New Central Mediators as Targets of Centrally Acting Antihypertensive Drugs

The modulation of peripheral sympathetic activity by the central nervous system may involve various pathways, neurotransmitters and receptors. In particular central catecholaminergic neurones and α-adrenoceptors have been analysed in detail, and they are recognized as important targets of the classic centrally acting antihypertensives clonidine, guanfacine and α-methyl-DOPA. Initially these drugs have been assumed to reduce elevated blood pressure via the stimulation of central α₂-adrenoceptors in the brain stem, thus leading to peripheral sympathoinhibition and a reduction of elevated blood pressure, heart rate and plasma catecholamines. In a later stage it has been recognized that central imidazoline (I₁) receptors, probably located in the nucleus reticularis lateralis in the medullary region may also be involved in the central regulation of peripheral sympathetic activity, and for that matter as a target of centrally acting antihypertensives. Moxonidine and rilmenidine are the prototypes of such agents. Accordingly, the receptor profile of the various types of centrally acting antihypertensives may be characterized as follows     

Different types of centrally acting antihypertensives and their targets in the central nervous system

Summary The central regulation of blood pressure and other cardiovascular parameters may involve the baroreceptor reflex arc, including both adrenergic and serotonergic pathways, as well as amino acids, as neurotransmitters. Both adrenergic and serotonergic pathways have been recognized as targets for clinically relevant, centrally acting antihypertensives, such as clonidine, guanfacine, and -methyl-DOPA. The central components of the hybrid drugs urapidil and ketanserin also involve serotonergic pathways and receptors. For urapidil the stimulation of 5-HT_1A-receptors is assumed to induce peripheral sympathoinhibition, whereas for ketanserin the central mechanism is unknown in detail. More recently central imidazoline (I₁) receptors have been proposed as the major target for the newer antihypertensives rilmenidine and moxonidine. Clonidine, however, is assumed to be mixed I₁- and alpha₂-receptor agonist. The distinction between central I₁- and alpha₂-receptors may potentially offer the design of new antihypertensives, acting like clonidine but with fewer side effects. Finally, the amino acid pathways should be considered as potential targets for centrally acting antihypertensives. Experimental compounds on this basis are available but clinical implications appear to be very remote. In the present survey an outline is given of the various pathways, neurotransmitters, and receptors involved in the central regulation of blood pressure. The different types of centrally acting antihypertensives are subsequently discussed on this basis.     

Imidazoline antihypertensive drugs: selective i(1) -imidazoline receptors activation

Involvement of imidazoline receptors (IR) in the regulation of vasomotor tone as well as in the mechanism of action of some centrally acting antihypertensives has received tremendous attention. To date, pharmacological studies have allowed the characterization of three main imidazoline receptor classes, the I(1) -imidazoline receptor which is involved in central inhibition of sympathetic tone to lower blood pressure, the I(2) -imidazoline receptor which is an allosteric binding site of monoamine oxidase B (MAO-B), and the I(3) -imidazoline receptor which regulates insulin secretion from pancreatic β-cells. All three imidazoline receptors represent important targets for cardiovascular research. The hypotensive effect of clonidine-like centrally acting antihypertensives was attributed both to α(2) -adrenergic receptors and nonadrenergic I(1) -imidazoline receptors, whereas their sedative action involves activation of only α(2) -adrenergic receptors located in the locus coeruleus. Since more selective I(1) -imidazoline receptors ligands reduced incidence of typical side effects of other centrally acting antihypertensives, there is significant interest in developing new agents with higher selectivity and affinity for I(1) -imidazoline receptors. The selective imidazoline receptors agents are also more effective in regulation of body fat, neuroprotection, inflammation, cell proliferation, epilepsy, depression, stress, cell adhesion, and pain. New agonists and antagonists with high selectivity for imidazoline receptor subtypes have been recently developed. In the present review we provide a brief update to the field of imidazoline research, highlighting some of the chemical diversity and progress made in the theoretical studies of imidazoline receptor ligands.     

