Evidence that the hypotensive action of methyldopa is mediated by central actions of methylnoradrenaline.
12 Apr 2011-Journal of Pharmacy and Pharmacology (Blackwell Publishing Ltd)-Vol. 23, Iss: 6, pp 407-411
TL;DR: The formation ofα‐methylnoradrenaline from α‐MD was prevented after FLA‐63 but there was a significant increase in the amounts of α‐methyldopamine formed.
Abstract: Mean arterial blood pressure was recorded in conscious normotensive rats through indwelling arterial catheters. The effect of l-α-methyldopa (α-MD) (400 mg/kg, i.p.) was studied in animals pretreated with α-methyl-m-tyrosine (400 mg/kg i.p.) 27 and 15 h before α-MD, α-methyl-p-tyrosine methylester (H 44/68) (250 mg/kg, i.p.) 1 h before α-MD, and dl-α-hydrazino-α-methyl-β-(3,4-dihydroxyphenyl) propionic acid (MK 485, 100 mg/kg, i.p.) 30 min before α-MD. This pretreatment, which resulted in a severe depletion of endogenous catecholamines, did not alter the hypotensive effect of α-MD. The effect of α-MD (200 mg/kg, i.p.) was studied 30 min after pretreatment with the dopamine β-hydroxylase inhibitor, bis (4-methyl-l-homopiperazinyl-thiocarbonyl) disulphide (FLA-63) (25 mg/kg, i.p.). The hypotensive response to α-MD was completely abolished in these experiments. The formation of α-methylnoradrenaline from α-MD was prevented after FLA-63 but there was a significant increase in the amounts of α-methyldopamine formed.
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TL;DR: It is concluded that CAs and clonidine are inhibitory to the maintained activity of SPNs and that an alpha2-adrenergic receptor may be involved in the action of these compounds.
Abstract: The neuropil surrounding sympathetic preganglionic neurons (SPNs) receives an abundant catecholaminergic innervation originating from the brain stem. The effect of catecholamines (CA) released at this spinal level on the activity of SPNs is still controversial as is the extent to which this particular CA transmission is affected by central antihypertensive drugs, such as clonidine and alpha-methyldopa. The present study was initiated, therefore, to determine the effects of iontophoretic applications of CAs and clonidine on the discharges of identified SPNs and to determine the type of receptor mediating the action of these compounds. Extracellular recordings were made with five- or six-barrel electrodes in 20 pigeons anesthetized with urethane, artificially ventilated, and immobilized. Data were obtained on 83 SPNs localized in the three first thoracic segments and identified on the basis of constancy of antidromic activation latency and collision. All of the cells sampled were inhibited by the application of low iontophoretic currents of clonidine and by a series of CAs, including alpha-methylnorepinephrine, epinephrine, and phenylephrine. For each compound, the amount of charge necessary to decrease the level of cell firing to 50% of control was calculated. Using this value as an index of drug potency, the following rank order could be determined: clonidine greater than alpha-methylnorepinephrine greater than epinephrine greater than norepinephrine greater than phenylephrine. The inhibitory effects of both clonidine and norepinephrine were antagonized by iontophoretic applications of the alpha antagonists, yohimbine, piperoxan, and phentolamine. In contrast, the beta antagonist, sotalol, and the alpha 1 antagonist, prazosin, were found ineffective when similarly applied. It is concluded that CAs and clonidine are inhibitory to the maintained activity of SPNs and that an alpha2-adrenergic receptor may be involved in the action of these compounds.
190 citations
Cites background from "Evidence that the hypotensive actio..."
...It is amply documented that this centrally active drug has to be converted by noradrenergic or adrenergic terminals into cu-methyl- NE or cY-methylepinephrine in order to exert its hypotensive action (Henning and Rubenson, 1971; Van Zwieten, 1980)....
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TL;DR: This report reviews a number of significant developments in the fields of noradrenergic transmission and adrenergic receptors which suggest that, in addition to the classical postsynaptic adrenoceptors, there are also presynaptic adrenOceptors that help modulate tbe release of norepinephrine from peripheral as well as central norADrenergic nerve endings during nerve stimulation.
Abstract: This report reviews a number of significant developments in the fields of noradrenergic transmission and adrenergic receptors which suggest that, in addition to the classical postsynaptic adrenoceptors, there are also presynaptic adrenoceptors that help modulate the release of norepinephrine (NE) from peripheral as well as central noradrenergic nerve endings during nerve stimulation. In particular, stimulation of presynaptic alpha-adrenoceptors reduces this release of transmitter and the reverse is observed after blockade of these receptors. Clearcut pharmacological differences exist between the postsynaptic alpha 1-adrenoceptors that mediate the responses of certain organs and the presynaptic alpha 2-adrenoceptors that modulate the NE release during nerve stimulation. Therefore, subclassification of alpha-adrenoceptors into alpha 1 and alpha 2 subtypes is warranted but must be considered to be independent of the anatomical location of these receptors. Some noradrenergic nerve endings have also been shown to possess beta-adrenergic receptors, the stimulation of which increases the quantity of transmitter released by nerve impulses. Physiologically, these receptors could be activated by circulating epinephrine (E) and be involved in essential hypertension. A third type of catecholamine receptor found at the noradrenergic nerve ending is the inhibitory dopamine (DA) receptor, which might be of significance in the development of new antihypertensive agents. Application of these new concepts of noradrenergic neurotransmission and the subclassification of alpha-adrenoceptors to the treatment of hypertension is presented. Clonidine, for example, appears to be a potent alpha 2-adrenoceptor agonist; the central receptor involved in its antihypertensive action is pharmacologically an alpha 2-type but located postsynaptically. Clonidine also induces activation of peripheral presynaptic alpha 2-adrenoceptors, which might contribute to its cardiovascular action. The antihypertensive effects of alpha-methyldopa are related to the formation of alpha-methylnorepinephrine, a preferential alpha 2-adrenoceptor agonist, which can stimulate peripheral presynaptic alpha 2-adrenoceptors leading to a decrease of NE release and a reduction in sympathetic tone. Prazosin is a new antihypertensive agent the mechanism of action of which involves a selective blockade of postsynaptic alpha 1-adrenoceptors. This drug does not antagonize several effects of clonidine that are mediated via alpha 2-adrenoceptors. The mechanisms presently considered to account for the antihypertensive activity of beta-adrenoceptor blocking agents are numerous. It is proposed that blockade of peripheral presynaptic facilitatory beta-adrenoceptors could be of significance in the antihypertensive action of these drugs.
