Relationship between imidazoline and α2-adrenoceptors involved in the sympatho-inhibitory actions of centrally acting antihypertensive agents (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).
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.
Journal of Hypertension, 2007
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).
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.
British Journal of Pharmacology, 2001
The aim of the present study was to compare the eects of the centrally acting antihypertensive drugs rilmenidine, moxonidine, clonidine and guanabenz on sympathetic tone with their eects on noradrenaline release in the cerebral cortex. In particular, the hypothesis was tested that rilmenidine and moxonidine, due to their high anity for sympatho-inhibitory imidazoline I 1 receptors and low anity for a 2-adrenoceptors, lower sympathetic tone without causing an a 2-adrenoceptor-mediated inhibition of cerebrocortical noradrenaline release. 2 In rats anaesthetized with urethane, blood pressure and heart rate were measured and the concentration of noradrenaline in arterial blood plasma was determined. The release of noradrenaline in the medial prefrontal cortex was estimated by microdialysis. Intravenous administration of rilmenidine (30, 100, 300 and 1000 mg kg 71), moxonidine (10, 30, 100 and 300 mg kg 71), clonidine (1, 3, 10 and 30 mg kg 71) and guanabenz (1, 3, 10 and 30 mg kg 71) led to dose-dependent hypotension and bradycardia; the plasma noradrenaline concentration also decreased. After the two highest doses, all four drugs lowered noradrenaline release in the prefrontal cortex. At doses eliciting equal hypotensive and sympatho-inhibitory responses, rilmenidine and moxonidine inhibited cerebral cortical noradrenaline release at least as much as clonidine and guanabenz. 3 The results show that rilmenidine and moxonidine lower cerebrocortical noradrenaline release at doses similar to those which cause sympatho-inhibition. This eect was probably due to an a 2adrenoceptor-mediated inhibition of the ®ring of locus coeruleus neurons and, in addition, to presynaptic inhibition of noradrenaline release at the level of the axon terminals in the cortex. The results argue against the hypothesis that rilmenidine and moxonidine, due to their selectivity for sympatho-inhibitory I 1 imidazoline receptors, do not suppress noradrenergic neurons in the central nervous system.
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.
British Journal of Pharmacology, 2001
1 The hypotensive eect 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 anities and activities at a 2 ARs but with high anities for non-adrenergic imidazoline binding sites (IBS). 5 S23515 decreased BP dose-dependently (727+5% maximal eect) 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 eect 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 eect of S23515. 6 Finally, whilst 3 mg kg 71 of S23515 or 0.5 mg kg 71 of a-MNA had weak hypotensive eects, 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.
Autonomic Neuroscience, 2008
Imidazoline derivatives (e.g. clonidine and moxonidine) and α 2 -adrenoceptor agonists (e.g. B-HT 933) have been shown to inhibit sympathetically-induced [ 3 H]noradrenaline release in several isolated blood vessels. The present study has compared the potential capability of agonists at imidazoline I 1/2 receptors and/or α 1/2adrenoceptors to inhibit the sympathetically-induced vasopressor responses in pithed rats. For this purpose, male Wistar rats were pithed and prepared for measurement of diastolic blood pressure and heart rate. Then, the vasopressor responses induced by either selective electrical stimulation (2 ms, 60 V; 0.03, 0.1, 0.3, 1 and 3 Hz) of the vascular sympathetic outflow (T 7 -T 9 ) or i.v. bolus injections of exogenous noradrenaline (0.03, 0.1, 0.3, 1 and 3 μg/kg) were determined before and during i.v. continuous infusions of the agonists B-HT 933 (α 2 ), clonidine (α 2 , I 1 ), moxonidine (α 2 , I 1 ), cirazoline (α 1 , I 2 ), agmatine (putative endogenous ligand of imidazoline receptors) and methoxamine (α 1 ), or equivalent volumes of physiological saline. Electrical sympathetic stimulation elicited frequency-dependent vasopressor responses which were significantly inhibited during the continuous infusions of B-HT 933, clonidine, moxonidine, cirazoline and agmatine, but not of physiological saline. Interestingly, the vasopressor responses to exogenous noradrenaline, which remained unaffected during the infusions of physiological saline, B-HT 933, moxonidine, cirazoline and agmatine, were significantly blocked during the infusions of clonidine or methoxamine. These results suggest that B-HT 933, moxonidine, cirazoline and agmatine induced a prejunctional inhibition of the vasopressor sympathetic outflow in pithed rats, whilst clonidine inhibited the vasopressor sympathetic outflow by both prejunctional and postjunctional mechanisms.