Clonidine Antagonizes Pressor Effect of N-Methyl-D-Aspartate in the Rostral Ventrolateral Medulla of Rats

The purpose of the present study was to investigate the modulatory actions of adrenoreceptor agonists on N-methyl-D-aspartate (NMDA)-induced pressor effect in rostral ventrolateral medulla (RVLM). These drugs were locally applied into RVLM of urethane-anesthetized Sprague-Dawley rats through multibarrel pipettes. Microinjection of NMDA increased the arterial pressure, an effect which was abolished by pretreatment with clonidine, whereas neither the β-adrenergic agonist isoproterenol nor the α₁-adrenergic agonist phenylephrine did alter this pressor response. Previous experiments demonstrated that clonidine binds to noradrenergic α₂ and imidazoline receptors in the RVLM. Norepinephrine, which has high affinity for the α₂ receptor and low affinity to the imidazoline receptor, partially antagonized NMDA-induced hypertension. On the other hand, administration of selective imidazoline receptor antagonist idazoxan partially reversed clonidine-mediated antagonism of NMDA. Taken together, these results suggest that clonidine may modulate the excitatory amino acid -induced pressor response through noradrenergic α₂ and imidazoline receptors in the RVLM.     

Involvement of imidazoline receptors in the baroreflex effects of rilmenidine in conscious rabbits

OBJECTIVE : It has been suggested that imidazoline receptors rather than alpha2-adrenoceptors are involved in the sympathoinhibitory action of centrally acting antihypertensive drugs such as rilmenidine. In the present study, we examined the relative importance of alpha2-adrenoceptors and imidazoline receptors in modulating the renal sympathetic and heart rate (HR) baroreflex in response to central administration of rilmenidine in conscious normotensive rabbits. METHODS : In seven conscious rabbits, chronically instrumented with a fourth ventricular (4V) catheter, aortic and vena caval cuff occluders and a renal nerve electrode, we continuously recorded renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and HR and assessed baroreflex MAP-RSNA and MAP-HR relationships with balloon-induced ramp rises and falls in MAP. Rabbits were treated with 4V rilmenidine (22 microg/kg) followed by 4V idazoxan (30 microg/kg; a mixed alpha2-adrenoceptor and imidazoline receptor antagonist) or 4V 2-methoxy-idazoxan (1 microg/kg; an alpha2-adrenoceptor antagonist with little affinity for imidazoline receptors). RESULTS : Rilmenidine lowered blood pressure by 24% and reduced both upper and lower plateaus of the renal sympathetic baroreflex curve, such that the RSNA range (difference between plateaus) was reduced by 40% (-32 +/- 10 normalized units). Curves were shifted to the left with the fall in MAP. Idazoxan restored MAP, maximum RSNA and the RSNA baroreflex range. By contrast the alpha2-adrenoceptor antagonist 2-methoxy-idazoxan caused only a partial recovery of MAP and RSNA baroreflex upper plateau and range (-9 +/- 2 mmHg, 29 and 33% lower than control). Both antagonists partially restored the HR baroreflex. CONCLUSION : These findings suggest that in conscious rabbits, both imidazoline receptors and alpha2-adrenoceptors are involved in the central antihypertensive and baroreflex actions of rilmenidine, but that activation of imidazoline receptors is more important for its renal sympathoinhibitory action.     

Recent developments in noradrenergic neurotransmission and its relevance to the mechanism of action of certain antihypertensive agents

