Pyrrolizidine aminoalcohols: Indirect cholinomimetic activity in guinea-pig ileum

The pyrrolizidine aminoalcohols supinidine, hydroxyheliotridane, isoretronecanol, heliotridine, retronecine, desoxyretronecine and retronecanol possess stimulant actions in the guinea-pig ileum preparation at 37°C, while platynecine and hastanecine lack this activity. Contractions induced by the aminoalcohols are unaffected by hexamethonium and occur in nicotine-depolarized and in ganglion-free preparations. The stimulant activity is abolished by atropine and potentiated after cholinesterase inhibition with physostigmine. Stimulant activity is abolished by procaine, excess magnesium, morphine, tetrodotoxin and cooling to 25°C. These results suggest that the cholinomimetic action of the aminoalcohols involves the release of acetylcholine from post-ganglionic sites, and this was confirmed in experiments in which acetylcholine release was assessed in the presence of the aminoalcohols. When the temperature is lowered to 25°C weak anticholinergic and antihistaminic actions are unmasked. No correlation exists between the stimulant and the anticholinergic actions of the compounds.