Chronic imidazoline receptor activation in spontaneously hypertensive rats1

Ménaouar, Ahmed; El-Ayoubi, Rouwayda; Jankowski, Marek; Gutkowska, Jolanta; Mukaddam‐Daher, Suhayla

doi:10.1016/s0895-7061(02)02971-0

Cited by 8 publications

(17 citation statements)

References 28 publications

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“…Cardiac I 1 -receptor normalization occurred after 1 week of treatment, the time point when moxonidine resulted in reversal of left ventricular hypertrophy in these rats (Menaouar et al, 2002). Also, the presence of I 1 -receptors in atria, tissues known to secrete or respond to natriuretic peptides, atrial natriuretic peptide and brain natriuretic peptide, suggest a functional relationship between the two systems.…”

Section: Cardiac Imidazoline I 1 Receptors In Shr 449mentioning

confidence: 77%

“…Treatment with moxonidine inhibits or counteracts these effects and eventually may indirectly lead to downregulation of its receptor. We have previously shown that moxonidine dose dependently reduced blood pressure in SHR (Menaouar et al, 2002). However, the dose of 10 g of moxonidine, which had no effect on blood pressure in those rats (Menaouar et al, 2002), significantly reduced I 1 -receptor protein and B max .…”

Section: Cardiac Imidazoline I 1 Receptors In Shr 449mentioning

confidence: 84%

“…We have previously shown that moxonidine dose dependently reduced blood pressure in SHR (Menaouar et al, 2002). However, the dose of 10 g of moxonidine, which had no effect on blood pressure in those rats (Menaouar et al, 2002), significantly reduced I 1 -receptor protein and B max . Furthermore, treatment of SHR with hydralazine, a vasodilator antihypertensive compound that reduced blood pressure to a similar magnitude achieved by 120 g of moxonidine, had no effect on imidazoline receptor proteins.…”

Section: Cardiac Imidazoline I 1 Receptors In Shr 449mentioning

confidence: 84%

“…Alzet osmotic mini-pumps (2ML1 and 2ML4; Alzet, Cupertino, CA) were implanted subcutaneously in SHR, under isoflurane anesthesia, as we have described previously (Menaouar et al, 2002). These minipumps allowed continuous delivery of moxonidine (generous gift from Solvay Pharmaceuticals, Hannover, Germany) or saline vehicle at the rate of 10 l/h (2ML1), for 1 week, and 2.5 l/h (2ML4) for 4 weeks.…”

Section: Methodsmentioning

confidence: 99%

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Imidazoline Receptors but Not α₂-Adrenoceptors Are Regulated in Spontaneously Hypertensive Rat Heart by Chronic Moxonidine Treatment

El-Ayoubi¹,

Ménaouar²,

Gutkowska³

et al. 2004

J Pharmacol Exp Ther

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We have recently identified imidazoline I 1 -receptors in the heart. In the present study, we tested regulation of cardiac I 1 -receptors versus ␣ 2 -adrenoceptors in response to hypertension and to chronic exposure to agonist. Spontaneously hypertensive rats (SHR, 12-14 weeks old) received moxonidine (10, 60, and 120 g/kg/h s.c.) for 1 and 4 weeks. Autoradiographic binding of 125 I-paraiodoclonidine (0.5 nM, 1 h, 22°C) and inhibition of binding with epinephrine (10 Ϫ10 -10 Ϫ5 M) demonstrated the presence of ␣ 2 -adrenoceptors in heart atria and ventricles. Immunoblotting and reverse transcription-polymerase chain reaction identified ␣ 2A -, ␣ 2B -, and ␣ 2C -adrenoceptor proteins and mRNA, respectively. However, compared with normotensive controls, cardiac ␣ 2 -adrenoceptor kinetic parameters, receptor proteins, and mRNAs were not altered in SHR with or without moxonidine treatment. In contrast, autoradiography showed that up-regulated atrial I 1 -receptors in SHR are dose-dependently normalized by 1 week, with no additional effect after 4 weeks of treatment. Moxonidine (120 g/kg/h) decreased B max in right (40.0 Ϯ 2.9 -7.0 Ϯ 0.6 fmol/unit area; p Ͻ 0.01) and left (27.7 Ϯ 2.8 -7.1 Ϯ 0.4 fmol/unit area; p Ͻ 0.01) atria, and decreased the 85-and 29-kDa imidazoline receptor protein bands, in right atria, to 51.8 Ϯ 3.0% (p Ͻ 0.01) and 82.7 Ϯ 5.2% (p Ͻ 0.03) of vehicle-treated SHR, respectively. Moxonidine-associated percentage of decrease in B max only correlated with the 85-kDa protein (R 2 ϭ 0.57; p Ͻ 0.006), suggesting that this protein may represent I 1 -receptors. The weak but significant correlation between the two imidazoline receptor proteins (R 2 ϭ 0.28; p Ͻ 0.03) implies that they arise from the same gene. In conclusion, the heart possesses I 1 -receptors and ␣ 2 -adrenoceptors, but only I 1 -receptors are responsive to hypertension and to chronic in vivo treatment with a selective I 1 -receptor agonist.