This report reviews a number of significant developments in the fields of noradrenergic transmission and adrenergic receptors which suggest that, in addition to the classical postsynaptic adrenoceptors, there are also presynaptic adrenoceptors that help modulate the release of norepinephrine (NE) from peripheral as well as central noradrenergic nerve endings during nerve stimulation. In particular, stimulation of presynaptic alpha-adrenoceptors reduces this release of transmitter and the reverse is observed after blockade of these receptors. Clearcut pharmacological differences exist between the postsynaptic alpha 1-adrenoceptors that mediate the responses of certain organs and the presynaptic alpha 2-adrenoceptors that modulate the NE release during nerve stimulation. Therefore, subclassification of alpha-adrenoceptors into alpha 1 and alpha 2 subtypes is warranted but must be considered to be independent of the anatomical location of these receptors. Some noradrenergic nerve endings have also been shown to possess beta-adrenergic receptors, the stimulation of which increases the quantity of transmitter released by nerve impulses. Physiologically, these receptors could be activated by circulating epinephrine (E) and be involved in essential hypertension. A third type of catecholamine receptor found at the noradrenergic nerve ending is the inhibitory dopamine (DA) receptor, which might be of significance in the development of new antihypertensive agents. Application of these new concepts of noradrenergic neurotransmission and the subclassification of alpha-adrenoceptors to the treatment of hypertension is presented. Clonidine, for example, appears to be a potent alpha 2-adrenoceptor agonist; the central receptor involved in its antihypertensive action is pharmacologically an alpha 2-type but located postsynaptically. Clonidine also induces activation of peripheral presynaptic alpha 2-adrenoceptors, which might contribute to its cardiovascular action. The antihypertensive effects of alpha-methyldopa are related to the formation of alpha-methylnorepinephrine, a preferential alpha 2-adrenoceptor agonist, which can stimulate peripheral presynaptic alpha 2-adrenoceptors leading to a decrease of NE release and a reduction in sympathetic tone. Prazosin is a new antihypertensive agent the mechanism of action of which involves a selective blockade of postsynaptic alpha 1-adrenoceptors. This drug does not antagonize several effects of clonidine that are mediated via alpha 2-adrenoceptors. The mechanisms presently considered to account for the antihypertensive activity of beta-adrenoceptor blocking agents are numerous. It is proposed that blockade of peripheral presynaptic facilitatory beta-adrenoceptors could be of significance in the antihypertensive action of these drugs.     

Centrally acting antihypertensive drugs. Present and future.

The classic centrally acting antihypertensives such as clonidine, guanfacine and alpha-methyl-DOPA (via its active metabolite alpha-methyl-noradrenaline) induce peripheral sympathoinhibition and a fall in blood pressure as a result of alpha2-adrenoceptor stimulation in the brain stem. These drugs have lost much of their clinical importance because of their unfavourable side-effects (sedation, dry mouth, impotence), which are also mediated by alpha2-adrenoceptors, although in other anatomical regions. Moxonidine and rilmenidine are the examples of a new class of centrally acting antihypertensives, which cause peripheral sympathoinhibition mediated by imidazoline (I1)-receptors in the rostral ventromedulla (RVLM). Their side-effect profile appears to be better than that of clonidine and alpha-methyl-DOPA, probably because of a weaker affinity for alpha2-adrenoceptors. The mode of action, haemodynamic profile, antihypertensive efficacy and adverse reactions of the classic and newer centrally acting antihypertensives are the subject of the present survey. Attention is also paid to other therapeutic applications of centrally acting antihypertensives, such as congestive heart failure and the metabolic syndrome.     

Historic aspects in the identification of the I1 receptor and the pharmacology of imidazolines

The central nervous system is involved in the control of arterial blood pressure. Stimulation of central ₂-adrenoceptors in the nucleus tractus solitarii (NTS) decreases sympathetic outflow, resulting in a fall in arterial blood pressure. One of the first antihypertensive substances with actions on the ₂-adrenoceptors of the NTS was -methylnoradrenaline. Later on the imidazoline clonidine was developed for which numerous effects, mediated by ₂-adrenoceptors, in the CNS could be demonstrated. Since the centrally acting ₂-adrenoceptor agonists possess severe side effects, the development of more specific and selective centrally acting imidazolines resulted in the derivatives moxonidine and rilmenidine. The effects of the second-generation imidazolines could not be fully understood as ₂-adrenoceptor agonists. In the meantime, the rostral ventrolateral medulla (RVLM) has been identified as the site of action of the imidazolines and an I₁-imidazoline binding site was characterized in this region. For the antihypertensive action of the imidazolines, agonism at the I₁-imidazoline subtype seems to be responsible. In addition, an acid- and heat-stable endogenous substance, calledclonidine displacing substance (CDS), was reported to bind at the putative I receptor. In 1992 a receptor protein for I receptors (70 kD) could be separated that is different from that of ₂-adrenoceptors. However, up to now we are still lacking the amino-acid sequence of the I receptor and its second messenger system.     

