Sympathoinhibition by rilmenidine in conscious rabbits: involvement of ?2-adrenoceptors

Szabó, Béla; Urban, Rolf; Starke, Klaus

doi:10.1007/bf00167235

Cited by 32 publications

(12 citation statements)

References 37 publications

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“…Furthermore, it may be argued that the neuronal signal and/or the hypotensive response resulted, at least in part, from the activation of the ␣ 2 -AR because 1) the RVLM contains I 1 -and ␣ 2 -ARs (Reis, 1996); and 2) rilmenidine, although a selective I 1 agonist, also activates the ␣ 2 -AR (Szabo, 2002). In effect, some investigators suggest that the hypotensive action of the second generation, centrally acting drugs depends, directly or indirectly, on the ␣ 2 -AR (Szabo et al, 1993;Regunathan et al, 1995;Zhu et al, 1999).…”

Section: Rvlm Mapk Contributes To I 1 -Receptor-mediated Hypotension 947mentioning

confidence: 99%

“…We focused on the RVLM, the major site of action for the selective I 1 -receptor agonists such as rilmenidine and moxonidine (Gomez et al, 1991;Haxhiu et al, 1994). However, since rilmenidine exhibits ␣ 2 -AR agonist activity (Szabo et al, 1993;Regunathan et al, 1995;Zhu et al, 1999) and the RVLM contains both I 1 -and ␣ 2 -ARs (Reis, 1996), we investigated the effects of the pure ␣ 2 -AR agonist ␣-MNE on MAPK phosphorylation in the RVLM. As a control, we investigated whether rilmenidine enhanced the phosphorylation of MAPK in the NTS, which is devoid of functional I 1 -receptor (Gomez et al, 1991).…”

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confidence: 99%

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Mitogen-Activated Protein Kinase Phosphorylation in the Rostral Ventrolateral Medulla Plays a Key Role in Imidazoline (I₁)-Receptor-Mediated Hypotension

Zhang¹,

Abdel‐Rahman²

2005

J Pharmacol Exp Ther

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Our previous study showed that rilmenidine, a selective I 1 -imidazoline receptor agonist, enhanced the phosphorylation of mitogen-activated protein kinase (MAPK) p42/44 , via the phosphatidylcholine-specific phospholipase C pathway in the pheochromocytoma cell line (PC12). In the present study, we tested the hypothesis that enhancement of MAPK phosphorylation in the rostral ventrolateral medulla (RVLM) contributes to the hypotensive response elicited by I 1 -receptor activation in vivo. Systemic rilmenidine (600 g/kg i.v.) elicited hypotension and bradycardia along with significant elevation in MAPK p42/44 , detected by immunohistochemistry, in RVLM neurons. To obtain conclusive evidence that the latter response was I 1 -receptormediated, similar hypotensive responses were elicited by intracisternal (i.c.) rilmenidine (25 g/rat) or the highly selective ␣ 2 -agonist ␣-methylnorepinephrine (4 g/rat). An increase in RVLM MAPK p42/44 occurred only after rilmenidine. Furthermore, pretreatment with efaroxan (0.15 g/rat i.c.), a selective I 1 -imidazoline receptor antagonist, or with PD98059 (2Ј-amino-3Ј-methoxyflavone) (5 g/rat i.c.), a selective extracellular signal-regulated kinase 1/2 inhibitor, significantly attenuated the hypotensive response and the elevation in RVLM MAPK p42/44 elicited by i.c. rilmenidine. The findings suggest that MAPK phosphorylation in the RVLM contributes to the hypotensive response induced by I 1 -receptor activation and presents in vivo evidence that distinguishes the neuronal responses triggered by the I 1 -receptor from those triggered by the ␣ 2 -adrenergic receptor.

