Marvin B. Bacaner

Quantitative comparison of bretylium with other antifibrillatory drugs

Abstract By measuring fibrillation thresholds, it was possible to assess the antifibrillatory actions of quinidine, procainamide, lidocaine, diphenylhydantoin, propranolol and guanethidine and compare them quantitatively with bretylium. Quinidine, lidocaine, procainamide, diphenylhydantoin and guanethidine did not increase fibrillation threshold and were judged to be without effect in suppressing electrically induced ventricular fibrillation. Moreover, these agents are all negatively inotropic. Propranolol was inconsistent in its effects, causing a moderate increase in threshold in 2 of 6 animals. Propranolol depressed cardiac function, causing acute dilatation of the heart, a fall in cardiac output and increase in pulmonary arterial and left atrial pressure. The antifibrillatory effect of bretylium was manifested by a threefold increase in fibrillation threshold. In addition, bretylium had a stabilizing effect on ventricular rhythmicity, and induced fibrillation spontaneously reverted to sinus rhythm after fibrillation periods to 70 seconds (“spontaneous defibrillation phenomenon”). In contrast to the other antiarrhythmic agents bretylium was positively inotropic. Bretylium given after other drugs to the same animals increased the fibrillation threshold significantly and produced the defibrillation phenomenon. Quinidine, guanethidine and high doses of diphenylhydantoin tended to block bretylium action to varying degrees.

Treatment of ventricular fibrillation and other acute arrhythmias with bretylium tosylate

Abstract In a pilot study of 30 consecutive patients, bretylium tosylate was found an effective therapeutic agent for treating ventricular fibrillation and other arrhythmias, particularly of ventricular origin. It was of clear value as an adjunct in the treatment of patients with ventricular fibrillation and ventricular tachycardia that had been resistant to other drugs and electrical countershock. In 5 patients bretylium was considered to be livesaving. In 27 patients suppression of the arrhythmia occurred within five minutes to several hours after initial treatment. In 2 the response was delayed until a second dose was given; in a third the arrhythmia was not reversed for seven hours. The duration of antiarrhythmic action was relatively long, lasting from 10 to 20 hours after a dose. Recurrence of the arrhythmia after this period could be suppressed by an additional dose. Unlike all other known antiarrhythmic agents that suppress myocardial contractile strength, bretylium is positively inotropic and normally augments cardiac output. The side effect of orthostatic hypotension usually requires the patient to be kept in bed.

Bretylium tosylate for suppression of induced ventricular fibrillation

Abstract Bretylium tosylate exerts a potent effect in protecting the canine heart against electrically induced ventricular fibrillation. The protection is observed in normal hearts as well as after coronary ligation. The study suggests a potential clinical use for this agent in the prevention and treatment of ventricular fibrillation that warrants further evaluation.

Use of bretylium tosylate in the management of acute myocardial infarction

Abstract Sixty-two patients with acute myocardial infarction were treated for 4 days with bretylium tosylate. This agent was effective in suppressing and preventing ventricular fibrillation as well as other irritable arrhythmias and heart block. On admission 37 patients had arrhythmias and 2 complete atrioventricular (A-V) block; 23 had no rhythm disturbances and were treated prophylactically. Of the 37 patients with arrhythmias, 11 had been treated with lidocaine without success. Eight patients had from 1 to 5 episodes of ventricular fibrillation (not suppressed by lidocaine in 7) before treatment with bretylium, but no patient had ventricular fibrillation after bretylium therapy was started. Ventricular arrhythmias were suppressed in from 10 minutes to 12 hours on routine dose therapy; the response indicated a sharp dose-dependent effect for complete suppression. Twenty-two of the 23 patients treated prophylactically had no arrhythmias. One patient had fatal ventricular fibrillation 5 1 2 hours after the first dose was administered and just before the second dose was due; this was the only death due to arrhythmia in the 62 patients. Of the 60 patients without heart block on admission, only 1 had heart block of any degree during treatment. There were 8 deaths in the hospital (12.9 percent), 7 as a result of pump failure. If 2 patients who were in extremis before treatment was started, and who died before an effect could have occurred, are excluded, mortality was under 10 percent. Our previous mortality in the unit was 20 percent. The actions of bretylium in increasing contractile strength, impulse formation and conduction velocity in addition to suppressing rhythm disturbance make it a valuable agent for the management of the major complications of acute myocardial infarction.

