on the right ventricle is mainly due to reduction of serum triiodothyronine, which requires long-term administration of amiodarone.

Effects of verapamil on accessory pathway properties and induction of circus movement tachycardia in patients with the Wolf-Parkinson-White syndrome.

Summary: The electrophysiological effects of 0.2 mg/kg of intravenously administered verapamil (mean plasma level, 51.3 ng/ml) were evaluated using intracardiac recordings and electrical stimulation in 10 patients with the concealed or manifest Wolff-Parkinson-White syndrome. Verapamil produced a minimal effect on both the antegrade and retrograde effective refractory periods of the accessory pathway and the retrograde conduction time over the accessory pathway. but significantly lengthened the intranodal conduction time as well as the effective and functional refractory periods of the atrioventricular (AV) node. Reproducible sustained circus movement tachycardia was initiated in 8 patients before administration of verapamil and in 2 after verapamil. The sustained tachycardia could no longer be initiated in 6 patients because of an increase in AV nodal refractoriness. In 4 patients. atrial echoes were induced at longer premature beat intervals due to a greater AV conduction delay of the atrial impulse. The cycle length of the tachycardia was lengthened in 2 patients, reflecting an increase in the A-H interval after verapamil administration.-In conclusion, these results show that verapamil has no apparent effect on either antegrade or retrograde accessory pathway properties and suggest that verapamil does indeed prevent sustained circus movement tachycardia by increasing the AV nodal refractoriness in some patients with the Wolff-Parkinson-White syndrome.

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 × 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 < 0.01) or D (115 ± 11%, p < 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 × 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 Ds antiarrhythmic efficacy.

Electrophysiological effects of melperone on isolated rabbit heart muscles

1 Electrophysiological effects of melperone on isolated atrial and ventricular muscle preparations of the rabbit were studied by a conventional microelectrode technique. 2 Melperone (3.3 μm) prolonged the action potential duration and effective refractory period of the atrial preparations without affecting the maximum rate of depolarization (). These effects of melperone on action potential duration and effective refractory period were inhibited by a low potassium perfusate (2.7 mm). 3 A high concentration of melperone (16.6 μm) decreased of atrial preparations. In ventricular muscles, melperone at either concentration decreased , although the increase in action potential duration was greater than in the atrium. 4 Depression of of ventricular muscles by melperone was found to be augmented by an increase of stimulation frequency and drug concentration. 5 The rate of onset of rate‐dependent block of in ventricle was increased with drug concentration and frequency of stimulation. However, the time constant of recovery from rate‐dependent block was almost constant. The kinetics of rate‐dependent block of by melperone were approximately similar to those of quinidine and disopyramide. Consequently it is concluded that melperone possesses class la antiarrhythmic activity as well as class 3 activity.

Effects of perhexiline maleate on the refractory periods of isolated atrial muscle and atrioventricular node of the rabbit.

Summary The electrophysiologic effects of perhexiline maleate were studied with glass microelectrodes in three types of isolated rabbit heart preparations: (a) sinoatrial node preparation; (b) left atrial free-wall preparation; and (c) atrioventricular node preparation. The spontaneous firing rate of the sinoatrial node was decreased by 10–15% at a concentration of 10−5 g/ml. The sinus node recovery time after atrial overdrive was prolonged by about 50%. The effective refractory period of the left atrial free wall showed concentration-dependent prolongation at concentrations above 10−7 g/ml. Although this period was shortened after washing with perhexiline-free Tyrode solution, it did not return to the control level. The effective refractory period of the right atrium was prolonged by 15% at a concentration of 10−5 g/ml, but the functional refractory period did not change. The conduction time, effective refractory period, and functional refractory period of the atrioventricular node were significantly increased. Previous reports had claimed that perhexiline had pharmacologic effects on Purkinje fibers and ventricular myocardium at lower concentrations than on the atrium, but we found significant actions on the atrium and the atrioventricular node in therapeutic concentrations.

Effect of Nifedipine on Relaxation and Early Left Ventricular Filling During Postpacing Ischemic Period

Nifedipine has been shown to improve left ventricular performance during ischemia (Emanuelsson and Holmberg 1983; Lorell et al. 1981; Nelson et al. 1984; Tiefenbrunn et al. 1983). Although it has been reported that nifedipine can improve diastolic properties of hypertrophic cardiomyopathy (Lorell et al. 1982), whether it can modify relaxation and ventricular filling abnormalities during ischemia is not yet know. Since left ventricular relaxation and filling are important functions for ventricular ejection, which comes next in the cardiac cycle, we studied the effects of nifedipine on relaxation and early ventricular filling in patients with coronary artery disease during postpacing ischemic periods.