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B J Scherlag

Publications and source records attributed to B J Scherlag.

At least 19 recordsLinked to original sources
PubMed1992

High-performance liquid chromatographic determination of BRB-I-28, a novel antiarrhythmic agent, in dog plasma and urine.

A sensitive reversed-phase high-performance liquid chromatographic (HPLC) technique with ultraviolet detection has been developed to determine the concentration of BRB-I-28 (I), a novel antiarrhythmic agent, in dog plasma and urine. The mobile phase was acetonitrile-methanol-37.5 mM phosphate buffer, pH 6.8-triethylamine (50:50:75:0.1, v/v). The compound was extracted from dog plasma and urine with chloroform after alkalinization with sodium hydroxide. The extraction recovery was 83% from plasma and 84% from urine. Good linearity (r > 0.996) was observed throughout the ranges 0.1-12.0 micrograms/ml (plasma) and 0.1-8.0 micrograms/ml (urine). Intra- and inter-assay variabilities were less than 4%. The lower limit of quantitation was 0.08 microgram/ml in either plasma or urine. HPLC analysis of plasma and urine samples from a dog treated with I has demonstrated that the method was accurate and reproducible.

Animals↗
PubMed1992

Conversion of Mobitz type II AV block to 1:1 AV conduction by premature ventricular beats.

Preliminary experiments in a canine model of Mobitz type II atrioventricular (AV) block showed improvement of conduction after premature ventricular beats. In this investigation, the authors studied the mechanism(s) responsible for this response. In vivo studies were performed in 16 anesthetized dogs. Block was induced by ischemia after septal artery occlusion or by mechanical trauma. Two pairs of plunge electrodes were inserted in the proximal and distal His bundle. An electrode catheter was positioned at the level of the aortic root to provide an overall view of His bundle activation. Bipolar pacing was performed from the high right atrium, right ventricular outflow tract, and proximal and distal His bundle. Infra-nodal 2:1 AV block was consistently induced at an atrial rate of 238 +/- 21 beats/min. In 15 dogs a narrow time window (10-60 ms; mean, 32 +/- 6 ms) was found during which premature beats resulted in transient (2-11 beats; n = 9) or persistent (n = 8) restoration of 1:1 AV conduction. Retrograde penetration of the site of block, that is, Hb, was found even when the anterograde impulse was blocked, demonstrating the asymmetric nature of anterograde versus retrograde conduction. In vitro studies were performed in the same hearts. Intracellular recordings were obtained in the damaged His bundle and proximal right bundle. The site of block showed frequent displacements along the bundle. The introduction of a retrograde stimulus during 2:1 block restored 1:1 anterograde conduction.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Mapping in the atrioventricular junction.

Ectopic conduction is defined as the premature exit of the cardiac impulse from the specialized conduction system across a damaged Purkinje-ventricular muscle interface. This anomalous form of atrioventricular (AV) conduction was induced in the dog heart by lidocaine injection of the His bundle-interventricular septum interface and by ischemic damage of the AV junction subsequent to anterior septal artery ligation in the dog heart. The electrocardiogram (ECG) manifestation of ectopic conduction is the loss of initial forces and replacement of the Q waves with delta waves. In order to verify these effects, the authors devised a multi-electrode, malleable plaque (63 electrode sites) that could be secured at the AV junction during venous occlusion in the open-chest, anesthetized dog. Preliminary maps indicated a dramatic change in activation that proceeded from apex to base of the heart in the control state and reversed after ischemic damage to the His bundle. In vitro, it was possible to induce ectopic conduction by lidocaine injection at the interface of the right bundle branch and septal muscle. Microelectrode studies demonstrated that foot potentials, for example, electrotonic, or subthreshold potentials mediated the connection from Purkinje to muscle in the damaged zone. In a recent set of experiments in vivo, subthreshold stimulation (STS) was delivered to simulate electrotonic potentials to the His bundle region, and right ventricular apex, using multipolar electrode catheters. In the normal heart, STS delivered as DC constant current or pulse trains (1000 Hz, 50 ms pulse duration) induced shortened P-R intervals and delta waves with or without bundle branch block patterns.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Distinct activation patterns of idioventricular rhythms and sympathetically-induced ventricular tachycardias in dogs with atrioventricular block.