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Section: Rvlm Mapk Contributes To I 1 -Receptor-mediated Hypotension 947mentioning

confidence: 99%

mentioning

confidence: 99%

Mitogen-Activated Protein Kinase Phosphorylation in the Rostral Ventrolateral Medulla Plays a Key Role in Imidazoline (I₁)-Receptor-Mediated Hypotension

Zhang¹,

Abdel‐Rahman²

2005

J Pharmacol Exp Ther

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“…The results, however, have not been conclusive. On the one hand, it has been repeatedly observed that selective α 2 -adrenoceptor antagonists counteract the hypotensive effects of clonidine, rilmenidine and moxonidine (Timmermans et al 1981;Tibiriça et al 1988;Hieble and Kolpak 1993;Szabo et al 1993;Sannajust and Head 1994;Urban et al 1994Urban et al , 1995aChan et al 1996), supporting an involvement of α 2 -adrenoceptors. Some authors, however, interpret these findings as functional antagonism: the imidazoline drugs, it is suggested, primarily activate an imidazoline receptor, but in the chain of events eventually leading to sympathoinhibition (downstream) intact α 2 -adrenoceptors are necessary (e.g.…”

Section: Introductionmentioning

confidence: 99%

Analysis of the receptor involved in the central hypotensive effect of rilmenidine and moxonidine

Bock¹,

Niederhoffer²,

Szabó³

1999

Naunyn-Schmiedeberg's Arch Pharmacol

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The aim of this study was to determine whether alpha2-adrenoceptors or imidazoline I1-receptors are responsible for the central sympathoinhibition produced by rilmenidine and moxonidine, two clonidine-like antihypertensive drugs. Rilmenidine and moxonidine were compared with the indirectly acting alpha2-adrenoceptor agonist alpha-methyldopa. Three antagonists were used. Yohimbine and SK&F86466 were used as selective alpha2-adrenoceptor antagonists. They were compared with efaroxan which is also an alpha2-adrenoceptor antagonist, but, in addition, possesses affinity for imidazoline I1-receptors. According to some but not all studies, the affinity of efaroxan for I1-receptors is much higher than its affinity for alpha2-adrenoceptors. Drugs were administered into the cisterna cerebellomedullaris of conscious rabbits by a catheter implanted previously under halothane anaesthesia. Rilmenidine (10 microg kg(-1)), moxonidine (0.3 microg kg(-1)) and alpha-methyldopa (0.4 mg kg(-1)) lowered blood pressure and the plasma noradrenaline concentration; the degree of sympathoinhibition produced by the three agonists was very similar. When injected after the agonists, efaroxan (0.1-14 microg kg(-1); cumulative doses), yohimbine (0.4-14 microg kg(-1)) and SK&F86466 (0.4-44 microg kg(-1)) counteracted the effects of the agonists on blood pressure and the plasma noradrenaline concentration. Efaroxan was about tenfold more potent than yohimbine and SK&F86466 at antagonizing the hypotensive effects of alpha-methyldopa. Similarly, efaroxan was two- to tenfold more potent than yohimbine and SK&F86466 against rilmenidine and moxonidine. Finally, efaroxan was about as potent against alpha-methyldopa as against rilmenidine and moxonidine. The results confirm previous observations that selective alpha2-adrenoceptor antagonists are capable of completely antagonizing effects of rilmenidine and moxonidine. The effects of the alpha2-adrenoceptor antagonist with an additional high affinity for imidazoline I1-receptors, efaroxan, can also be explained by blockade of alpha2-adrenoceptors. Efaroxan was more potent against rilmenidine and moxonidine than the selective alpha2-adrenoceptor antagonists. This was probably due to the fact that the affinity of efaroxan for alpha2-adrenoceptors is higher than the affinity of yohimbine and SK&F86466, since efaroxan was also the most potent of the three antagonists against the indirectly acting alpha2adrenoceptor agonist alpha-methyldopa. The observation that efaroxan was equally potent against rilmenidine and moxonidine and against alpha-methyldopa suggests that the same receptors were involved in the effects of the three agonists, alpha2-adrenoceptors; this observation is not compatible with the high I1/alpha2 selectivity of efaroxan and the hypothesis that rilmenidine and moxonidine activate I1-receptors, whereas alpha-methyldopa activates alpha2-adrenoceptors. Thus, the data do not indicate involvement of I1 imidazoline receptors in the central sympathoinhibition elicited by rilmenidine and moxonidine ...

