RT Journal Article
SR Electronic
T1 THE POTENTIATION OF RESPONSES TO ADRENERGIC NERVE STIMULATION IN THE PRESENCE OF COCAINE: ITS RELATIONSHIP TO THE METABOLIC FATE OF RELEASED NOREPINEPHRINE
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 431
OP 443
VO 191
IS 3
A1 S. Z. Langer
A1 María A. Enero
YR 1974
UL http://jpet.aspetjournals.org/content/191/3/431.abstract
AB Responses of the nerve-muscle preparation of the isolated medial muscle of the cat nictitating membrane were determined to nerve stimulation and to exogenous norepinephrine. Cocaine, 0.9 x 10-6 M, induced a shift to the left and an increase in the maximum of the frequency-response curve to nerve stimulation. The responses to nerve stimulation were not affected when monoamine oxidase was inhibited by pretreatment with pargyline or when catechol-O-methyltransferase was inhibited by exposure to U-0521 (3,4-dihydroxy-α-methylpropiophenone). The responses to nerve stimulation remained unchanged when both metabolizing enzymes were simultaneously inhibited. Similar results were obtained for exogenous norepinephrine with the exception of pretreatment with pargyline which induced a small shift to the left in the dose-response curve to norepinephrine. In the medial muscle of the nictitating membrane labeled with 3H-norepinephrine (3H-NE), the deaminated glycol, 3,4-dihydroxyphenylglycol (3H-DOPEG), was the main metabolite in the spontaneous outflow. Unmetabolized 3H-NE represented only 23.3 ± 1.6% of the total increase in radioactivity elicited by nerve stimulation while 3H-DOPEG accounted for 48.2 ± 2.7%. Exposure to cocaine, 0.9 x 10-6 M, did not increase transmitter overflow, but modified the metabolism of 3H-NE released by stimulation. In the presence of cocaine, the 3H-NE fraction increased to 44.1 ± 2.2% of the total overflow whereas the contribution of 3H-DOPEG was reduced to 7.0 ± 1.0%. These results indicate that 3H-DOPEG formation from 3H-NE released by nerve stimulation resulted from the presynaptic metabolism by monoamine oxidase and aldehyde reductase of the released transmitter which was recaptured by adrenergic nerve endings. Potentiation of responses to nerve stimulation in the presence of cocaine appears to be mainly due to an increase in the proportion of the released transmitter which is not metabolized and which therefore reaches the adrenergic receptors of the effector organ. © 1974 by The Williams & Wilkins Co.