Review of Therapeutic Modalities Acting Directly Via Central Pathways

The brain influences arterial pressure through central mediation of a variety of neurotransmitters, including norepinephrine, and translates this action into changes in peripheral autonomic tone. Two opposed adrenergic systems have been described in brain: a hypothalamic pathway in which adrenergic receptor stimulation raises arterial pressure and a brainstem pathway related to the baroreflex arc in which adrenergic receptor stimulation lowers arterial pressure. Antihypertensive drugs with primarily central effects, including clonidine and alpha methyldopa, act as alpha₂ adrenoceptor agonists. The central receptor involved in their antihypertensive action is of the alpha₂ type but is located postsynaptically. Activation of this receptor by either clonidine or alpha methylnorepinephrine, a metabolite of alpha methyldopa, engages the depressor pathway in the brainstem and leads to a decrease in norepinephrine release and a reduction in peripheral sympathetic tone. Clonidine and alpha methyldopa share a similar pattern of peripheral effects, including reductions in preganglionic sympathetic nerve traffic, bradycardia, decreases in plasma renin activity, reductions in blood pressure in the supine position and adverse effects such as depression, sedation and bad dreams. Because of the frequency and severity of these side effects, there is an ongoing search for new centrally acting antihypertensive agents which might be better tolerated.     

Guanfacine and Other Centrally Acting Drugs in Antihypertensive Therapy; Pharmacological and Clinical Aspects

Centrally acting antihypertensive agents exert an agonist action on α-adrenoceptors in certain areas of the brain, thereby reducing sympathetic outflow and lowering blood pressure without paralysing peripheral homeostatic control mechanisms. Some also stimulate peripheral α-adrenoceptors, both postsynaptic and presynaptic. Guanfacine, a representative member of this class of drugs, resembles clonidine in most of its basic pharmacological properties. In some respects, however, clear differences exist and may account for an improved therapeutic usefulness. In cats the two drugs have a different site of action within the CNS. Unlike clonidine, guanfacine does not inhibit dopamine turnover in the corpus striatum of the rat and its hypotensive effect is not inhibited by central H₂-receptor blockade. In rat EEG studies guanfacine is much less sedative than clonidine. The newer drug shows a higher selectivity for (peripheral) presynaptic α-adrenoceptors than clonidine. On a weight basis guanfacine is about 10 times less potent in lowering blood pressure, but at equipotent doses its antihypertensive effect lasts longer. With an elimination half-life of approximately 18 to 21 h in man guanfacine is suitable for once-a-day treatment. The long duration of action is likely to explain the lack of rebound hypertension in chronically treated spontaneously hypertensive rats as well as the very low incidence and the remarkably mild nature of withdrawal symptomatology in man.     

Central Actions of Agmatine in Conscious Spontaneously Hypertensive Rats

Agmatine (decarboxylated arginine) is an endogenous ligand at alpha-2 adrenergic and imidazoline nonadrenergic receptors. In conscious spontaneously hypertensive rats (SHRs), we have studied its central effects on cardiovascular function and its interaction with the second generation centrally acting antihypertensive agent, rilmenidine, and the reference imidazoline, clonidine, which are mixed alpha-2 adrenoceptor/imidazoline receptor agonists. Agmatine, when administered in low doses (30–100 µg/kg) into the fourth ventricle had no effect on blood pressure and caused an increase in heart rate. A higher dose of 1000 µg/kg produced an adverse reaction in conscious SHRs and a marked and long-lasting increase in blood pressure. The effects of fourth ventricular rilmenidine (300 µg/kg) and clonidine (10 µg/kg) were equihypotensive and equibradycardic. The antihypertensive and bradycardic effects of rilmenidine were not reversed by cumulative intracisternal doses (30-100-300 µg/kg) of agmatine. The bradycardia obtained 20 min after intracisternal administration of clonidine in the fourth ventricle was reversed by 30 µg/kg agmatine. Only the highest dose of agmatine (1000 µg/kg) did reverse the antihypertensive effects of rilmenidine and clonidine. Agmatine neither did mimic nor block the antihypertensive response to rilmenidine and clonidine at well-tolerated doses. Yet agmatine produced a small tachycardia at relatively low doses and was able to reverse the bradycardia induced by clonidine. Therefore, its affinity for alpha-2 adrenoceptors in vitro might partially explain its cardiovascular effects in vivo.     