To investigate mechanisms of ventricular impulse formation in response to sympathetic stimulation in the healthy canine heart in situ, we compared the patterns of ventricular activation during the idioventricular rhythms arising after complete atrioventricular (AV) block and ventricular tachycardias induced by RSG or LSG stimulation. Isochronal maps were generated by computer from 116-127 unipolar electrograms recorded from the entire ventricular epicardium in 15 open chest, anesthetized dogs. In eight of these, bipolar electrograms were recorded with plunge electrodes from 11 selected endocardial sites located below epicardial breakthrough areas. Intracardiac recordings from the His-Purkinje system were made with electrode catheters. After electrograms were recorded during sinus rhythm, complete AV block was induced by injecting formaldehyde into the AV node and idioventricular rhythms occurred spontaneously at a rate of 37 +/- 12 beats/min (mean +/- SD, n = 25). During idioventricular rhythms, endocardial activation preceded the earliest epicardial breakthrough, which occurred in either the right anterior paraseptal region, antero-apical left ventricle, or postero-apical left ventricle. These sites were consistent with a focal origin in the subendocardial His-Purkinje system. Total epicardial activation times lasted for 47 +/- 13 msec (n = 40). Idioventricular rhythms were suppressed by overdrive pacing (intermittent trains of ten beats with decremental cycle length from 500 to 200 msec) or by intravenous calcium infusion (to plasma levels of 10.1-15.2 mM). Right or left stellate ganglion stimulation increased idioventricular rhythm rates (to 52 +/- 13 beats/min, n = 28) and also induced, in all preparations, ventricular tachycardias that had significantly faster rates (189 +/- 55 beats/min, n = 27, P less than 0.005). Ventricular fibrillation was induced after brief runs of ventricular tachycardia in five of the preparations. During ventricular tachycardias, epicardial activation occurred on the right ventricular outflow tract or the postero-lateral wall of the left ventricle, and preceded endocardial activation in 50% of cases. Total epicardial activation times (103 +/- 29 beats/min) were significantly longer than during idioventricular rhythms (P less than 0.005). Ventricular tachycardias displayed overdrive excitation at critical pacing cycle lengths (360-280 msec) and were not suppressed by calcium infusion. Thus, differential mechanisms of impulse formation with distinct localizations can be elicited from healthy ventricular myocardium.

Animals↗
PubMed1992

Effects of BRB-I-28, a novel antiarrhythmic agent, and its derivatives on cardiac Na+,K(+)-ATPase, Mg(2+)-ATPase activities and contractile force.

The effects of BRB-I-28, SAZ-VII-22 and SAZ-VII-23, a novel class of antiarrhythmic agents and other 3,7-diheterobicyclo[3.3.1]nonane (DHBCN) derivatives on guinea pig myocardial Na+,K(+)-ATPase and Mg(2+)-activated ATPase activities were investigated in comparison with those of tedisamil, lidocaine and ouabain. BRB-I-28, SAZ-VII-22, SAZ-VII-23, tedisamil and their derivatives produced concentration-dependent inhibition on both Na+,K(+)-ATPase and Mg(2+)-activated ATPase. Ouabain had no effect on the Mg(2+)-activated ATPase activity and GLG-IV-44 had no significant inhibition on Na+,K(+)-ATPase. Molar refractivity, retention time in reverse-phase HPLC, and partition coefficients were determined and the influence of these three parameters on the inhibitory effects of DHBCN on ATPase was examined. It seems that inhibitory effects of DHBCN derivatives on Na+,K(+)-ATPase and Mg(2+)-activated ATPase increase with an increase in lipophilicity, while hydrophilic groups of the drugs may not be important for interaction between drugs and ATPases. The effects of BRB-I-28 on contractile force development in rabbit atrial and papillary muscles were studied. At paced rates of 0.5 and 1.0 Hz in atrial muscle, BRB-I-28 produced an apparent positive inotropic effect in isolated rabbit atrial muscle, which is consistent with its inhibitory effects on Na+,K(+)-ATPase and Mg(2+)-ATPase activities. Inhibitory effects on myocardial Na+,K(+)-ATPase and Mg(2+)-activated ATPase activities may be the basis of some electrophysiological effects of antiarrhythmic properties of BRB-I-28, SAZ-VII-22, SAZ-VII-23, and tedisamil.

