The nature and action of a hypotensive agent from Eucalyptus robusta

Abstract

Extracts of some species of Eucalyptus have been found to be hypotensive in rats, guinea pigs, cats, and dogs. Of the 29 species of this genus available for assay, Eucalyptus robusta contained the highest concentration of the hypotensive principle. Active and inactive species were randomly distributed throughout the sections and subsections of the genus, indicating that activity is not associated with any particular group of the eucalypts. The active principle occurs in highest concentration in the leaves but is also found in the phloem, roots, and to a lesser extent in the xylem. Little or no activity is present in> the bark. The hypotensive factor is soluble in water, lower alcohols and acetone but insoluble in chloroform or ether. Addition of chloroform or ether to the alcoholic extracts precipitated a more purified fraction. Attempts to purify the active component further by adsorption, steam distillation, gel filtration, heavy metal ion precipitation, liquid-liquid extraction, and dialysis met With little success. The molecular weight of the active principle was found to be approximately 3000, using Craig's dialysis method. The active component's molecular weight, solubility characteristics, precipitability by heavy metals (especially ferric chloride), base lability, strong adsorptive tendencies especially to Sephadex), non-volatility, ease of oxidation, and ineffectiveness orally indicate that it is probably a specific tannin. Five mg/kg of the partially purified material depressed the blood pressure of rats to less than 50% of its original value for approximately 15 minutes. Larger doses lowered the blood pressure to 30% of normal and for periods greater than several hours. The active agent was effective intravenously and intraperitoneally but ineffective orally. The absence of an effect when it was given to the vascularly isolated heads of cross-circulated animals indicated that the agent's action was peripheral. Prior treatment with hexamethonium, reserpine, phenoxybenzamine, pronethalol, and atropine had little or no effect on the action of the Eucalyptus factor. The antihistaminics tripellenamine and diphenhydramine, however, did attenuate the depressor effect of the extracts. When the active principle was given first, it had little or no effect on the response to subsequently administered phenylephrine, angiotensin, isoproterenol, or methacholine. However, there was an interference with the response to histamine. These results suggest that the hypotensive agent acts on the histamine pathway. Depletion of the histamine stores With the drug 48/80 blocked the action of the hypotensive agent, as did a one-week pretreatment With the agent itself. These results, along With the blockade by antihistamines and the interference with the response to histamine, indicate that the active principle is a histamine liberator.