The high-risk hypertensive patient and the potential for brain imidazoline receptor binding by rilmenidine

K is a fact that sympathetic outflow is a player in most, if not all, hypertensive conditions. A selective, effective, and relatively benign means of controlling it remains high on every clinician's wish list. In this supplement we examine the neurobiologic and pharmacologic evidence that the wish is nearing fulfillment. Recent evidence has documented the existence of nonadrenegic receptors in the brainstem, other than the wellknown ₂-adrenergic receptors, that bind the imidazoline portion of vasoactive molecules. Pharmacologic science has wasted little time in developing compounds rich in imidazoline-like structures that, by supplanting norepinephrine (the natural cerebral neurotransmitter for sympathetic nervous system outflow) quiet sympathetic outflow, restrain heart rate and vasomotor influence, and reduce the negative quality-of-life effects induced by earlier centrally acting agents. This is because specific ligands for the imidazoline-preferring receptors appear to lower blood pressure without attendant drowsiness, dry mouth, and impaired mentation. Rilmenidine, the subject of this supplement, is the newest such agent, and the scientists involved in its development and clinical trials have produced heartening data. These developments presage good news in the clinic, and I am excited by their potential, particularly that for gaining deeper insight into human pressor phenomena.     

第二代中枢降压药——咪唑啉受体激动剂

传统中枢降压药因其激动α2肾上腺素受体而产生口干、嗜睡等严重副作用 ,已受到临床医生冷落。近年发现的非肾上腺素能咪唑啉受体激动剂 (第二代中枢降压药 )因较少激动 α2 -ARs受体 ,故副作用发生率和严重性均显著减少而倍受关注。本文对咪唑啉受体的基本概念、第二代中枢降压药的作用机制、药理作用、临床特性、不良反应等有关情况进行了综述     

Central actions of agmatine in conscious spontaneously hypertensive rats

Agmatine (decarboxylated arginine) is an endogenous ligand at alpha-2 adrenergic and imidazoline nonadrenergic receptors. In conscious spontaneously hypertensive rats (SHRs), we have studied its central effects on cardiovascular function and its interaction with the second generation centrally acting antihypertensive agent, rilmenidine, and the reference imidazoline, clonidine, which are mixed alpha-2 adrenoceptor/imidazoline receptor agonists. Agmatine, when administered in low doses (30-100 microg/kg) into the fourth ventricle had no effect on blood pressure and caused an increase in heart rate. A higher dose of 1,000 microg/kg produced an adverse reaction in conscious SHRs and a marked and long-lasting increase in blood pressure. The effects of fourth ventricular rilmenidine (300 microg/kg) and clonidine (10 microg/kg) were equihypotensive and equibradycardic. The antihypertensive and bradycardic effects of rilmenidine were not reversed by cumulative intracisternal doses (30-100-300 microg/kg) of agmatine. The bradycardia obtained 20 min after intracisternal administration of clonidine in the fourth ventricle was reversed by 30 microg/kg agmatine. Only the highest dose of agmatine (1,000 microg/kg) did reverse the antihypertensive effects of rilmenidine and clonidine. Agmatine neither did mimic nor block the antihypertensive response to rilmenidine and clonidine at well-tolerated doses. Yet agmatine produced a small tachycardia at relatively low doses and was able to reverse the bradycardia induced by clonidine. Therefore, its affinity for alpha-2 adrenoceptors in vitro might partially explain its cardiovascular effects in vivo.     

