Role of imidazoline receptors in cardiovascular regulation (original) (raw)
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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.
I1 imidazoline receptors in cardiovascular regulation: the place of rilmenidine&ast
American journal of hypertension, 2000
From the very earliest suggestion of a distinction between imidazoline receptors and ␣ 2adrenoceptors, there has been much debate as to their contribution to the antihypertensive actions of clonidine-like agents. However, with the development of drugs such as rilmenidine that are more selective for I 1 imidazoline receptors, their role and also their close relationship with ␣ 2adrenoceptors has become clearer. We have examined this question using a range of imidazoline and ␣ 2-adrenoceptor antagonists given centrally and peripherally to conscious rabbits. We found that second-generation agents such as rilmenidine preferentially act via imidazoline receptors but that ␣ 2-adrenoceptors are important for the hypotension produced by the firstgeneration agents clonidine and ␣-methyldopa. In addition to the hypotension, rilmenidine facilitates cardiac vagal baroreflexes and inhibits cardiac sympathetic baroreflexes and diminishes the increase in renal sympathetic activity produced by environmental stress. In other studies using anesthetized rabbits and direct measures of sympathetic nerve activity, we confirmed that the major site of sympathoinhibitory actions and sympathetic baroreflex effects of rilmenidine is the rostral ventrolateral medulla. Our results also suggest that ␣ 2-adrenoceptors are activated as a consequence of imidazoline receptor activation by rilmenidine. Thus, though imidazoline receptors appear to be the primary target of rilmenidine, "downstream" ␣ 2-adrenoceptors within the brainstem are also involved and need to be considered in developing pharmacologic strategies for antihypertensive treatment involving imidazoline agents. Am J Hypertens 2000;
I1 imidazoline receptors in cardiovascular regulation: the place of rilmenidine
American journal of hypertension, 2000
From the very earliest suggestion of a distinction between imidazoline receptors and alpha2-adrenoceptors, there has been much debate as to their contribution to the antihypertensive actions of clonidine-like agents. However, with the development of drugs such as rilmenidine that are more selective for I1 imidazoline receptors, their role and also their close relationship with alpha2-adrenoceptors has become clearer. We have examined this question using a range of imidazoline and alpha2-adrenoceptor antagonists given centrally and peripherally to conscious rabbits. We found that second-generation agents such as rilmenidine preferentially act via imidazoline receptors but that alpha2-adrenoceptors are important for the hypotension produced by the first-generation agents clonidine and alpha-methyldopa. In addition to the hypotension, rilmenidine facilitates cardiac vagal baroreflexes and inhibits cardiac sympathetic baroreflexes and diminishes the increase in renal sympathetic activit...
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.
Rilmenidine lowers arterial pressure via imidazole receptors in brainstem C1 area
European journal of …, 1991
We sought to determine the site of action and receptor type responsible for the antihypertensive actions of rilmenidine, an oxazoline analogue of clonidine. In anesthetized paralyzed rats decerebration did not aher the dose dependent reductions in arterial pressure and heart rate elicited by i.v. drug. Rilmenidine microinjected bilaterally into the Cl area of the rostra1 ventrolateral medulla (RVL), but not nucleus tractus solitarii (NTS) nor caudal ventrolateral medulla (CVL), elicited dose-dependent falls in arterial pressure and heart rate at doses an order of magnitude less than required systemically. Prior microinjection into the Cl area of the selective a,-adrenoceptor antagonist SKF-86466, even at high doses, failed to modify the hypotension to i.v.
… drugs and therapy, 1994
Sympathoadrenal inhibition by a direct action within the central nervous system is an advantageous route to blood pressure control. Stimulation of brain oLz-adrenergic receptors is one mechanism for sympathoadrenal suppression, but comes at the cost of nonspecific depression of CNS function, including sedation and decreased salivary flow. Evidence is accumulating for a second pathway for pharmacological control of sympathoadrenal outflow, mediated by a novel receptor specific for imidazolines. First-generation central antihypertensive agents, which are imidazolines such as clonidine, act primarily to stimulate these II-imidazoline receptors in the rostral ventrolateral medulla oblongata (RVLM) to lower blood pressure, but have sufficient agonism at a2-adrenergic receptors to produce side effects. Secondgeneration centrally acting antihypertensive agents, such as moxonidine and rilmenidine, are selective for Ix relative to az receptors. The reduced a z potency of these agents correlates with reduced severity of side effects. In this study we further established the selectivity of moxonidine for 11imidazoline sites by characterizing the direct interaction of [alt]moxonidine with these receptors in the RVLM and in adrenomedullary chromaffin cells.
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).