Down-regulation of imidazoline sites in rabbit kidney

Hamilton, Carlene A.; Jardine, Emma; Reid, John L.

doi:10.1016/0014-2999(93)90174-g

Cited by 19 publications

(7 citation statements)

References 13 publications

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“…3A). These findings in STZ rats are supported by similar responses caused by chronic moxonidine administration in other model systems including SHRs and cardiomyocytes (Aceros et al, 2011; El-Ayoubi et al, 2004; Ernsberger et al, 1999; Hamilton et al, 1993; Mukaddam-Daher, 2012). Second, we present a novel molecular mechanism for the favorable cardiovascular and redox effects of moxonidine in diabetes based on recent evidence that identified DAPK3 as an upstream activator of MAPKs, and as a mediator of oxidative stress and hypertension (Usui et al, 2012).…”

Section: Discussionsupporting

confidence: 56%

Cystathionine-γ lyase-derived hydrogen sulfide mediates the cardiovascular protective effects of moxonidine in diabetic rats

El-Sayed

Zakaria

Abdel-Ghany

et al. 2016

European Journal of Pharmacology

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Blunted cystathionine-γ lyase (CSE) activity (reduced endogenous H2S-level) is implicated in hypertension and myocardial dysfunction in diabetes. Here, we tested the hypothesis that CSE derived H2S mediates the cardiovascular protection conferred by the imidazoline I1 receptor agonist moxonidine in a diabetic rat model. We utilized streptozotocin (STZ; 55 mg/kg i.p) to induce diabetes in male Wistar rats. Four weeks later, STZ-treated rats received vehicle, moxonidine (2 or 6 mg/kg; gavage), CSE inhibitor DL-propargylglycine, (37.5 mg/kg i.p) or DL-propargylglycine with moxonidine (6 mg/kg) for 3 weeks. Moxonidine improved the glycemic state, and reversed myocardial hypertrophy, hypertension and baroreflex dysfunction in STZ-treated rats. Ex vivo studies revealed that STZ caused reductions in CSE expression/activity, H2S and nitric oxide (NO) levels and serum adiponectin and elevations in myocardial imidazoline I1 receptor expression, p38 and extracellular signal-regulated kinase, ERK1/2, phosphorylation and lipid peroxidation (expressed as malondialdehyde). Moxonidine reversed these biochemical responses, and suppressed the expression of death associated protein kinase-3. Finally, pharmacologic CSE inhibition (DL-propargylglycine) abrogated the favorable cardiovascular, glycemic and biochemical responses elicited by moxonidine. These findings present the first evidence for a mechanistic role for CSE derived H2S in the glycemic control and in the favorable cardiovascular effects conferred by imidazoline I1 receptor activation (moxonidine) in a diabetic rat model.

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Section: Discussionsupporting

confidence: 56%

Cystathionine-γ lyase-derived hydrogen sulfide mediates the cardiovascular protective effects of moxonidine in diabetic rats

El-Sayed

Zakaria

Abdel-Ghany

et al. 2016

European Journal of Pharmacology

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“…This study, however, provides strong evidence that ␣ 2 -adrenoceptors are present, albeit at low levels, in the rat heart atria and ventricles, at the levels of synthesis, protein expression, and binding activity, but these receptors seem not to be regulated by moxonidine, a selective agonist of imidazoline I 1 -receptors. Because brain ␣ 2 -adrenoceptors have been shown to be selectively down-regulated in response to ␣ 2 -adrenoceptor agonists (Yakubu et al, 1990), and kidney imidazoline receptors to be down-regulated in response to imidazoline receptor agonists (Hamilton et al, 1993), the present findings imply that ␣ 2 -adrenoceptors in the heart interact weakly with moxonidine.…”

Section: Cardiac Imidazoline I 1 Receptors In Shr 449mentioning

confidence: 54%

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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“…The vasodepressor response to imidazoline is consistent with each of the four major criteria of specificity, function, location, and correlation of affinity with function. In addition, I 1 -receptors are subject to physiologic regulation, in a manner distinct from α2-adrenoceptors and, similar to other neurotransmitter receptors, imidazoline I 1 binding can be downregulated by chronic exposure to agonists (10,11). Imidazoline I 1 -receptors have at least one endogenous ligand, a "clonidine displacing substance" isolated from the brain and identified by Reis and coworkers (12) as agmatine (decarboxylated arginine), previously unknown in mammals.…”

Section: Discovery Of Imidazoline Receptorsmentioning

confidence: 99%

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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Down-regulation of imidazoline sites in rabbit kidney

Cited by 19 publications

References 13 publications

Cystathionine-γ lyase-derived hydrogen sulfide mediates the cardiovascular protective effects of moxonidine in diabetic rats

Cystathionine-γ lyase-derived hydrogen sulfide mediates the cardiovascular protective effects of moxonidine in diabetic rats

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

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Down-regulation of imidazoline sites in rabbit kidney

Cited by 19 publications

References 13 publications

Cystathionine-γ lyase-derived hydrogen sulfide mediates the cardiovascular protective effects of moxonidine in diabetic rats

Cystathionine-γ lyase-derived hydrogen sulfide mediates the cardiovascular protective effects of moxonidine in diabetic rats

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

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Product

Resources

About

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