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Study of the action of two naturally-occuring tropolone derivatives on vascular smooth muscle. Leathem, Ann Marie

Abstract

Gamma-thujaplicin (GT) and beta-hydroxy thujaplicin (BHT) are two of the isopropyl derivatives of tropolone found in the heartwood of western red cedar (Thuja plicata D. Don). Several of the tropolones are effective inhibitors of the enzyme catechol-O-methyltransferase (COMT). In this work, the isolated, spirally-cut rabbit thoracic aorta preparation has been used to study possible COMT inhibition as well as other pharmacological properties of the sodium salts of GT and BHT. It was found that GT, BHT and pyrogallol, a known COMT inhibitor, all potentiated the response of the aortic strip to norepinephrine (NE). However, since it was shown that the chelating agent EDTA also potentiated the NE response, the potentiation by GT and BHT could not be attributed to COMT inhibition without further evidence. GT and BHT were found to have a stimulatory effect of their own on aortic smooth muscle tissue. BHT was a more potent agonist than GT. Phenoxybenzamine blocked the stimulatory effects of BHT and GT. This suggested alpha-adrenergic receptor involvement although the halogenoalkylamine blocking agents are not absolutely specific in their action. Cocaine produces a small potentiation of the contraction produced by GT and BHT. This potentiation suggests the involvement of endogenous NE. Cocaine does not cause relaxation of the GT and BHT responses which indicates that GT and BHT differ in mode and perhaps site of action from tyramine. BHT potentiates the tyramine response on the rabbit aortic strip. This may be due to COMT inhibition, increased NE release or merely additive effects. GT was found to produce relaxation of a histamine-induced contraction. This relaxant effect was not prevented by beta-adrenergic blockade and is likely due to a nonspecific depressant effect by GT. Both GT and BHT have produced non-specific blocking effects against NE and histamine as well as acetylcholine throughout this work. In reserpinized preparations, GT no longer produced a contraction of the aortic strip. Instead, a relaxation below normal tone was produced. It would seem that the presence of endogenous NE is required in the tissue stores before GT can cause the strips to contract. GT causes relaxation of tyramine-induced contractions in reserpinized strips. The isolated rabbit thoracic aorta was found not to be a suitable preparation for the pharmacological investigation of COMT inhibition by GT and BHT due to their own agonistic effects on this tissue as well as their nonspecific chelating properties. However, this tissue was useful in providing information on other pharmacological actions of these compounds.

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