Animals↗
PubMed1992

Electrophysiologic actions of clofilium and lidocaine in ischemically injured canine epicardium.

The electrophysiologic actions of the Class III antiarrhythmic drug, clofilium, and the Class IB antiarrhythmic drug, lidocaine, were examined in ischemically injured canine epicardium, 4 days after coronary artery occlusion. Experiments were performed utilizing 1) composite electrode recordings from the intact heart in the anesthetized dog and 2) intracellular and extracellular recordings from superfused canine epicardium. In intact hearts, both clofilium (2 mg/kg i.v.) and lidocaine (6 mg/kg i.v.) increased refractoriness (188 +/- 16 to 331 +/- 39 and 288 +/- 18 msec, respectively, P less than .01), and produced tachycardia-dependent conduction disorders in ischemically injured epicardium. For both drugs, slowing the sinus heart rate with vagus nerve stimulation (32 +/- 6/min) returned activation delays to predrug values. Unlike lidocaine, clofilium failed to increase maximal activation delays in ischemically injured epicardium preceding conduction block (116 +/- 14 msec vs. 71 +/- 7 msec and 147 +/- 16 msec for clofilium and lidocaine, respectively, P less than .01 for both drugs). In superfused epicardium, both clofilium (3 x 10(-7) M) and lidocaine (4 mg/l) prolonged refractoriness in ischemically injured epicardium (175 +/- 16 predrug vs. 273 +/- 33 msec, P less than .01) and (181 +/- 3 predrug vs. 216 +/- 10 msec, P less than .01), respectively, whereas only lidocaine reduced Vmax and prolonged local conduction times in the same tissue. The results demonstrate that 1) lidocaine increases refractoriness in ischemically injured tissue via a decrease in Vmax and conduction velocity and 2) clofilium increases refractoriness in ischemically injured tissue without altering action potential duration, Vmax or conduction velocity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

The monophasic action potential in clinical cardiology.

For more than 30 years, the monophasic action potential has been used as an experimental tool for the study of myocardial repolarization. With recent improvements in catheter design, the utility of the tool as a means to identify the bases for ventricular arrhythmias in humans has been greatly improved. Abnormalities of repolarization leading to ventricular arrhythmia formation can be identified and specific pharmacologic therapies may be evaluated. Further evaluation of the technique by cardiac electrophysiologists may improve both the diagnosis and the treatment of ventricular arrhythmias dependent upon afterdepolarization formation (acquired and familial long QT syndromes).

Action Potentials↗
PubMed1991

Electrophysiological actions of BRB-I-28 in canine myocardial tissues.

To obtain a better understanding of the possible electrophysiological bases of the antiarrhythmic actions of 7-benzyl-3-thia-7-azabicyclo[3.3.1]nonane hydroperchlorate (BRB-I-28), microelectrode recordings of myocardial electrical activity were obtained in canine Purkinje and ventricular tissue, and in isolated canine ventricular myocytes. BRB-I-28 (1.0 and 3.2 mg/l) reduced Vmax, action potential amplitude, overshoot potential and conduction velocity in Purkinje tissues without altering action potential duration or spontaneous automaticity. Vmax and conduction velocity were reduced only at paced cycle lengths of 500 msec or less. BRB-I-28 (3.2 and 10 mg/l) also reduced Vmax, action potential amplitude and overshoot potential in subendocardial and epicardial ventricular muscle, with Vmax reduced only at cycle lengths of 500 msec or less. Recovery half-times for Vmax estimated in canine subendocardium were 330 +/- 28 and 336 +/- 25 msec at BRB-I-28 concentrations of 3.2 and 10 mg/l, respectively. In epicardium, conduction velocity longitudinal to fiber orientation was depressed more than conduction velocity transverse to fiber orientation, despite similar changes in Vmax. In both epicardial and subendocardial ventricular muscle, a reduction in Vmax is observed in the absence of alterations in action potential duration. Experiments using myocytes isolated from canine epicardial tissue demonstrated similar rate-dependent changes in Vmax as ventricular epicardium. The data demonstrate a rate-dependent depression of Vmax by BRB-I-28 in canine ventricular tissues. The depression of conduction occurs only at rapid paced rates and occurs in the absence of changes in Purkinje cell automaticity or action potential duration.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1990

