Selective Antihypertensive Action of Moxonidine Is Mediated Mainly by I1-Imidazoline Receptors in the Rostral Ventrolateral Medulla

Haxhiu, Musa A.; Dreshaj, Ismail A.; Schäfer, S. G.; Ernsberger, Paul

doi:10.1097/00005344-199424001-00002

Cited by 105 publications

(90 citation statements)

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“…Pharmacologic characterization by binding assays confirmed the existence of a population of imidazoline-specific binding sites that are insensitive to catecholamines in the brainstem RVLM of animals and man (2,5,6). These studies clearly demonstrated that imidazoline binding sites are distinct from α2-adrenoceptors.…”

Section: Discovery Of Imidazoline Receptorsmentioning

confidence: 71%

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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Section: Discovery Of Imidazoline Receptorsmentioning

confidence: 71%

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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“…( Figure 5). We performed the same experiments using reference imidazoline and a 2 ARs antagonists, efaroxan (Haxhiu et al, 1994) and rauwolscine, respectively. The e ect of S23515 (100 mg kg 71 , i.c.)…”

Section: Cardiovascular Effects Of S23515 and S23757mentioning

confidence: 99%

“…In addition, a 2 ARs antagonists failed to prevent imidazolines-induced hypotension when administered directly in the RVLM. On the contrary, microinjection of antagonists with imidazoline structures, such as idazoxan and efaroxan, prevented the action of clonidine analogues (Chan & Head, 1996;Haxhiu et al, 1994;Feldman et al, 1990). The assumption that there are non-adrenergic receptors sensitive to imidazolines was based on these data.…”

Section: Introductionmentioning

confidence: 99%

Respective contributions of α‐adrenergic and non‐adrenergic mechanisms in the hypotensive effect of imidazoline‐like drugs

Bruban¹,

Feldman²,

Greney³

et al. 2001

British J Pharmacology

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1 The hypotensive e ect of imidazoline-like drugs, such as clonidine, was ®rst attributed to the exclusive stimulation of central a 2 -adrenoceptors (a 2 ARs). 2 However, a body of evidence suggests that non-adrenergic mechanisms may also account for this hypotension. 3 This work aims (i) to check whether imidazoline-like drugs with no a 2 -adrenergic agonist activity may alter blood pressure (BP) and (ii) to seek a possible interaction between such a drug and an a 2 ARs agonist a-methylnoradrenaline (a-MNA). 4 We selected S23515 and S23757, two imidazoline-like drugs with negligible a nities and activities at a 2 ARs but with high a nities for non-adrenergic imidazoline binding sites (IBS). 5 S23515 decreased BP dose-dependently (727+5% maximal e ect) when administered intracisternally (i.c.) to anaesthetized rabbits. The hypotension induced by S23515 (100 mg kg 71 i.c.) was prevented by S23757 (1 mg kg 71 i.c.) and efaroxan (10 mg kg 71 i.c.), while these compounds, devoid of haemodynamic action by themselves, did not alter the hypotensive e ect of a-MNA (3 and 30 mg kg 71 i.c.). Moreover, the a 2 ARs antagonist rauwolscine (3 mg kg 71 i.c.) did not prevent the e ect of S23515. 6 Finally, whilst 3 mg kg 71 of S23515 or 0.5 mg kg 71 of a-MNA had weak hypotensive e ects, the sequential i.c. administration of these two drugs induced a marked hypotension (723+2%). 7 These results indicate that an imidazoline-like drug with no a 2 -adrenergic properties lowers BP and interacts synergistically with an a 2 ARs agonist.

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“…Moxonidine has been demonstrated to produce hypotensive and sympathoinhibitory effects through selectively stimulating I 1 R in the central nervous system [3] . The affinity of moxonidine at I 1 R is at least 40-fold higher than its affinity at α 2 AR, and moxonidine has been recognized as a selective agonist for I 1 R [3,37] .…”

Section: Discussionmentioning

confidence: 99%

“…It is well known that the rostral ventrolateral medulla (RVLM) plays a critical role in tonic and reflex control of sympathetic outflow and BP [2] . The presympathetic neurons in the RVLM project directly to sympathetic preganglionic neurons in the spinal cord and are recognized as a major target responsible for the action of centrally acting antihypertensive agents such as clonidine and moxonidine [3,4] . In many cardiovascular diseases such as hypertension, the baroreflex, a prime regulator for sympathetic outflow, is blunted, which is closely related to the mortality of this disease [5,6] .…”

Section: Introductionmentioning

confidence: 99%

Low dose of moxonidine within the rostral ventrolateral medulla improves the baroreflex sensitivity control of sympathetic activity in hypertensive rat

Wang

et al. 2009

Acta Pharmacol Sin

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Aim: To determine the effects of the centrally antihypertensive drug moxonidine injected into the rostral ventrolateral medulla (RVLM) on baroreflex function in spontaneously hypertensive rats (SHR). Methods: Baroreflex sensitivity control of renal sympathetic nerve activity (RSNA) and barosensitivity of the RVLM presympathetic neurons were determined following application of different doses of moxonidine within the RVLM. Results: Three doses (0.05, 0.5, and 5 nmol in 50 nL) of moxonidine injected bilaterally into the RVLM dose-dependently reduced the baseline blood pressure (BP) and RSNA in SHR. At the highest dose (5 nmol) of moxonidine injection, the maximum gain (1.24%±0.04%/mmHg) of baroreflex control of RSNA was significantly decreased. However, the lower doses (0.05 and 0.5 nmol) of moxonidine injection into the RVLM significantly enhanced the baroreflex gain (2.34%±0.08% and 2.01%±0.07%/mmHg). The moxonidine-induced enhancement in baroreflex function was completely prevented by the imidazoline receptor antagonist efaroxan but not by the α 2 -adrenoceptor antagonist yohimbine. A total of 48 presympathetic neurons were recorded extracellularly in the RVLM of SHR. Iontophoresis of applied moxonidine (30-60 nA) dose-dependently decreased the discharge of RVLM presympathetic neurons but also significantly increased the barosensitivity of RVLM presympathetic neurons.Conclusion: These data demonstrate that a low dose of moxonidine within the RVLM has a beneficial effect on improving the baroreflex function in SHR via an imidazoline receptor-dependent mechanism.

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Selective Antihypertensive Action of Moxonidine Is Mediated Mainly by I1-Imidazoline Receptors in the Rostral Ventrolateral Medulla

Cited by 105 publications

References 0 publications

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

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

Respective contributions of α‐adrenergic and non‐adrenergic mechanisms in the hypotensive effect of imidazoline‐like drugs

Low dose of moxonidine within the rostral ventrolateral medulla improves the baroreflex sensitivity control of sympathetic activity in hypertensive rat

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