SUPERSENSITIVITY TO NOREPINEPHRINE INDUCED BY CONTINUOUS NERVE STIMULATION

¹ Department of Pharmacology, Harvard Medical School, Boston, Massachusetts

A new procedure is described that results in supersensitivity of the nictitating membrane of the spinal cat to l-norepinephrine. After pretreatment with reserpine (to deplete the norepinephrine stores) , continuous preganglionic stimulation caused a very small sustained contraction of the nictitating membrane; the doseresponse curve for l-norepinephrine, however, was shifted to the left by a factor of 4.2. After additional pretreatment with iproniazid (to inhibit monoamine oxidase), nerve stimulation produced a 10-fold supersensitivity of the stimulated nictitating membrane to l-norepinephrine. This supersensitivity resembles that observed after cocaine in being 1) more pronounced for l-norepinephrine than for the d-isomer, 2) pronounced for phenylephrine but not for the corresponding p-hydroxy compound, synephrine, and 3) observed with small but not with high doses of acetylcholine. These findings indicate that a presynaptic mechanism is involved. Prevention of uptake did not appear to be the mechanism responsible, because the effects of tyramine were increased during nerve stimulation. The observed supersensitivity appears to be the result of immediate release by nerve stimulation of the amines taken up into the nerve terminals after their intravenous injection. Neither pretreatment with reserpine nor pretreatment with reserpine plus iproniazid affected the sensitivity of the unstimulated nictitating membrane to l-norepinephrine. The duration of the responses to l-norepinephrine was not affected by pretreatment with reserpine, but the additional inhibition of monoamine oxidase by iproniazid resulted in a marked prolongation of the responses.