Seasonal variation in sudden cardiac death after experimental myocardial infarction.

The authors studied the incidence of sudden death by monitoring the ECG after ligation of the left anterior descending coronary artery in 184 dogs. A significant number of sudden deaths (46 dogs) occurred in the cold weather months, November-February (42%), compared to the summer months, July and August (6%). All deaths resulted from ventricular tachyarrhythmias (greater than or equal to 300/min) and occurred between 13 and 22 hours after coronary artery ligation. The survivors (138 dogs) were subjected to electrophysiological study, during which a significantly higher number showed induced sustained monomorphic ventricular tachycardia (VT) (heart rate greater than or equal to 300/min) during the winter months than during the summer months. Heart weight and infarct mass were not significantly different throughout the year. Higher sympathetic tone or catecholamine levels may account for the seasonal variation in sudden death during evolving myocardial infarction.

Animals↗
PubMed1990

Early and delayed afterdepolarizations associated with cesium chloride-induced arrhythmias in the dog.

Monophasic action potentials (MAPs) were utilized to examine the basis for cesium-induced arrhythmia in the dog. Cesium chloride (1 mmol/kg i.v.) produced an immediate prolongation of MAP (250 +/- 11 to 396 +/- 34 ms, p less than 0.05). Coupled premature ventricular beats (345 +/- 46 ms) and polymorphic ventricular tachycardia developed in association with early afterdepolarizations during the first 1-3 min after cesium administration. A slowing of the sinus heart rate with vagus nerve stimulation exacerbated the arrhythmia. During the subsequent 7 min, the MAP duration decreased from 396 +/- 34 to 316 +/- 19 ms. At 8-10 min, the premature ventricular beats were associated with delayed afterdepolarizations in the MAP recordings. However, there was no change in the coupling intervals of the premature ventricular beats (351 +/- 29 ms). Ventricular arrhythmias and delayed afterdepolarizations during this phase were exacerbated by increasing the heart rate with atrial pacing. T wave alternans and U wave formation in the ECG were associated with early or delayed afterdepolarizations in MAP. Cesium chloride (1 mmol) injected into the left anterior descending coronary artery produced local MAP prolongation and ventricular bigeminy. Although the MAP duration returned to predrug values after intracoronary cesium injection, the severity of ventricular arrhythmia increased with succeeding doses. These data suggest that early and delayed afterdepolarizations, T wave alterations, and ventricular beats can be dissociated from the initial action potential prolongation with cesium and closely resemble altered calcium transients observed in vitro.

Action Potentials↗
PubMed1988

Generation of arrhythmias in myocardial ischemia and infarction.

