RT Journal Article
SR Electronic
T1 SPECIES DIFFERENCES IN THE CARDIAC EFFECTS OF A MONOAMINE OXIDASE INHIBITOR
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 142
OP 151
VO 136
IS 2
A1 Nelson D. Goldberg
A1 F. E. Shideman
YR 1962
UL http://jpet.aspetjournals.org/content/136/2/142.abstract
AB Concentrations of catecholamines in the hearts of rats and cats were determined before and at various times after the administration of trans-2-phenylcyclopropylamine (SKF-385). The inotropic effects of this compound were investigated in isolated preparations of rat and cat atria and the metabolism of norepinephrine by homogenates of rat, cat and human heart was studied. Intraperitoneal injection of SKF-385 in doses ranging from 2 to 30 mg/kg produced significant depletion (50 to 70%) of myocardial catecholamines in the cat. A reduction in concentration was observed as soon as 3 hours after administration of the drug and a maximal effect occurred at 12 hours. Within 48 hours concentrations were within the normal range. A qualitatively opposite effect on the catecholamine content of the rat heart was observed. In this species concentrations of these amines were increased 27 to 90% after doses of 2 to 20 mg/kg. A significant change in concentration in the rat heart was slower in occurring (6 to 12 hours) and of longer duration (> 48 hours) than that observed in the cat myocardium. The qualitative effects of multiple daily doses of SKF-385 were similar to those obtained with a single injection, depletion of myocardial catecholamines occurring in the cat and accumulation in the rat. Iproniazid also was shown to be capable of producing a reduction in concentration of catecholamines in the cat heart. SKF-385 (5 x 10-9 M) exhibited positive inotropic effects on both rat and cat atria. The most striking and significant difference in the two species was in the duration of the response, being more than five times longer in the rat than in the cat. The responses in both species were inhibited by DCI, βTM10 and prior treatment of the animal with reserpine. Studies of homogenates of ventricular myocardium of the rat, cat and human also disclosed species differences in the metabolism of norepinephrine. Metabolism of this catecholamine by homogenates of rat heart proceeded at a rapid, linear rate. Addition of an active methyl donor to the system enhanced metabolism only slightly. Whereas the monoamine oxidase inhibitor, SKF-385, inhibited metabolism approximately 90%, catechol, an inhibitor of catechol-O-methyl transferase, was only slightly inhibitory. Homogenates of the cat heart demonstrated only a negligible capacity to metabolize norepinephrine unless supplemented with S-adenosylmethionine. Using preparations so supplemented a graded inhibition of metabolism in the presence of increasing concentrations of catechol was observed. SKF-385 had little effect. Homogenates prepared from biopsy specimens of human ventricular myocardium displayed a pattern of metabolism and response to inhibitors similar to those observed with homogenates of rat heart. The results have been discussed with regard to the mechanism of MAO inhibitor-induced cardiac stimulation, the availability of different myocardial catecholamine inactivating mechanisms, and the relationship of these factors to the observed species differences in the effects of MAO inhibitors.