Rinya Kato

Electrophysiologic effects of the levo- and dextrorotatory isomers of sotalol in isolated cardiac muscle and their in vivo pharmacokinetics

Dl-sotalol is a specific beta-adrenergic blocking agent that markedly lengthens cardiac action potential duration. To determine whether d-sotalol, with little or no beta-blocking effect, also lengthens repolarization, standard microelectrode studies were used to determine the electrophysiologic properties of dl-sotalol and its stereoisomers in isolated rabbit and canine myocardial fibers. D- and l-sotalol produced concentration-dependent increases in action potential duration to 50% (APD50) and 90% (APD90) repolarization, respectively, and in the effective refractory period without changes in the maximal rate of rise of action potential. In rabbit sinoatrial node, d- and l-sotalol produced concentration-dependent increases in spontaneous sinus cycle length (29 and 35%, respectively) by lengthening the action potential duration (by 58 and 55%) without effect on phase 4 depolarization. At the highest concentration (27.2 micrograms/ml), d- and l-sotalol prolonged APD90 (by 38 and 54%, respectively, in Purkinje fibers and by 32 and 34% in ventricular muscle) and effective refractory period (by 49 and 49% in Purkinje fibers and 29 and 40% in ventricular muscle). The effects of the two isomers were not significantly different. At the middle concentration (2.7 micrograms/ml), d-sotalol, unlike l-sotalol, had no beta-adrenergic blocking effect, but the electrophysiologic effects of dl-, d- and l-sotalol were indistinguishable. The data indicate that d-sotalol is equipotent with l-sotalol in lengthening the action potential duration and effective refractory period in cardiac muscle, an action unrelated to adrenergic antagonism or pharmacokinetic differences between the stereoisomers.

Electropharmacology of amiodarone: Absence of relationship to serum, myocardial, and cardiac sarcolemmal membrane drug concentrations

Plasma concentrations are often of major consideration in the evaluation of therapeutic efficacy of cardiovascular drugs. This approach is based on the assumptions that the concentration of the drug in the cardiac muscle is in equilibrium with the plasma drug level and that pharmacologic efficacy is proportional to the myocardial drug concentration. The more pronounced pharmacologic efficacy of amiodarone following chronic administration, despite low plasma drug concentrations, and the lesser effects of the drug after acute intravenous administration, when drug levels are maximum, has not been explained on the basis of the pharmacokinetic behavior of the drug. Data obtained from the transmembrane action potential recordings from rabbit ventricular myocardium were therefore correlated with drug concentrations in the serum, myocardium, and myocardial sarcolemma following acute intravenous administration and after 4 weeks of oral administration of 20 mg/kg/day of amiodarone. Following 15 minutes of acute drug administration, when amiodarone concentrations were maximal in the serum (4.72 +/- 1.23 micrograms/ml), cardiac muscle (34.5 +/- 7.6 micrograms/gm), and sarcolemma (1.94 mg/gm protein), the electrophysiologic changes were insignificant. However, following chronic treatment, when levels of amiodarone were low in the serum (0.05 +/- 0.01 micrograms/ml amiodarone, 0.25 +/- 0.08 micrograms/ml desethylamiodarone), cardiac muscle (1.91 +/- 0.9 micrograms/gm amiodarone, 1.35 +/- 1.33 micrograms/gm desethylamiodarone), and myocardial membranes (0.043 mg/gm protein [amiodarone], 0.097 mg/gm protein [desethylamiodarone], there was a 54.3% increase in action potential duration at 90% repolarization (p less than 0.01) and 65% increase in the effective refractory period (p less than 0.01) of rabbit ventricular myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)