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Section: Cardiac Imidazoline I 1 Receptors In Shr 449mentioning

confidence: 77%

Section: Cardiac Imidazoline I 1 Receptors In Shr 449mentioning

confidence: 84%

Section: Cardiac Imidazoline I 1 Receptors In Shr 449mentioning

confidence: 84%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Imidazoline Receptors but Not α₂-Adrenoceptors Are Regulated in Spontaneously Hypertensive Rat Heart by Chronic Moxonidine Treatment

El-Ayoubi¹,

Ménaouar²,

Gutkowska³

et al. 2004

J Pharmacol Exp Ther

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“…Also, in these hearts, moxonidine decreased elevated interleukin 1ß levels (ELISA Kit, Biosource International Inc., Camarillo, CA, USA) in left ventricles from 166 ± 4 to 119 ± 11 pg/ mg protein (P < 0.01) (Figure 4). Most im-portantly, the effects were associated with increased atrial synthesis and release of natriuretic peptides, ANP and BNP ( Figure 5), after 1 week, and normalization by 4 weeks of treatment (34,35). Since natriuretic peptides and their receptors are present in the heart, we propose that moxonidine-stimulated ANP may act in a paracrine/autocrine manner to oppose the inflammatory and hypertrophic effect of overactive SNS and hypertension-associated cardiovascular environment.…”

Section: Imidazoline and Natriuretic Peptidesmentioning

confidence: 90%

Imidazoline receptors in the heart: a novel target and a novel mechanism of action that involves atrial natriuretic peptides

Mukaddam‐Daher

Gutkowska

2004

Braz J Med Biol Res

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Chronic stimulation of sympathetic nervous activity contributes to the development and maintenance of hypertension, leading to left ventricular hypertrophy (LVH), arrhythmias and cardiac death. Moxonidine, an imidazoline antihypertensive compound that preferentially activates imidazoline receptors in brainstem rostroventrolateral medulla, suppresses sympathetic activation and reverses LVH. We have identified imidazoline receptors in the heart atria and ventricles, and shown that atrial I 1 -receptors are up-regulated in spontaneously hypertensive rats (SHR), and ventricular I 1 -receptors are up-regulated in hamster and human heart failure. Furthermore, cardiac I 1 -receptor binding decreased after chronic in vivo exposure to moxonidine. These studies implied that cardiac I 1 -receptors are involved in cardiovascular regulation. The presence of I 1 -receptors in the heart, the primary site of production of natriuretic peptides, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), cardiac hormones implicated in blood pressure control and cardioprotection, led us to propose that ANP may be involved in the actions of moxonidine. In fact, acute iv administration of moxonidine (50 to 150 µg/rat) dose-dependently decreased blood pressure, stimulated diuresis and natriuresis and increased plasma ANP and its second messenger, cGMP. Chronic SHR treatment with moxonidine (0, 60 and 120 µg kg -1 h -1 , sc for 4 weeks) dosedependently decreased blood pressure, resulted in reversal of LVH and decreased ventricular interleukin 1ß concentration after 4 weeks of treatment. These effects were associated with a further increase in already elevated ANP and BNP synthesis and release (after 1 week), and normalization by 4 weeks. In conclusion, cardiac imidazoline receptors and natriuretic peptides may be involved in the acute and chronic effects of moxonidine. Correspondence S. Mukaddam-Daher

