FLA 136: Selective agonist at central alpha-adrenoreceptors mediating changes in the turnover of noradrenaline
- 11 Downloads
FLA 136 [4-amino-3-(2,6-dichlorobenzylidenehydrazino)-1,2,4-triazol] did not change the hindlimb flexor reflex of spinal rats, but it reduced the clonidine-induced increase in this reflex at high doses.
The α-methyltyrosine-induced disappearance of noradrenaline in the rat central nervous system was decelerated by FLA 136, with a peak effect after 15 mg/kg i.p. The accumulation of Dopa following decarboxylase inhibition was inhibited by FLA 136 (15 mg/kg i.p.) in a noradrenaline-predominant region (brain stem). The effect on the utilization appeared to be greater than that on the synthesis in agreement with a slight increase observed in the concentration of noradrenaline in the brain and the spinal cord.
FLA 136 reduced the α-methyltyrosine-induced disappearance of dopamine, decreased the Dopa accumulation following decarboxylase inhibition in the dopamine-rich corpus striatum and increased the concentration of dopamine. These effects might be secondary to inhibition of the noradrenergic neurotransmission.
Yohimbine almost completely inhibited the effect of FLA 136 on the utilization and on the synthesis of noradrenaline whereas phenoxybenzamine was much less effective on the change in the utilization. Yohimbine and phenoxybenzamine were about equipotent, however, in accelerating the disappearance of noradrenaline produced by α-methyltyrosine alone.
FLA 136 does not stimulate the postsynaptic α-adrenoreceptors mediating the increase in flexor reflex activity but it probably decelerates the utilization of noradrenaline by a stimulation of another kind of α-adrenoreceptors sensitive to yohimbine. The latter receptors might occur on the noradrenergic neurones (presynaptic receptors).
Key wordsNoradrenaline Dopamine Utilization Synthesis Central alpha-adrenoreceptors Presynaptic receptors Postsynaptic receptors
Unable to display preview. Download preview PDF.
- Andén, N.-E., Corrodi, H., Dahlström, A., Fuxe, K., Hökfelt, T.: Effects of tyrosine hydroxylase inhibition on the amine levels of central monoamine neurons. Life Sci. 5, 605–611 (1966)Google Scholar
- Andén, N.-E., Corrodi, H., Fuxe, K., Hökfelt, B., Hökfelt, T., Rydin, C., Svensson, T.: Evidence for a central noradrenaline receptor stimulation by clonidine. Life Sci. 9 (1), 513–523 (1970)Google Scholar
- Andén, N.-E., Grabowska, M.: Pharmacological evidence for a stimulation of dopamine neurons by noradrenaline neurons in the brain. Europ. J. Pharmacol. 39, 275–282 (1976)Google Scholar
- Andén, N.-E., Grabowska, M., Strömbom, U.: Different alphaadrenoreceptors in the central nervous system mediating biochemical and functional effects of clonidine and receptor blocking agents. Naunyn-Schmiedeberg's Arch. Pharmacol. 292, 43–52 (1976)Google Scholar
- Atack, C. V.: The determination of dopamine by a modification of the dihydroxyindole fluorimetric assay. Brit. J. Pharmacol. 48, 699–714 (1973)Google Scholar
- Atack, C. V., Magnusson, T.: Individual elution of noradrenaline (together with adrenaline), dopamine, 5-hydroxytryptamine and histamine from a single, strong cation exchange column, by means of mineral acid-organic solvent mixtures. J. Pharm. Pharmacol. 22, 625–627 (1970)Google Scholar
- Bertler, Å., Carlsson, A., Rosengren, E.: A method for the fluorimetric determination of adrenaline and noradrenaline in tissues. Acta physiol. scand. 44, 273–292 (1958)Google Scholar
- Carlsson, A., Davis, J. N., Kehr, W., Lindqvist, M., Atack, C. V.: Simultaneous measurement of tyrosine and tryptophan hydroxylase activities in brain in vivo using an inhibitor of the aromatic amino acid decarboxylase. Naunyn-Schmiedeberg's Arch. Pharmacol. 275, 153–168 (1972)Google Scholar
- Corrodi, H., Hanson, L. C. F.: Central effects of an inhibitor of tyrosine hydroxylation. Psychopharmacologia (Berl.) 10, 116–125 (1966)Google Scholar
- Eriksson, H. E., Florvall, L. G.: The preparation and antihypertensive activity of 4-amino-3-(2,6-dichlorobenzylidenehydrazino)-1,2,4-triazole and some related compounds. Acta pharmaceut. suec. 13, 79–96 (1976)Google Scholar
- Häggendal, J.: An improved method for fluorimetric determination of small amounts of adrenaline and noradrenaline in plasma and tissues. Acta physiol. scand. 59, 242–254 (1963)Google Scholar
- Hoefke, W., Kobinger, W.: Pharmakologische Wirkungen des 2-(2,6-Dichlorphenylamino)-2-imidazolin-hydrochlorids, einer neuen, antihypertensiven Substanz. Arzneimittel-Forsch. 16, 1038–1058 (1966)Google Scholar
- Kehr, W., Carlsson, A., Lindqvist, M.: A method for the determination of 3,4-dihydroxyphenylalanine (DOPA) in brain. Naunyn-Schmiedeberg's Arch. Pharmacol. 274, 273–280 (1972)Google Scholar
- Schmitt, H., Schmitt, H., Fénard, S.: Action of α-adrenergic blocking drugs on the sympathetic centres and their interactions with the central sympatho-inhibitory effect of clonidine. Arzneimittel-Forsch. 23, 40–45 (1973)Google Scholar
- Spector, S., Sjoerdsma, A., Udenfriend, S.: Blockade of endogenous norepinephrine synthesis by α-methyltyrosine, an inhibitor of tyrosine hydroxylase. J. Pharmacol. exp. Ther. 147, 86–95 (1965)Google Scholar