The ability of digoxin and a 4-aminocardenolide, ASI-222, to alter atrioventricular nodal refractory period (AVRP) was determined as a function of the maximum subarrhythmic dose (MSAD) in the dog anesthetized with morphine-pentobarbital. ASI-222, a highly polar and potent inhibitor of Na+, K+-adenosine triphosphatase produces a cardiotoxicity in dogs prominently involving atrioventricular nodal blockade rather than ventricular premature ectopic beats and tachycardia seen with digoxin. AVRP was assessed with trains of electrically isolated stimuli of decreasing pulse interval delivered to the right atria. Digoxin and ASI-222 were infused i.v. at rates which produced cardiac arrhythmias in about 100 min in dogs either: with intact nerves, pretreated with atropine, without reflex receptors (without vagus and carotid sinus nerves, without cardiac sympathetic nerves and adrenals or pretreated with metoprolol. In dogs with intact nerves, ASI-222 produced greater increases in AVRP than digoxin at fractions of the MSAD; however, both glycoside produced a similar elevation at the MSAD (~30% increase). Atropine did not alter the AVRP response to ASI-222 but prevented the lengthening due to digoxin except for that which occurred near the MSAD. Removal of reflex receptor afferents (and vagi) had an effect similar to atropine on the AVRP response to digoxin, but completely prevented any response to ASI-222. Prior sympathectomy or beta adrenergic blockade abolished the AVRP response to ASI-222 but did not alter the responses to digoxin. Our data indicate that ASI-222 increases AVRP by inhibiting cardiac sympathetic nervous influences in contrast to the effects of digoxin which are exerted mainly through vagal and direct means. Furthermore, they suggest the aminocardenolide increases AVRP more effectively at subarrhythmic doses than does digoxin.
|Original language||English (US)|
|Number of pages||6|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Dec 1 1985|
ASJC Scopus subject areas
- Molecular Medicine