A novel mechanism of action for hypertension control: Moxonidine as a selective I 1-imidazoline agonist (original) (raw)
Related papers
Neuroscience, 2005
We determined whether the cardiovascular actions of central anti-hypertensive agents clonidine and moxonidine are dependent on noradrenergic or serotonergic innervation of the rostral ventrolateral medulla (RVLM) in conscious rabbits. 6-Hydroxydopamine (6-OHDA) or 5,6-dihydroxytriptamine (5,6-DHT) was injected into the RVLM to deplete noradrenergic and serotonergic terminals respectively. One, 2 and 4 weeks later, responses to fourth ventricular (4V) clonidine (0.65 g/kg) and moxonidine (0.44 g/kg) were examined. Destruction of noradrenergic pathways in the RVLM by 6-OHDA reduced the hypotensive response to 4V moxonidine to 62%, 47% and 60% of that observed in vehicle treated rabbits at weeks 1, 2 and 4 respectively. The moxonidine induced bradycardia was similarly attenuated (to 46% of vehicle). Conversely, 6-OHDA had no effect on the hypotensive or bradycardic effects of 4V clonidine. Efaroxan (I 1 -imidazoline receptor/␣ 2 -adrenoceptor antagonist; 3.5, 11, 35 g/kg) and 2-methoxyidazoxan (␣ 2 -adrenoceptor antagonist; 0.3, 0.9, 3 g/kg) equally reversed the hypotension to 4V clonidine, suggesting a mainly ␣ 2 -adrenoceptor mechanism. Efaroxan preferentially reversed responses to moxonidine in both vehicle and 5,6-DHT groups and in the 1st week after 6-OHDA, suggesting a mechanism involving mainly I 1imidazoline receptors. This selectivity was subsequently lost in the 2nd and 4th weeks when the remaining hypotension was mainly mediated by ␣ 2 -adrenoceptors. Depletion of serotonergic terminals did not alter the responses to either agonist nor did it change the relative effectiveness of the antagonists. Western blots of RVLM tissues probed with imidazoline and ␣ 2 -adrenoceptor antisera showed a pattern of bands close to that reported in other species. The main effect of 6-OHDA was an 18% lower level of the 42 kDa imidazoline protein (P<0.05). We conclude that the hypotensive and bradycardic actions of moxonidine but not clonidine are mediated through imidazoline receptors and are dependent on intact noradrenergic pathways within the RVLM. Furthermore, the norad-renergic innervation may be associated with a 42 kDa imidazoline receptor protein. © 2005 Published by Elsevier Ltd on behalf of IBRO. (G. A. Head).
Journal of the Autonomic Nervous System, 1998
Since the first suggestion of the existence of imidazoline receptors, there has been a continuing and yet unresolved debate as to their contribution to the antihypertensive actions of clonidine-like agents. In this review we bring together a number of studies from our laboratory which have examined the importance and interdependence of imidazoline receptors and a -adrenoceptors in the mechanism of 2 action of centrally acting antihypertensive drugs. Using conscious rabbits and a range of imidazoline and specific a -adrenoceptor 2 antagonists we have consistently found that second generation agents rilmenidine and moxonidine preferentially act via imidazoline receptors but that a -adrenoceptors are important for the hypotension produced by clonidine and a-methyldopa. Despite this difference in 2 receptor mechanism, the hypotension produced by all these drugs is dependent on central noradrenergic pathways. In other studies using anaesthetised rabbits and direct measures of sympathetic nerve activity we confirmed the generally held view that the major site of sympatho-inhibitory actions and sympathetic baroreflex effects of centrally acting antihypertensive agents is the rostral ventrolateral Ž . medulla RVLM . We also found, using microinjection of specific antagonists, that a -adrenoceptors in this nucleus appear to be 2 activated as a consequence of imidazoline receptor activation. Thus, there appears to be a close relationship between imidazoline receptors and a -adrenoceptors located in the RVLM in mediating the hypotension and inhibition of renal sympathetic nerve activity.
Central Imidazoline Receptors and Centrally Acting Anti-Hypertensive Agents
Clinical and Experimental Hypertension, 1997
We have examined the location and contribution of imidazoline receptors (IR) in mediating the hypotensive and sympatholytic actions of first and second generation anti-hypertensive agents in rabbits. We found that the hypotension produced by rilmenidine and moxonidine given intravenously (IV) or into the fourth ventricle (4V) was preferentially reversed by the IR antagonists idazoxan and efaroxan (compared to a selective R-adrenoceptor antagonist 2-methoxy-idazoxan), suggesting that IR are important in the sympatho-inhibition produced by these agents. Clonidine was not 591 Copyright 0 1997 by Marcel Dekker, Inc. Clin Exp Hypertens Downloaded from informahealthcare.com by Monash University on 02/14/13 For personal use only.
Annals of the New York Academy of Sciences, 1995
It has been suggested that baroreflex control of blood pressure by the autonomic nervous system is limited to the short term, while the kidney plays a major role in determining the long-term level of blood pressure.' However, much evidence now supports the view that the sympathetic nervous system is activated in the early phases of hypertension and that this may be a contributory factor to the disease.* The increase in sympathetic drive is not generalized but is confined to renal and cardiac beds.
Imidazoline antihypertensive drugs: a critical review on their mechanism of action
Pharmacology & Therapeutics, 2002
It was long thought that the prototypical centrally acting antihypertensive drug clonidine lowers sympathetic tone by activating a 2-adrenoceptors in the brain stem. Supported by the development of two new centrally acting drugs, rilmenidine and moxonidine, the imidazoline hypothesis evolved recently. It assumes the existence of a new group of receptors, the imidazoline receptors, and attributes the sympathoinhibition to activation of I 1 imidazoline receptors in the medulla oblongata. This review analyzes the mechanism of action of clonidine-like drugs, with special attention given to the imidazoline hypothesis. Two conclusions are drawn. The first is that the arguments against the imidazoline hypothesis outweigh the observations that support it and that the sympathoinhibitory effects of clonidine-like drugs are best explained by activation of a 2-adrenoceptors. The second conclusion is that this class of drugs lowers sympathetic tone not only by a primary action in cardiovascular regulatory centres in the medulla oblongata. Peripheral presynaptic inhibition of transmitter release from postganglionic sympathetic neurons contributes to the overall sympathoinhibition.
Journal of Pharmacology and Experimental Therapeutics, 2004
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 1receptors 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.
International Journal of Advances in Medicine, 2019
Hypertension, often referred to as ‘The silent killer’, is christened so, as it is seldom preceded by any warning signs or symptoms. With the new ACC/AHA guidelines lowering the Blood Pressure (BP) threshold values, it has resulted in a 140% relative increase in the hypertension prevalence in India, which is 3 times higher than that of in United States. Imidazoline receptor agonists control BP effectively with minimal adverse effects of sedation and mental depression that are usually associated with centrally acting antihypertensives. While having a low affinity to the α2-adrenergic receptors, these new generation centrally acting antihypertensive agents are highly selective for imidazoline receptor. Moxonidine, a second-generation centrally acting antihypertensive drug having selective agonist activity on imidazoline I1 receptors and minor activity on imidazoline α2 adrenoceptors, reduces the activity of Sympathetic Nervous System (SNS) by activating I1 imidazoline receptors in Ros...