THE PHARMACOLOGICAL ACTIONS OF ANDROMEDOTOXIN, AN ACTIVE PRINCIPLE FROM RHODODENDRON MAXIMUM

¹ The National Heart Institute and the Department of Pharmacology, Emory University School of Medicine, Emory University, Georgia

1. Andromedotoxin, a nitrogen-free, neutral, crystalline substance isolated from the leaves of Rhododendron maximum has been studied.

2. The rapid intravenous injection of andromedotoxin produces bradycardia, hypotension, and respiratory depression. Atropine prevents the bradycardia and diminishes the hypotensive component. Vagotomy abolishes the entire response. Three manometer technique studies demonstrate a reflex vasodilatation, as well as bradycardia, as contributing to the hypotensive effect. The minimal effective dose in eliciting this reflex is two to three microgm./kgm.

3. A distinct hypotensive action in vagotomized animals occurs in a dose range of 2 to 20 microgm./kgm., the magnitude of the depressor effect being proportional to the dose. Associated with this response is a blockade of the carotid sinus pressor reflex and the production of postural hypotension. The absence of a peripheral autonomic blocking action, the failure to obtain the response in the spinal cat, and the absence of direct vasodilatation on intra-arterial administration demonstrate a lack of peripheral action. Studies with the three manometer technique indicate a nerve mediated vasodilatation. It is believed that the action is a direct depression of the vasomotor center or a stimulation of receptors in the head and neck with a reflex vasodilatation.

4. Electrocardiographic changes such as ventricular extrasystoles, A-V nodal and ventricular tachycardia, conduction impairment, and ventricular fibrillation occur with doses of 35 microgm./kgm. and greater.

5. Andromedotoxin in doses of 40 microgm./kgm. and greater causes a rise in blood pressure due largely to the release of epinephrine from the adrenal medulla, as shown by the absence of the greater part of the effect after adrenergic blocking doses of phentolamine and after adrenalectomy. Because of a transient venous pressure lowering effect, the possibility exists of a positive inotropic action on the heart as a contributory factor in this pressor effect.

6. A veratrine-like action on the isolated frog sartorius muscle appears in concentrations of 1:250,000, along with a progressive decrease in the twitch height. Unlike veratridine there is no significant initial increase in twitch height, only a delayed relaxation. Andromedotoxin also antagonizes the action of veratridine.

7. Emesis occurs in unanesthetized dogs upon parenteral administration of andromedotoxin in doses of 7 microgm./kgm. and greater.

8. Respiratory stimulation or depression occur in vagotomized dogs with doses of 20 microgm./kgm. and greater. The mechanisms of these actions are unknown.

9. Stimulation of the central nervous system followed by depression occurs with high doses.

10. The actions of andromedotoxin are of short duration, lasting less than one hour even with toxic doses.

11. The close similarity in actions of andromedotoxin to the veratrum alkabids has been discussed.