In recent years an enhanced interest among researchers combined with the availability of new technologies has increased our knowledge of the mechanisms that generate arrhythmias in patients with ischemic heart disease. Convincing evidence has been obtained to support the occurrence of reentry in ischemic myocardium. This has been especially apparent in canine studies in the surviving layers overlying infarctions several days after coronary occlusion. In this planar model, the reentry circuit forms a figure-8 configuration around an arc of functional block due to refractoriness; the center of the arc is the site of unidirectional block and reentry. The reentry circuit is sustained by wavefronts of activation encircling segments in which the tissue on either side is alternately receptive and refractory, a variant of the leading circle model of reentry. The relatively prolonged refractoriness in ischemic tissue is due to time-dependent refractoriness, i.e., postrepolarization refractoriness, which is most prominent in more severely depolarized cells. Slow conduction is related in part to primary depression of the fast channels. There is a great variation in refractory periods in ischemic tissue because of variation in action potential duration and in the duration of time-dependent refractoriness. The depolarized resting potentials of cells in acute ischemia are due in part to extracellular accumulation of potassium and intracellular accumulation of calcium. In the latter stages of ischemia it is likely that abnormalities of ion distribution across the sarcolemma play a role. It has also been demonstrated that ischemic Purkinje fibers show abnormal automaticity, i.e., enhanced phase 4 depolarization at depolarized diastolic potentials, and afterdepolarizations with triggered firing.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Synthesis and antiarrhythmic properties of novel 3-selena-7-azabicyclo[3.3.1]nonanes and derivatives. Single-crystal X-ray diffraction analysis of 7-benzyl-3-selena-7-azabicyclo[3.3.1]nonan-9-one and 7-benzyl-3-selena-7-azabicyclo[3.3.1]nonane hydroperchlorate.

Several members of the heterocyclic family 3-selena-7-azabicyclo[3.3.1]nonane have been synthesized and characterized via IR, 1H, 13C, 15N, and 77Se NMR spectroscopy and, in some cases, by X-ray diffraction analysis. Select members, namely the hydroperchlorates of the amines, were examined for antiarrhythmic properties in anesthetized dogs in which myocardial infarctions were induced by techniques previously described. In the predrug, or control state, sustained ventricular tachycardia were induced by ventricular paced beats at rates above 300/min. When 7-benzyl-3-selena-7-azabicyclo[3.3.1]nonane hydroperchlorate was administered at 3 and 6 mg/kg, the sustained ventricular tachycardia could no longer be induced. Similar doses of lidocaine, a commonly used antiarrhythmic, caused slowing of the sustained ventricular tachycardia below 300/min but did not abolish their inducibility. In addition, select members of the hydroperchlorates caused a moderate 10-20% increase in mean blood pressure whereas lidocaine caused either no change in or slightly reduced mean blood pressure. Some general conclusions are delineated concerning the structural requirements that appear to be necessary for activity in this family of heterocycles and that have not been reported previously.

Animals↗
PubMed1986

Mechanism of prevention of sudden death by nadolol: differential actions on arrhythmia triggers and substrate after myocardial infarction in the dog.

Electrocardiographic monitoring and provocative ventricular pacing were used to evaluate control and nadolol treatment groups 6 to 24 hours after left anterior descending coronary artery ligation in the dog. During the 6 to 24 hour period, the control group (n = 20) developed ventricular triplets at rates exceeding 270/min. Seven dogs spontaneously developed sustained monomorphic ventricular tachycardia (421 +/- 12 beats/min) at 13 +/- 2 hours. Sustained monomorphic ventricular tachycardia was present for 38 +/- 8 seconds before ventricular fibrillation developed. One dog developed recurrent monomorphic ventricular tachycardia, with six episodes lasting from 8 to 72 seconds (375 to 425 beats/min). At 24 hours, ventricular pacing produced sustained monomorphic ventricular tachycardia (378 +/- 12 beats/min) in 9 of 13 surviving animals. Nadolol administration 6 hours after coronary artery ligation (n = 19) lowered both the rate (241 +/- 8 versus 328 +/- 8 beats/min; p = 0.001) and the incidence (8 +/- 6 versus 198 +/- 61 per hour; p = 0.004) of rapid ventricular triplets and prevented sudden arrhythmic death (0%; p = 0.005). Nadolol failed to prevent sustained monomorphic ventricular tachycardia (88%; 365 +/- 12 beats/min) produced by ventricular pacing. The data suggest that nadolol prevents spontaneous sustained monomorphic ventricular tachycardia by selectively suppressing the arrhythmia trigger (rapid ventricular triplets) without altering the underlying arrhythmia substrate.

Animals↗