The disposition of 3H-(--)noradrenaline in the perfused cat and rabbit heart.
1. Hearts of cats and rabbits were perfused at a constant rate with 3H-(--)noradrenaline for 60-120 min. During the perfusion the rate of net removal of 3H-noradrenaline from the perfusion fluid and the rate of efflux of 3H-metabolites from the hearts were followed. From these results and from the amount of 3H-metabolites recovered from the hearts (at the end of experiments), the time course of the cumulative metabolite formation was obtained. The following metabolites were determined: 3,4-dihydroxyphenylethyleneglycol (DOPEG), 3,4-dihydroxymandelic acid (DOMA), normetanephrine (NMN) and a fraction consisting of 3-methoxy-4-hydroxyphenylethyleneglycol and 3-methoxy-4-hydroxymandelic acid (OMDA). 2. In normal hearts, the rate of formation of DOPEG, DOMA and OMDA became constant only after a considerable delay, and the rate of efflux of these metabolites did not reach a constant value within 120 min. By contrast, the formation of NMN proceeded at a constant rate throughout the perfusion with 3H-noradrenaline, and the rate of efflux of NMN approached a steady level within about 30 min. 3. In hearts of reserpine-pretreated animals not only NMN, but also DOPEG, DOMA and OMDA quickly approached a constant rate of formation. In addition, the efflux of all metabolites attained a steady level, and after about 70 min, the hearts of both species reached a steady state in which the net removal of 3H-noradrenaline was fully accounted for by the formation of metabolites. 4. The metabolite pattern during the steady state showed striking species differences. The rate of metabolite formation (expressed % of the steady-state rate of 3H-noradrenaline removal) decreased in the order DOPEG (40.0%) greater than NMN (30.8%) greater than DOMA (18.1%) greater than OMDA (9.0%) in the cat heart and DOPEG (66.8%) greater DOMA (20.0%) greater than OMDA (6.6%) greater than NMN (1.5%) in the rabbit. 5. In both species, 30 mumol . 1-1 cocaine (to inhibit neuronal uptake) decreased the rate of formation of DOPEG, DOMA and OMDA to very low values, but increased the formation of 3H-NMN. 6. In the cat heart, 30 mumol . 1-1 hydrocortisone (to inhibit extraneuronal uptake) decreased the formation of NMN, while having no effect on the formation of DOPEG, DOMA and OMDA. Moreover, in the cat and rabbit heart perfused in the presence of cocaine, inhibition of extraneuronal uptake markedly affected the formation of NMN. 7. A linear relationship was found for all metabolites between the rate of efflux and the tissue content (both parameters being determined during steady state), indicating first-order kinetics of efflux. The ranking order of the overall rate constants for efflux was DOPEG much greater than NMN greater than DOMA.
D000588:Amines / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D002415:Cats; D003042:Cocaine / Q000494:pharmacology; D005260:Female; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D011817:Rabbits; D012110:Reserpine / Q000494:pharmacology; D013045:Species Specificity
D000588:Amines; D012110:Reserpine; D003042:Cocaine; D009638:Norepinephrine