DIFFERENTIAL EFFECTS OF Α-Methyldopa, CLONIDINE AND HYDRALAZINE ON NOREPINEPHRINE AND EPINEPHRINE SYNTHESIZING ENZYMES IN THE BRAINSTEM NUCLEI OF SPONTANEOUSLY HYPERTENSIVE RATS

Nakamura, Kazuo; Okada, Toshikazu; Ishii, Hisae; Nakamura, Keiji

doi:10.1254/jjp.30.1

Cited by 7 publications

(4 citation statements)

References 30 publications

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“…Consistent with the idea that catecholamine synthesis in the central nervous system and in the periphery is differently regulated and in agreement with previous reports [26–28], we also show that the activity of tyrosine hydroxylase and catecholamine levels in the brain of spontaneously hypertensive rats was reduced after clonidine treatment. Catecholamine synthesis in spontaneously hypertensive rat brain has been shown to be decreased in the pre‐hypertensive stage and increased in hypertensive animals [29].…”

Section: Discussionsupporting

confidence: 94%

Effect of Clonidine on Tyrosine Hydroxylase Activity in the Adrenal Medulla and Brain of Spontaneously Hypertensive Rats

Moura

Afonso

Serrão

et al. 2009

Basic Clin Pharma Tox

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Abstract:In the present study, we evaluated the effect of the α 2 -adrenoceptor agonist clonidine on tyrosine hydroxylase activity in adrenal medulla and brain of spontaneously hypertensive rats and Wistar Kyoto rats. Six-week-old animals were treated with clonidine (100 μ g/kg body weight, daily, i.p.) for 4 weeks. Treatment with clonidine significantly reduced mean arterial blood pressure in spontaneously hypertensive rats to values similar to normotensive Wistar Kyoto rats. In the adrenal medulla of spontaneously hypertensive rats, clonidine treatment produced a significant increase in tyrosine hydroxylase activity with higher V max values and no changes in K M values. This effect was accompanied by a significant increase in tyrosine hydroxylase protein expression and of noradrenaline and adrenaline levels. In the brain of spontaneously hypertensive rats, treatment with clonidine produced a significant decrease in tyrosine hydroxylase activity with lower V max values and no changes in K M values accompanied by a significant decrease in tyrosine hydroxylase protein expression and of dopamine and noradrenaline levels. In Wistar Kyoto rats, clonidine treatment had no effect on tyrosine hydroxylase activity and protein expression or catecholamine levels in adrenal medulla or brain. Clonidine treatment significantly reduced noradrenaline and adrenaline plasma levels in spontaneously hypertensive rats and Wistar Kyoto rats. In conclusion, treatment with the α 2 -adrenoceptor agonist clonidine prevented the increase in mean arterial blood pressure in young spontaneously hypertensive rats. This effect was accompanied by opposite effects on tyrosine hydroxylase activity in spontaneously hypertensive rat adrenal medulla and brain: an increase in adrenal medulla and a decrease in brain, bringing sympathetic function to a similar profile found in normotensive Wistar Kyoto rats.The endogenous catecholamines noradrenaline and adrenaline mediate sympathetic regulation of blood pressure [1]. These effectors of the sympathetic nervous system are synthesized within sympathetic neurons and chromaffin cells of the adrenal medulla by a well-defined series of reactions that start with the conversion of tyrosine to 3,4-dihydroxyphenylalanine mediated by tyrosine hydroxylase, the initial and rate-limiting enzyme of the pathway [2]. Noradrenaline is the principal neurotransmitter of sympathetic neurons, whereas adrenaline is secreted from the chromaffin cells of the adrenal medulla into the circulation. Whereas the actions of noradrenaline are mostly restricted to the sites of release from sympathetic nerves, adrenaline acts as a neurohormone to activate cardiovascular and metabolic responses via the blood stream.Increased sympathetic nervous system activity with higher tyrosine hydroxylase activity and catecholamine levels are common features of hypertension in human beings and in the spontaneously hypertensive rat [3,4], an animal model used to investigate the mechanisms of essential hypertension [5]. It is noteworthy that in spont...