169 citations
TL;DR: Evidence is presented supporting the hypothesis that clonidinelike drugs act either directly or indirectly on CNS postsynaptic alpha 2-adrenoceptors to cause pupillary dilation by reduction of parasympathetic neural tone to the iris.
139 citations
TL;DR: In anaesthetized rats, bilateral injections of α‐methylnoradrenaline, noradrenalin or adrenaline into the area of the nucleus tractus solitarii of the brain stem caused dose‐dependent decreases of systemic arterial blood pressure and heart rate.
Abstract: 1 In anaesthetized rats, bilateral injections of alpha-methylnoradrenaline, noradrenaline or adrenaline into the area of the nucleus tractus solitarii (NTS) of the brain stem caused dose-dependent decreases of systemic arterial blood pressure and heart rate. The effects of alpha-methylnoradrenaline were most pronounced and lasted longest. 2 The cardiovascular effects of alpha-methylnoradrenaline appeared to be restricted to the medio-caudal part of the NTS. 3 Prior administration of the alpha-adrenoceptor blocking agent, phentolamine, reversed the fall in blood pressure and heart rate induced by alpha-methylnoradrenaline into an increase. 4 Systemic administration of atropine combined with vagotomy potentiated the inhibitory effects of alpha-methylnoradrenaline on the cardiovascular system.
101 citations
References
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TL;DR: A method for chemical assay of small amounts of adrenaline and noradrenaline in tissues is described, utilizing the difference in the activation spectra of the fluoro-phores to identify the two amines.
Abstract: Summary.
A method for chemical assay of small amounts of adrenaline and noradrenaline in tissues is described. The catechol amines are extracted with perchloric acid. The extracts are passed through a cation exchange column (Dowex 50) which takes up the catechol amines. Elution of the amines from the column is performed by hydrochloric acid. Estimation of the two amines in the eluates is made fluorimetrically after oxidation and rearrangement in alkali. Differentiation between adrenaline and noradrenaline is performed by utilizing the difference in the activation spectra of the fluoro-phores.
993 citations
TL;DR: Clonidine increased the flexor reflex of spinal rats also after depletion of all known noradrenaline stores, indicating a stimulation of also central noradRenaline receptors.
545 citations
TL;DR: In this paper, α-Methyl DOPA (DOPA = 3,4-dihydroxyphenylalanine) and α-methyl metatyrosine were injected to mice (400 mg/kg intraperitoneally).
Abstract: α-Methyl DOPA (DOPA = 3,4-dihydroxyphenylalanine) and α-methyl metatyrosine were injected to mice (400 mg/kg intraperitoneally). The former amino acid was also injected to rabbits (200 mg/kg intravenously). At varying intervals after the injection the brains were examined for monoamines (5-hydroxytryptamine, noradrenaline, dopamine, and α-methyl analogues). A transient decrease in 5-hydroxytryptamine and dopamine and a prolonged and more marked decrease in noradrenaline were observed. The α-methyl amino acids were found to undergo decarboxylation and subsequent β-hydroxylation in vivo. The drop in noradrenaline and dopamine levels in brain caused by the α-methyl amino acids appears to be largely due to displacement by these decarboxylation products, which may possibly also take over the functions of the physiological amines.
498 citations
Journal Article•
TL;DR: The prolonged depletion of norepinephrine for days after its precursor dopamine, and serotonin have returned to normal levels is clearly not related to inhibition of the decarboxylation enzyme and is caused by the impairment of the tissues to hold the hormone.
Abstract: α-Methyl-3-hydroxyphenylalanine and L-α-methyl-3,4-dihydroxyphenylalanine are decarboxylase inhibitors in vitro and in vivo . Both compounds deplete endogenous norepinephrine in brains and hearts and serotonin levels in the brains of rats and guinea pigs. Although the levels of serotonin return to normal in less than 24 hours, approximating the return to normal activity of the decarboxylation enzyme, the norepinephrine levels in the heart remain depressed for days longer. This study has shown that biosynthesis of norepinephrine can occur during this period and that the ability of the heart to hold norepinephrine is impaired. The prolonged depletion of norepinephrine for days after its precursor dopamine, and serotonin have returned to normal levels is clearly not related to inhibition of the decarboxylation enzyme. This report further demonstrates that the longlasting effect on norepinephrine is caused by the impairment of the tissues to hold the hormone.
195 citations