Effect of 5-isopropyltropolone on the adrenergic responses of the isolated guinea-pig atria

5-Isopropyltropolone(gamma-thujaplicin) is one of the three isomeric isopropyltropolones found in the heartwood of western red cedar(Thuja plicata D. Don). The tropolones as a class have been shown to be inhibitors of the enzyme catechol-O-methyltransferase(COMT). The effect of this tropolone on the responses of the isolated guinea-pig atria to a number of sympathomimetic amines has been studied. Gamma-thujaplicin was used in the form of water soluble sodium salt(T-Na). T-Na itself was found to possess a slow but prolonged stimulating effect on the atria. In the presence of T-Na greater than 0.4 mcg./ml, both the positive inotropic and chronotropic effects of all of the sympathomimetic amines studied were increased. In the case of the short acting catechol amines, prolongation of these responses was also produced. The effect of T-Na on the responses to the adrenergic amines was compared with that of cocaine and ethylenedxa-minetetraacetic acid(EDTA). Potentiation of the responses to the adrenergic stimuli by T-Na and the last two agents appeared to follow a similar dose-response pattern although T-Na was twice as potent. Potentiation by T-Na of responses to the direct acting catechol amines was not affected by reserpinization. When used in place of EDTA for the repletion of norepinephrine stores in reserpinized atria, T-Na has been proved to be more effective than the former agent in retarding the oxidation of norepinephrine. The effect of histamine on the isolated atria was also studied. In a low concentration (0.2-0. 4mcg/ml) histamine stimulated the atria to a prolonged response that can only be terminated by changing the bathing fluid. The response of the atria to histamine was neither affected by the presence of a high concentration of antihistamine (3mcg./ml), nor was it blocked by the pre-addition of a beta-receptor blocking agent. Cocaine and pyrogallol had no effect on the histamine induced response. Therefore it is not likely that norepinephrine is involved in the response of the atria to histamine. In the presence of T-Na, however, the response to histamine was increased in the normal preparation, but T-Na had little or no effect on the histamine induced response in reserpinized atria. These results together with the fact that EDTA potentiated the action of sympathomimetic amines in a similar manner to T-Na do not support the assumption that T-Na potentiation of adrenergic responses is due to COMT inhibition. It would appear that T-Na produces like EDTA, a non-specific sensitization of the atria muscle. This mechanism is not clear and no evidence has been found to indicate that it is due to a general depletion of ions as a result of the chelating action of these compounds.Pharmaceutical Sciences, Faculty ofGraduat