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Section: Discussionsupporting

confidence: 94%

Effect of Clonidine on Tyrosine Hydroxylase Activity in the Adrenal Medulla and Brain of Spontaneously Hypertensive Rats

Moura

Afonso

Serrão

et al. 2009

Basic Clin Pharma Tox

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“…Co-exposure of cells with the CYP1A inhibitor α-naphthoflavone did not result in reduced bioactivity of 3- and 8-methylquinoline (Figure , +ANF). However, their effects were significantly suppressed in the presence of hydralazine, which is a known inhibitor of AOX and several NMTs. − The effect of 3-methylquinoline was reduced by 55% (one-way ANOVA with Dunnett’s multiple comparison test, p = 0.0013) and that of 8-methylquinoline by 23% ( p = 0.0324). On the basis of these findings, it is likely that the transformation of methylquinolines to bioactive metabolites was catalyzed by either AOXs or NMTs.…”

Section: Resultsmentioning

confidence: 99%

“…An E2 (Sigma-Aldrich) dilution series ranging from 0.1 to 100 pM and a DMSO solvent control (0.1%) were included in triplicates on each plate. In addition to testing of individual chemicals, cells were coexposed to 150 mg L –1 3-methylquinoline and 8-methylquinoline, respectively, and either the AOX/NMT inhibitor hydralazine, − or the CYP1A inhibitor α-naphthoflavone (both 25 μM). After 24 h exposure (37 °C, 5% CO 2 ), the cells were lysed with 30 μL of lysis reagent.…”

Section: Materials and Methodsmentioning

confidence: 99%

Bioactivation of Quinolines in a Recombinant Estrogen Receptor Transactivation Assay Is Catalyzed by N-Methyltransferases

Brinkmann

Barz

Carrière

et al. 2019

Chem. Res. Toxicol.

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Hydroxylation of polyaromatic compounds through cytochromes P450 (CYPs) is known to result in potentially estrogenic transformation products. Recently, there has been an increasing awareness of the importance of alternative pathways such as aldehyde oxidases (AOX) or Nmethyltransferases (NMT) in bioactivation of small molecules, particularly N-heterocycles. Therefore, this study investigated the biotransformation and activity of methylated quinolines, a class of environmentally relevant N-heterocycles that are no native ligands of the estrogen receptor (ER), in the estrogenresponsive cell line ERα CALUX. We found that this widely used cell line overexpresses AOXs and NMTs while having low expression of CYP enzymes. Exposure of ERα CALUX cells to quinolines resulted in estrogenic effects, which could be mitigated using an inhibitor of AOX/NMTs. No such mitigation occurred after coexposure to a CYP1A inhibitor. A number of N-methylated but no hydroxylated transformation products were detected using liquid chromatography−mass spectrometry, which indicated that biotransformations to estrogenic metabolites were likely catalyzed by NMTs. Compared to the natural ER ligand 17β-estradiol, the products formed during the metabolization of quinolines were weak to moderate agonists of the human ERα. Our findings have potential implications for the risk assessment of these compounds and indicate that care must be taken when using in vitro estrogenicity assays, for example, ERα CALUX, for the characterization of N-heterocycles or environmental samples that may contain them.

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“…Despite the large body of clinical experience, and its long use as an antihypertensive, its mechanism of action has been reconsidered several times since the recognition of its antihypertensive effect (17). Earlier works suggested a peripheral site of action, involving either the inhibition of transmitter synthesis or the metabolism to α‐methylnoradrenaline, which acts as a ‘false’ transmitter, thereby decreasing the sympathetic activity (7), (8), (18). It was later proved that α‐methyldopa acts centrally, though peripheral effects were not excluded (19).…”

Section: Discussionmentioning

confidence: 99%

The effects of α‐methyldopa on myometrial noradrenaline release and myometrial contractility in rat

Csonka¹,

Zupkó²,

Minorics³

et al. 2007

Acta Obstet Gynecol Scand

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DIFFERENTIAL EFFECTS OF Α-Methyldopa, CLONIDINE AND HYDRALAZINE ON NOREPINEPHRINE AND EPINEPHRINE SYNTHESIZING ENZYMES IN THE BRAINSTEM NUCLEI OF SPONTANEOUSLY HYPERTENSIVE RATS

Cited by 7 publications

References 30 publications

Effect of Clonidine on Tyrosine Hydroxylase Activity in the Adrenal Medulla and Brain of Spontaneously Hypertensive Rats

Effect of Clonidine on Tyrosine Hydroxylase Activity in the Adrenal Medulla and Brain of Spontaneously Hypertensive Rats

Bioactivation of Quinolines in a Recombinant Estrogen Receptor Transactivation Assay Is Catalyzed by N-Methyltransferases

The effects of α‐methyldopa on myometrial noradrenaline release and myometrial contractility in rat

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