Suppression of ventricular fibrillation and positive inotropic action of bethanidine sulfate, a chemical analog of bretylium tosylate that is well absorbed orally.

Bethanidine sulfate is a closely related chemical analog of bretylium that has virtually identical pharmacologic and antifibrillatory actions on the ventricle. Unlike bretylium, which is very poorly absorbed from the gut, bethanidine is rapidly and effectively absorbed after oral administration. Bethanidine increased ventricular fibrillation threshold in the normal dog heart from an average control value of 28.5 mA to an average peak value of 66.5 mA, an increase of 150 percent. In the infarcted heart, bethanidine increased ventricular fibrillation threshold from an average postinfarction level of 14.4 mA to an average peak value of 55.3 mA, an increase of 327 percent. Like bretylium, the antifibrillatory action of bethanidine was manifested by the appearance of nonsustained ventricular fibrillation when superthreshold shocks induced episodes of ventricular fibrillation lasting from 2 to 120 seconds and converting spontaneously to sinus rhythm. In contrast, the untreated dog heart must always be defibrillated electrically. The onset of antifibrillatory action began as early as 2 minutes after intravenous administration and 15 to 30 minutes after oral administration; peak action occurred in approximately 60 minutes. Bethanidine had prolonged positive inotropic action in the isolated heart as reflected by an increase in cardiac output and blood pressure lasting up to 60 minutes. Bethanidine lowered coronary vascular resistance and increased coronary blood flow. The oral efficacy and rapid onset of action gives bethanidine a potential role in the prevention of out-of-hospital ventricular fibrillation.

Effect of Bretylium Tosylate on the Prevention and Treatment of Postoperative Arrhythmias

Abstract A series of 35 consecutive patients undergoing single or multiple prosthetic valve replacement were treated with bretylium tosylate prophylactically (5mg/kg the night before operation and again 2 hours before induction of anesthesia) to test its efficacy in suppressing postoperative arrhythmias. In the treated group 4 patients (11.4 percent) had minor early (first 12 hours) postoperative arrhythmias. In a similar control group of 38 consecutive patients 22 (58 percent) had early postoperative arrhythmias. In contrast, late arrhythmias (after 12 hours) occurred with approximately equal frequency in both groups (26 patients treated with bretylium compared to 22 control patients) as the effect of bretylium diminished and latent suppressed arrhythmias in the treated group appeared. Bretylium successfully controlled acute postoperative arrhythmias in 42 of 45 instances. These arrhythmias included premature atrial and premature ventricular contractions, bigeminy, nodal tachycardia, atrial fibrillation, ventricular tachycardia and ventricular fibrillation. Bretylium was also effective in 5 patients who had rhythm disturbances after nonvalvular cardiac operations. Bretylium was particularly impressive in the treatment of patients whose hearts could not be electrically defibrillated postoperatively when elective fibrillatory arrest had been used. In 2 such cases in the control series regular rhythm was readily established 10 to 15 minutes after bretylium (400 to 600 mg) had been given.

Prevention of ventricular fibrillation, acute myocardial infarction (myocardial necrosis), heart failure, and mortality by bretylium: is ischemic heart disease primarily adrenergic cardiovascular disease?

