A new dopamine- -hydroxylase inhibitor: effects on the noradrenaline concentration and on the action of L-DOPA in the spinal cord.
1. The dopamine-beta-hydroxylase inhibitor bis(4-methyl-1-homopiperazinyl-thiocarbonyl) disulphide (FLA-63; 25 mg/kg i.p.) caused within 4 h a 65% loss of noradrenaline throughout the intact rat spinal cord and also cranial to a transection of the cut spinal cord. Caudal to the lesion, there was only an insignificant depletion of 17% indicating the importance of nerve impulses for the disappearance of noradrenaline.2. Dopamine accumulated in the spinal cord after treatment with FLA-63 although the amounts were not sufficient to replace the missing noradrenaline. Even after treatment with L-3,4-dihydroxyphenylalanine (L-DOPA), the catecholamine store was incompletely replenished by dopamine.3. After a large depletion of the noradrenaline stores, induced by repeated doses of FLA-63 or by reserpine plus FLA-63, the L-DOPA-induced increase in flexor reflex activity of the hind limbs of spinal rats was inhibited much more than after pretreatment with alpha-methyl-tyrosine or reserpine. FLA-63 blocked the formation of noradrenaline but not of dopamine from L-DOPA.4. The increase in flexor reflex activity induced by the noradrenaline receptor stimulating agent clonidine was not changed by FLA-63, indicating that the noradrenaline receptor sensitivity was not influenced.5. After depletion of the noradrenaline stores, the small formation of noradrenaline from L-DOPA may be of greater functional significance for the noradrenaline receptor stimulation than the greater formation of dopamine, but the dopamine formed also has a slight action. With intact noradrenaline stores, displacement of endogenous noradrenaline by newly formed dopamine contributes, at least after monoamine oxidase inhibition, to the increase in the flexor reflex activity caused by L-DOPA.
D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D004295:Dihydroxyphenylalanine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D004299:Dopamine beta-Hydroxylase / Q000037:antagonists & inhibitors; D008297:Male; D008856:Microscopy, Fluorescence; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D012026:Reflex, Stretch; D012110:Reserpine / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009435:Synaptic Transmission; D013859:Thiocarbamates / Q000494:pharmacology; D014443:Tyrosine / Q000494:pharmacology
D013859:Thiocarbamates; D014443:Tyrosine; D004295:Dihydroxyphenylalanine; D012110:Reserpine; D006899:Mixed Function Oxygenases; D004299:Dopamine beta-Hydroxylase; D003000:Clonidine; D004298:Dopamine; D009638:Norepinephrine