Suppressive effect of SUN1165 on supraventricular tachycardia

The electrophysiologic properties of SUN1165 and its suppressive effect on supraventricular tachycardia were assessed in 14 patients, nine with atrioventricular reentrant tachycardia (AVRT) and five with atrioventricular nodal reentrant tachycardia (AVNRT). This new agent prolonged the PR interval and QRS duration but did not alter the QT interval or the corrected QT interval. It did not alter the sinus cycle length or sinus node recovery time. The drug prolonged the AH interval, HV interval, and intraatrial conduction time but did not change the effective refractory periods of the right atrium or right ventricle. SUN1165 prevented the induction of tachycardia in six of nine patients with AVRT by a complete retrograde block of the accessory pathway and prevented AVNRT in four of five patients by a complete retrograde block of the fast atrioventricular nodal pathway as well. We conclude that SUN1165 is very effective in preventing AVRT or AVNRT. Larger studies with more patients are warranted.

Usefulness of rate responsive atrial pacing in patients with sick sinus syndrome.

We studied heart rate response and blood lactate changes during treadmill exercise testing in 10 patients with sick sinus syndrome (SSS) and normal atrioventricular (AV) conduction in whom an activity detecting multi‐programmable rate responsive pacemaker was implanted for atrial pacing (AAI pacing). Treadmill exercise testing was performed twice in each patient under the two different AAI pacing modes: rate responsive function off (fixed rate 60 pulses per minute [ppm]; RR‐off) and rate responsive function on (rate response 10, activity threshold medium, basic rate 60 ppm, and maximum rate 150 ppm; RR‐on). Chronotropic response and blood lactate change during exercise were compared among patients under each pacing mode and eight healthy volunteers of ages matching those of the patients. In patients under the RR‐off pacing mode (RR‐off patients), chronotropic response was lower (P < 0.01) and blood lactate level was higher (P < 0.05) than those in patients under the RR‐on pacing mode (RR‐on patients) and volunteers during exercise. In RR‐on patients, however, both chronotropic response and lactate level changes during exercise were comparatively improved, with no significant differences between RR‐on patients and volunteers. These data suggested that improvement of chronotropic response by rate responsive pacing, in comparison with nonrate responsive pacing, increased the blood supply to the working muscles and resulted in less lactate production during exercise. It was concluded that rate responsive AAI pacing which could maintain AV synchrony and normal intraventricular conduction was an optimal physiological pacing mode for SSS patients with normal AV conduction.

Comparative evaluation of depressed automaticity in sick sinus syndrome by Holter monitoring and overdrive suppression test

To ascertain whether the long cardiac pauses on the Holter ECGs of patients with the sick sinus syndrome were related to the spontaneously occurring overdrive suppression, the heart rates for the 12 seconds preceding the cardiac pauses longer than 5 seconds were compared with that averaged for 24 hours. Even in six out of seven patients with bradycardia-tachycardia syndrome the former rate was not significantly greater than the latter, indicating that episodes of such long cardiac pauses may not result from spontaneously occurring overdrive suppression. This observation was also consistent with the result that no statistically significant correlation was obtained between the maximum pauses measured from Holter ECGs of sick sinus syndrome and those obtained by the overdrive suppression test. In conclusion, many episodes of long life-threatening cardiac pauses observed in sick sinus syndrome may be attributed to accidental depression of the sinus nodal and subsidiary pacemaker activity rather than to spontaneously occurring overdrive suppression; therefore, Holter monitoring may be useful as an additional tool for diagnosis of sick sinus syndrome.

Amiodarone Effects on Developing Myocardium

An extensive investigational experience in adults has documented amiodarone’s efficacy against most supraventricular and ventricular arrhythmias [1, 2]. Although the exact basis for amiodarone’s antiarrhythmic potential is not known, it has been related to its propensity for prolonging action potential duration and refractoriness (class III effect). Recent data have shown that amiodarone is also extremely potent against most childhood arrhythmias refractory to conventional pharmacologic agents [3, 4]. This study was designed to compare the acute electrophysiologic actions of amiodarone on adult and neonatal canine cardiac tissues in vitro by using transmembrane microelectrode techniques.