ON THE MECHANISM OF ADRENALINE POTENTIATING ACTION OF COCAINE

Abstract

It is widely known that cocaine potentiates the responses of sympathetically innervated organs to adrenaline, sympathin, and to sympathetic nerve stimulation. Adrenaline potentiating action of cocaine was first observed by Froehlich and Loewi (1) in 1910. But the mode of this action has not yet been clearly established, though many experiments have since been carried out in order to account for the phenomenon. It has been suggested that cocaine enhances the sensitivity of adrenergic effector systems, or protects the autoxidation of adrenaline or increases the permeability of sympathetically innervated cells, thus favoring the entrance of stimulating agents. Recently, with the advance in the study of metabolism of adrenaline, it has been suggested that the potentiating action of cocaine is due to inhibition of the enzymatic systems which inactivate adrenaline in vivo.
On the other hand, the fate of adrenaline is still unknown, in spite of many experiments that have been done on this problem. Hynal (2) and many others reported that liver destroys adrenaline in vivo, while Markowitz (3) and others obtained the negative results. Even in vitro experiments, Embden (4) and others observed the destruction of adrenaline in blood but Machii (5) and others observed the fact that adrenaline is inactivated by perfusion through the isolated liver or other organs, or by addition of various tissue extracts. On the contrary, Oliver and Schaefer (6) found that small amount of suprarenal extract or adrenaline retained its activity much longer in blood than in aqueous solution, and this observation has many times been confirmed by Wiltshire (7) and many other investigators who suggested that in blood and tissues is present an inhibitor of autoxidation of adrenaline such as protein, amino acids, ascorbic acid or glutathion.
More recently, various enzymes inactivating adrenaline were discovered from animal and plant tissues and one of them is called amine oxidase. It is considered that amine oxidase is contained abundantly in liver and intestine, the inactivating power of which is much stronger than that in other organs. It is not yet clear, however, how much important part these enzymes play in the inactivation of adrenaline in the animal body. Richter (8) reported that the rapid inactivation of adrenaline in vivo is rather due to sulfoconjugation than to amine oxidase. Bacq (9) has also expressed doubts on the deamination of adrenaline due to amine oxidase in vivo. Okamura (10) described that the rapid disappearance of the biological action of adrenaline in vivo is mainly due to the adsorption of adrenaline by red blood-corpuscles but not due to the oxidative destruction. Since Gaddum (11) has explained the ephedrine potentiation to adrenaline by inhibition of amine oxidase, MacGregor (12), Tripot (13) and Philpot (14) have extended Gaddum's hypothesis, and have proved that not only ephedrine but also cocaine and other local anesthetics inhibit the action of enzymes which inactivate adrenaline. Philpot (14) pointed out that amine oxidase is much more strongly affected by these local anesthetics than other enzymes, but Bain et al. (15) described that cocaine cannot diminish the adrenaline inactivating power of liver in vitro. As above mentioned, the fate of adrenaline in vivo is very complicated, and the experimental evidences are not yet sufficient to show how cocaine prevents adrenaline from inactivation. It was, therefore, intended to study the effects of cocaine and other local anesthetics on the action or adrenaline, on the detoxication of adrenaline in liver in vivo and in vitro and also the correlation between blood and tissues (especially liver extract) which may possibly be connected with the inactivation of adrenaline. Furthermore, the influence of local anesthetics (especially cocaine) on the adrenaline inactivation in vitro was investigated.