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“…An effect on presynaptic alpha2-adrenoceptors might contribute to such peripheral effects as it is assumed to contribute as well to the hypotensive effects of i.v. rilmenidine (Laubie et al 1985;Koenig-Bdrard et al 1988;Szabo et al 1993;Urban et al 1995, Van Zwieten et al 1986). …”

Section: Discussionmentioning

confidence: 99%

Inhibition of centrally induced ventricular arrhythmias by rilmenidine and idazoxan in rabbits

Yannoulis

et al. 1996

Naunyn-Schmiedeberg's Arch Pharmacol

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In a model of ventricular arrhythmias of central origin, we investigated the effects of rilmenidine, an oxazoline with antihypertensive properties, and idazoxan, an imidazoline that is an antagonist of the hypotensive effects of rilmenidine. Bicuculline, a GABAA receptor antagonist, was administered intracisternally (i.c.) to produce arrhythmias in pentobarbitone anaesthetised rabbits; 10 micrograms/kg bicuculline i.c. induced polymorphic ventricular ectopic beats and ventricular tachycardia while blood pressure increased by about 50-60% and sinusal heart rate decreased by about 20%. Rilmenidine, either administered intravenously (0.01, 0.1, 1 mg/kg i.v.) or i.c. (3, 10, 30 micrograms/kg) dose-dependently prevented the occurrence of bicuculline-induced arrhythmias while, because of a lower base-line, the blood pressure values reached were less as compared to controls. Idazoxan administered i.v. (3, 10 mg/kg) had a similar action. Idazoxan i.c. (15 micrograms/kg) had no significant antiarrhythmic effect but antagonized in part the haemodynamic and antiarrhythmic effects of rilmenidine (1 mg/kg i.v.; 30 micrograms/kg i.c.). It is suggested that the antiarrhythmic effects observed with rilmenidine are mainly mediated by blunting the bicuculline-induced increase in the sympathetic nervous output to the heart and the vascular beds. These effects of rilmenidine are likely to originate both from the central and peripheral nervous system. The antiarrhythmic effects of idazoxan i.v. might be related to a blocking action on alpha 2-adrenoceptors at the level of the coronary arteries and other vascular beds.

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Sympathoinhibition by rilmenidine in conscious rabbits: involvement of ?2-adrenoceptors

Cited by 32 publications

References 37 publications

Mitogen-Activated Protein Kinase Phosphorylation in the Rostral Ventrolateral Medulla Plays a Key Role in Imidazoline (I₁)-Receptor-Mediated Hypotension

Mitogen-Activated Protein Kinase Phosphorylation in the Rostral Ventrolateral Medulla Plays a Key Role in Imidazoline (I₁)-Receptor-Mediated Hypotension

Analysis of the receptor involved in the central hypotensive effect of rilmenidine and moxonidine

Inhibition of centrally induced ventricular arrhythmias by rilmenidine and idazoxan in rabbits

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Sympathoinhibition by rilmenidine in conscious rabbits: involvement of ?2-adrenoceptors

Cited by 32 publications

References 37 publications

Mitogen-Activated Protein Kinase Phosphorylation in the Rostral Ventrolateral Medulla Plays a Key Role in Imidazoline (I1)-Receptor-Mediated Hypotension

Mitogen-Activated Protein Kinase Phosphorylation in the Rostral Ventrolateral Medulla Plays a Key Role in Imidazoline (I1)-Receptor-Mediated Hypotension

Analysis of the receptor involved in the central hypotensive effect of rilmenidine and moxonidine

Inhibition of centrally induced ventricular arrhythmias by rilmenidine and idazoxan in rabbits

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Mitogen-Activated Protein Kinase Phosphorylation in the Rostral Ventrolateral Medulla Plays a Key Role in Imidazoline (I₁)-Receptor-Mediated Hypotension

Mitogen-Activated Protein Kinase Phosphorylation in the Rostral Ventrolateral Medulla Plays a Key Role in Imidazoline (I₁)-Receptor-Mediated Hypotension