MODIFICATION OF THE EFFECTS OF SYMPATHOMIMETIC AMINES AND OF ADRENERGIC NERVE STIMULATION BY 1-ISONICOTINYL-2-ISOPYROPYLHYDRAZINE (IIH) AND ISONICOTINIC ACID HYDRAZIDE (INH)

¹ Department of Physiology and Pharmacology, Graduate School of Medicine, University of Pennsylvania, Philadelphia, Pa.
² Department of Physiology and Pharmacology, Graduate School of Medicine, Univeristy of Pennsylvania, Philadelphia, Pa.

The progressive effects of IIH and INH (0.4-0.5 mM/kgm., intraperitoneally) were measured on the response of the cat's nictitating membrane to stimulation of the cervical sympathetic trunk, and to the intraarterial intjection of epinephrine, norepinephrine and tyramine. Monoamine oxidase (MAO) activity of the liver, kidneys and brain was determined subsequently. IIH usually produced depression, followed by potentiation, of the response to both nerve stimulation and the amines; MAO activity was inhibited practically completely in all three organs. After INH, only potenitiation was usually seen and MAO was unaffected. The response to tyramine, in contrast to those to epinephrine and norepinephrine, was potentiated much more by IIH than by INH; MAO-inihibition was therefore probably a major causative factor in the increase in its activity.

IIH and INH produced reversible antagonism of the stimulant effect of epinephrine on the isolated guinea pig's uterus and rat seminal vesicle; IIH was conisiderably more potent in this respect. Hence, the initial depressant effect of the latter drug on the response of the cat's nictitatinig membrane was probably due to adrenergic blockade.

Both hydrazides produced significant inhibition of cytochrome oxidase activity in vitro only in extremely high concentrations (10-2 M) when ascorbate, epinephrine on norepintephrine was used as the reductant of cytochrome C. Thus, it is unlikely that this effect was responsible for the observed potentiation.

Inhibition of the autoxidation or copper-catalyzed oxidation of epinephrine Or norepinephrine likewise required high concentrations of IIH or INH. Both hydrazides were found to form complexes with adrenochrome; the latter reaction might have contributed to the apparent autoxidation-inhibition.

It was Concluded that the present findings do not indicate that the potentiatinig effect of IIH and INH on epinephrine and norepinephrine is due to enzymatic inhibition. The most likely explanation, as suggested by previous authors for similarly acting drugs, is that the hydrazides interfere with the penetration of the amines to intracellular sites, and thus prolong their presence in effective concentrations at receptor sites.