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Control of left ventricular mass by moxonidine involves reduced DNA synthesis and enhanced DNA fragmentation

Paquette

Duguay

Ayoubi

et al. 2008

British J Pharmacology

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Background and purpose: Left ventricular hypertrophy (LVH) is a maladaptive process associated with increased cardiovascular risk. Regression of LVH is associated with reduced complications of hypertension. Moxonidine is an antihypertensive imidazoline compound that reduces blood pressure primarily by central inhibition of sympathetic outflow and by direct actions on the heart to release atrial natriuretic peptide, a vasodilator and an antihypertrophic cardiac hormone. This study investigated the effect of moxonidine on LVH and the mechanisms involved in this effect. Experimental approach: Spontaneously hypertensive rats were treated with several doses of moxonidine (s.c.) over 4 weeks. Blood pressure and heart rate were continuously monitored by telemetry. Body weight and water and food intake were measured weekly. Measurements also included left ventricular mass, DNA content, synthesis, fragmentation, and apoptotic/ anti-apoptotic pathway proteins. Key results: The decrease in mean arterial pressure stabilized at B À10 mm Hg after 1 week of treatment and thereafter. Compared to vehicle-treated rats (100%), left ventricular mass was dose-and time-dependently reduced by treatment. This reduction remained significantly lower after normalizing to body weight. Moxonidine reduced left ventricular DNA content and inhibited DNA synthesis. DNA fragmentation transiently, but significantly increased at 1 week of moxonidine treatment and was paralleled by elevated active caspase-3 protein. The highest dose significantly decreased the apoptotic protein Bax and all doses stimulated anti-apoptotic Bcl-2 after 4 weeks of treatment. Conclusions and implications: These studies implicate the modulation of cardiac DNA dynamics in the control of left ventricular mass by moxonidine in a rat model of hypertension.

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Chronic imidazoline receptor activation in spontaneously hypertensive rats1

Abstract: ANP and BNP may be involved in the antihypertensive effect of chronic moxonidine treatment. Accordingly, natriuretic peptides may contribute to the sympatholytic and cardioprotective effects of chronic activation of imidazoline I1-receptors.

Cited by 8 publications

References 28 publications

Imidazoline Receptors but Not α₂-Adrenoceptors Are Regulated in Spontaneously Hypertensive Rat Heart by Chronic Moxonidine Treatment

Imidazoline Receptors but Not α₂-Adrenoceptors Are Regulated in Spontaneously Hypertensive Rat Heart by Chronic Moxonidine Treatment

Imidazoline receptors in the heart: a novel target and a novel mechanism of action that involves atrial natriuretic peptides

Control of left ventricular mass by moxonidine involves reduced DNA synthesis and enhanced DNA fragmentation

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Chronic imidazoline receptor activation in spontaneously hypertensive rats1

Abstract: ANP and BNP may be involved in the antihypertensive effect of chronic moxonidine treatment. Accordingly, natriuretic peptides may contribute to the sympatholytic and cardioprotective effects of chronic activation of imidazoline I1-receptors.

Cited by 8 publications

References 28 publications

Imidazoline Receptors but Not α2-Adrenoceptors Are Regulated in Spontaneously Hypertensive Rat Heart by Chronic Moxonidine Treatment

Imidazoline Receptors but Not α2-Adrenoceptors Are Regulated in Spontaneously Hypertensive Rat Heart by Chronic Moxonidine Treatment

Imidazoline receptors in the heart: a novel target and a novel mechanism of action that involves atrial natriuretic peptides

Control of left ventricular mass by moxonidine involves reduced DNA synthesis and enhanced DNA fragmentation

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Imidazoline Receptors but Not α₂-Adrenoceptors Are Regulated in Spontaneously Hypertensive Rat Heart by Chronic Moxonidine Treatment

Imidazoline Receptors but Not α₂-Adrenoceptors Are Regulated in Spontaneously Hypertensive Rat Heart by Chronic Moxonidine Treatment