Inactivation of acetylcholinesterase with a bretylium tosylate photoaffinity probe.

Azidobretylium tosylate (ABT), the p-azido analogue of bretylium tosylate, has been synthesized to serve as a photoaffinity probe for bretylium binding sites. Bretylium tosylate has antiarrhythmic action and also interacts with amiloride-sensitive sodium ion transport sites. Acetylcholinesterase was used as a model protein, and both bretylium and ABT are reversible inhibitors of this enzyme. The kinetic inhibition constants (Ki) were determined to be 40 microM for bretylium tosylate and 6 microM for ABT. The azido compound is photochemically labile and apparently irreversibly inactivates the enzyme. The rate was retarded by the addition of bretylium tosylate or 4-oxo-N,N,N-trimethylpentanaminium iodide (OTI). Sephadex G-25 chromatography further demonstrated the irreversible nature of the photoinactivation. Since ABT binds at or near the acetylcholinesterase active site, it may be a useful probe for the characterization of the enzyme active site.

Antiarrhythmic, antifibrillatory, and hemodynamic actions of bethanidine sulfate: an orally effective analog of bretylium for suppression of ventricular tachyarrhythmias.

Bethanidine sulfate is a chemical and pharmacologic analog of bretylium tosylate that has virtually identical antifibrillatory and inotropic actions on the heart. Bretylium is the only drug approved by the Food and Drug Administration specifically for the "prophylaxis and treatment of ventricular fibrillation." Unlike bretylium, which is poorly absorbed from the gut and limited to parenteral use, oral bethanidine is absorbed rapidly. Bethanidine was given to 23 patients with recurrent multiple drug refractory ventricular tachycardia and fibrillation. Eighteen patients (78%) had complete suppression of spontaneous or electrophysiologically inducible tachyarrhythmias; 3 were improved and 2 had no benefit. In 6 of a 9 patient subgroup studied by programmed electrophysiologic drug testing, bethanidine completely prevented previously inducible ventricular tachyarrhythmias at the maximal stimulus tested (including 4 extrastimuli and burst-pacing at 10 times threshold). Cardiac output measured in 6 patients 1 to 2 hours after bethanidine was increased in 4, unchanged in 2, and decreased in 1. Ten patients on long-term therapy with bethanidine and protriptylene (to prevent orthostatic hypotension) have been free of arrhythmias from 2 to 26 (average 13) months.

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.