It is widely, but mistakenly, believed that ischemic heart disease (IsHD) and its complications are the sole and direct result of reduced coronary blood flow by obstructive coronary artery disease (CAD). However, cardiac angina, acute myocardial infarction (AMI), and sudden cardiac death (SCD) occur in 15%–20% of patients with anatomically unobstructed and grossly normal coronaries. Moreover, severe obstructive coronary disease often occurs without associated pathologic myocardiopathy or prior symptoms, ie, unexpected sudden death, silent myocardial infarction, or the insidious appearance of congestive heart failure (CHF). The fact that catecholamines explosively augment oxidative metabolism much more than cardiac work is generally underappreciated. Thus, adrenergic actions alone are likely to be more prone to cause cardiac ischemia than reduced coronary blood flow per se. The autonomic etiology of IsHD raises contradictions to the traditional concept of anatomically obstructive CAD as the lone cause of cardiac ischemia and AMI. Actually, all the signs and symptoms of IsHD reflect autonomic nervous system imbalance, particularly adrenergic hyperactivity, which may by itself cause ischemia as in rest angina. Adrenergic activity causing ischemia signals cardiac pain to pain centers via sympathetic efferent pathways and tend to induce arrhythmogenic and necrotizing ischemic actions on the cardiovascular system. This may result in ischemia induced metabolic myocardiopathy not unlike that caused by anatomic or spasmogenic coronary obstruction. The clinical study and review presented herein suggest that adrenergic hyperactivity alone without CAD can be a primary cause of IsHD. Thus, adrenergic heart disease (AdHD), or actually adrenergic cardiovascular heart disease (ACVHD), appears to be a distinct entity, most commonly but not necessarily occurring in parallel with CAD. CAD certainly contributes to vulnerability as well as the progression of IsHD. This vicious cycle, which explains the frequent parallel occurrence of arteriosclerosis and IHD, an association that appears to be linked by the same cause, comprises a common vulnerability to deleterious adrenergic actions on the myocardium, lipid metabolism, and vascular system alike, rather than viewing CAD and IsHD as having a putative cause and effect relationship as commonly thought. Adrenergic actions can also cause the abnormal lipid metabolism that is associated with CAD and IsHD by catecholamine-induced metabolic actions on lipid mobilization by activation of phospholipases. This may also be part of toxic catecholamine hypermetabolic actions by enhancing deleterious cholesterol and lipid actions in damaging coronary vessels by plaque formation as well as inducing obstructive coronary spasm and platelet aggregation. This may also cause direct toxic necrosis on the myocardium as well as atherosclerosis in blood vessels. In fact, drugs that inhibit adrenergic actions like propranolol, reserpine, and guanethidine all inhibit arteriosclerosis induced by hypercholesterolemia in experimental animals and prevent carotid vascular disease (associated with stroke) in humans. The concomitant development of myocardiopathy and coronary vascular lesions or coronary and carotid artery intimal medial thickening by catecholamine toxicity is reflected by the frequent primary presentation of patients with catecholamine-secreting pheochromocytoma with cardiovascular disease, ie, hypertension arrhythmias, AMI, SCD, CHF, and vascular disease, which represents a clear example of the primary deleterious impact of catecholamines on the entire cardiovascular system causing adrenergic cardiovascular disease. Thus, like myocardiopathy, CAD and atherosclerosis in general may be the consequences of or a complication of catecholamine actions rather than its putative cause. This report shows how prophylactic bretylium not only prevents arrhythmias but prevents myocardial necrosis, shock, CHF, maintains or restores normal contractility, and lowers mortality in AMI patients by inducing adrenergic blockade.

Coronary blood flow, oxygen delivery rate and cardiac performance

1. Studies have been made on the isolated blood‐perfused heart of dogs in which isometric tension development at various settings of resting tension (RT) was measured at various levels of O2 delivery rates controlled by altering (a) coronary blood flow (CBF), (b) O2 capacity or (c) O2 saturation of the perfusate. Measurements were also made of O2 consumption and vascular perfusion resistance.

Instrumentation for direct microscopic elemental analysis of frozen biological tissue

A system has been devised to provide direct observation of frozen biological tissue in the scanning electron microscope. Both transmission and secondary electron methods of signal collection have been obtained. In combination with energy elective fluorescent x‐ray analysis, the elemental constituents of subcellular regions less than 1000 A in diameter have been analyzed in the transmission mode of operation. Transmission scanning electron micrographs of frozen muscle shows significant microstructural differences with conventionally obtained electron micrographs although dark bands, possibly corresponding to z zones of classically observed spacing, are seen.

Intracellular bretylium blocks Na+ and K+ currents in heart cells

The effects of intracellular and extracellular application of bretylium tosylate on outward potassium current and fast inward Na+ current have been studied in single ventricular cells of chick embryo (18-day-old) using the whole-cell voltage clamp technique. Extracellular superfusion with bretylium (3 x 10(-4) M) decreased the K+ current (IK) whereas the fast INa remained unaffected. Introducing bretylium intracellularly also decreased IK, but rapidly inhibited the fast INa. The addition of 3 x 10(-4) M bretylium to the superfusion medium in the presence of intracellular bretylium further decreased IK and caused the fast inward sodium current (INa) to recover. The decrease of IK by bretylium may account for the antifibrillatory properties of this drug in heart.