THE SYMPATHOMIMETIC EFFECTS OF SKF-385 ON BLOOD PRESSURE IN DOG

Abstract

The chemical structure of SKF-385, the potent monoamine oxidase inhibitor, is closely related to that of methamphetamine. The sympathomimetic effects of SKF-385 have already been reported (1, 2). Shideman et al. (1) and Horita et al. (3) have concluded that the sympathomimetic effects of SKF-385 as well as phenyl-isopropyl hydrazine (Catron) derived from the release of endogenous noradrenaline rather than from the inhibitory effect of the drugs on the monoamine oxidase. The adrenaline-like stimulating effects of SKF-385 on the isolated auricular preparation of rabbit (Toda, unpublished) and on the transmembrane potentials of the isolated atrium of rabbit (4) have been confirmed in this laboratory. Toda and Tachi also showed that the administration of SKF-385 retarded the manifestation of the depressive effects of re3erpine on the rhythmical contraction and the action potential of the isolated atrium. They further showed that although the isolated atrium depressed by addition of reserpine was not recovered by the washing-out of reserpine from the preparation, the isolated atrium of rabbit which had previously received SKF-385 was also depressed by addition of reserpine in vitro, but was easily recovered by the washing-out of reserpine from the preparation. Matsuo (5) in this laboratory showed that the administration of SKF-385 to the isolated atrium increased the content of noradrenaline in the tissue, and that the administration of reserpine to the isolated atrium pretreated with SKF-385 markedly increased the content of noradrenaline. From these results, the suggestion that the effect of SKF-385 on the atrium might correlate with the release of noradrenaline seems to be doubtful.
On the other hand, Burn and Rand (6) have proposed the working hypothesis that the sympathomimetic effects of amphetamine derived from the release of the endogenous noradrenaline, and that the tachyphylaxis caused by the repeated injection of the drug derived from the consumption of the stored amine. The sympathomimetic effects of SKF-385 on the blood pressure easily subjected to tachyphylaxis by the repeated injection.
The mode and mechanism of the sympathomimetic effect of SKF-385 have been analyzed in the anesthetized dog, whose blood pressure had shown a marked tachyphylaxis against the drug.