METABOLISM OF dl-NOREPINEPHRINE-7-H³ IN RABBITS TOLERANT TO l-NOREPINEPHRINE

¹ Department of Psychiatry and Neurology, New York University Medical Center, New York, N. Y., and Department of Medicine, Mt. Sinai Hospital, N. Y.

Rabbits made tolerant to narcotic and lethal doses of l-norepinephrine (3.2 mg/kg intravenous) were infused with dl-norepinephrine-H³ at a rate of 50 µc/kg min^-1 for 20 minutes. Concentrations of norepinephrine-H³ in plasma obtained during infusion and for 40 minutes thereafter were similar for the tolerant group, controls and a group treated 24 hours earlier with reserpine (1 mg/kg). Except for reduced concentrations in the heart, uptake of norepinephrine-H³ in organs of tolerant animals was found similar to the controls. In the groups treated with reserpine, norepinephrine-H³ binding was less in all organs but the kidney.

Only about half the normal catechol concentrations were found in hearts of tolerant animals, yet both spleen and kidney were found to contain several times the control amount. Although reserpine markedly diminished the catechol content of the heart, no significant decrease occurred in spleen or kidney.

Mean concentrations of unchanged norepinephrine-H³ in the urines of each group were similar although significantly less normetanephrine was found in the urines of tolerant animals, as well as higher concentrations of unknown catabolites. No increase in identified conjugated metabolites was found associated with tolerance.

Altered peripheral metabolism does not appear to be related to the development of tolerance to the lethal and narcotic effects of norepinephrine.