Comparison of the effects of SK & F 29661 and 64139 upon adrenal and cardiac catecholamines.

After 7 day dosing with SK & F 64139, an inhibitor of adrenal and CNS PNMT, a stoichiometric relationship is observed between epinephrine decrease and norepinephrine increase in adrenal tissue. However, this relationship is not found with the adrenal PNMT inhibitor, SK & F 29661. SK & F 64139 was found to possess significant adrenal MAO inhibitory activity, but SK & F 29661 does not. Three factors are presented which argue against MAO inhibition as the cause of the catecholamine profile difference. We then performed various studies with SK & F 29661 and 64139 to examine whether enzymes in the norepinephrine biosynthetic pathway are differentially affected by these drugs and found that they were not. However. when rats were dosed with either SK & F 29661 or 64139 over 24 h and the adrenal catecholamine stores were then radioactively labeled with a tracer dose of 3H-norepinephrine, the rate of 3H-norepinephrine disappearance was reduced in the SK & F 64139-treated animals as compared with those given SK & F 29661. A similar result was observed in the heart. These results suggest that SK & F 64139 may reduce norepinephrine turnover in the adrenal gland and heart via an effect not related to peripheral PNMT inhibition. These findings also demonstrate quite clearly that in intact animals all PNMT inhibitors do not produce identical endogenous catecholamine profiles.