%0 Journal Article %A L. Cubeddu X. %A W. Mosimann %A N. Weiner %T THE EFFECT OF METHYLGUANIDINE ON NOREPINEPHRINE METABOLISM IN ISOLATED, PERFUSED SPLEEN AND HEART %D 1974 %J Journal of Pharmacology and Experimental Therapeutics %P 93-106 %V 188 %N 1 %X Approximately 15 minutes after initiation of a continuous infusion of 6 pmol/min of l-3H-norepinephrine (NE) into the isolated cat spleen, a steady state develops in which 34% of the total 3H administered per minute is recovered in the effluent. During this steady-state condition, cocaine and methylguanidine inhibit the removal of l-3H-NE in a concentration-dependent manner. In spleens which have been labeled with 3H-NE one hour previously, there is a spontaneous efflux of radiolabeled substances, of which over 80% is deaminated metabolites, and only 5% is unchanged 3H-NE. Methylguanidine (4.1 mM) produces a 12-fold increase in the efflux of 3H-NE. Concentrations of cocaine which produce similar degrees of inhibition of the removal of l-3H-NE only slightly increase the percentage of NE released spontaneously, indicating a largely presynaptic origin of the deaminated metabolites. The in vitro inhibition of spleen monoamine oxidase using 5-hydroxytryptamine as substrate, the increase in 3H-NE retention in spleens from reserpine-treated cats and the marked decrease in the spontaneous efflux of 3H-deaminated metabolites produced by methylguanidine suggest that this substance affects NE metabolism in the spleen at least in part by inhibiting intraneuronal monoamine oxidase. The blockade of uptake and the monoamine oxidase inhibition may account for the progressive accumulation of spontaneously released NE in the perfusion fluid which is seen when the fluid is recirculated through the spleen. This progressive accumulation of NE could account for the delayed increase in NE levels and the delayed chronotropic effect observed by Krayer et al. (J. Pharmacol. Exp. Ther. 154: 73-82, 1966; 181: 108-115, 1972) when methylguanidine is present in the recirculating blood of the dog heart-lung preparation. © 1974 by The Williams & Wilkins Company %U https://jpet.aspetjournals.org/content/jpet/188/1/93.full.pdf