Effect of Meta-Chlorophenylpiperazine (mCPP), A Central Serotonin Agonist and Vascular Serotonin Receptor Antagonist,on Blood Pressure in SHR

mCPP (meta-chlorophenylpiperazine) has agonist activity at some central serotonin receptors and antagonist activity at peripheral vascular 5HT₂ receptors, both effects that have been postulated to lower blood pressure. mCPP (10 and 30 mg/kg, i.p. 1 hr after administration) increased serotonin and decreased 5-hydroxy-indolacetic acid (5-HIAA) brain concentrations and elevated serum corticosterone and prolactin, indications of central serotonergic agonist activities. The same doses of mCPP also antagonized vascular 5HT₂ receptors as measured by blockade of pressor responses to serotonin in pithed rats. Although mCPP could be demonstrated to activate central serotonergic receptors and block peripheral vascular 5HT₂ receptors, mCPP (10 and 30 mg/kg, i.p.) produced little effect on blood pressure in either the anesthetized or conscious spontaneously hypertensive rat (SHR) up to 1 hr after intraperitoneal administration. The findings are consistent with initial studies in normotensive humans that have not demonstrated a reduction in blood pressure clinically after mCPP in doses that produce elevations in serum cortisol and prolactin levels.     

Central sympatholytic drugs

J Clin Hypertens (Greenwich). 2011;13:658–661. ©2011 Wiley Periodicals, Inc.Key Points

• • Central sympatholytic drugs reduce blood pressure mainly by stimulating central α₂‐adrenergic receptors in the brainstem centers, thereby reducing sympathetic nerve activity and neuronal release of norepinephrine to the heart and peripheral circulation.
• • This class of drugs, however, is currently used mainly as fourth‐line (or beyond) drug therapy for hypertension because of side effects of drowsiness, fatigue, and dry mouth.
• • Rebound hypertension is also another major concern in certain drugs with a short half‐life, particularly in patients who are nonadherent to the regimen. Therefore, their use on a “PRN” basis for treatment of blood pressure surge in the absence of symptoms or acute target complications should also be avoided.

Central sympatholytic agents were first introduced into clinical use in the 1960s. α‐Methyldopa, the first drug to be widely used, is the only prodrug in this class. It is converted to α‐methylnorepinephrine, which was at first thought to act peripherally as a false neurotransmitter. Clonidine, the prototype of the second‐generation drugs in this class, all of which are imidazoline derivatives, was initially developed as a nasal decongestant because of its potential vasoconstrictor effect via postsynaptic α₂‐adrenergic receptor (AR) stimulation but was surprisingly found to have antihypertensive effects via activation of presynaptic α₂‐AR in the brainstem. ¹ A similar effect of centrally formed α‐methylnorepinephrine is now understood to account for the blood pressure (BP)–lowering effect of methyldopa. Subsequently, other direct‐acting central sympatholytic drugs such as guanfacine and guanabenz were approved for treatment of hypertension in the United States. Moxonidine and rilmenidine are also centrally acting drugs used in England and other European countries but are not available in the United States. In contrast to clonidine and other α₂ agonists, moxonidine and rilmenidine predominantly reduce sympathetic nerve activity (SNA) and BP by stimulating imidazoline‐1 (I₁) receptor, rather than α₂‐AR in the brainstem. ²      

Comparison of renal sympathetic baroreflex effects of rilmenidine and alpha-methylnoradrenaline in the ventrolateral medulla of the rabbit

OBJECTIVE: To determine the influence of imidazoline receptors and alpha2-adrenoceptors in the rostral ventrolateral medulla (RVLM) on the renal sympathetic baroreflex. METHODS: The effects of rilmenidine (4 nmol) and alpha-methylnoradrenaline (alpha-MNA, 80 nmol) micro-injected into the RVLM of urethane-anaesthetized rabbits previously implanted with renal nerve recording electrodes were examined before and after micro-injection of the imidazoline receptor/alpha2-adrenoceptor antagonist idazoxan and the alpha2-adrenoceptor antagonist 2-methoxyidazoxan (2-MI). RESULTS: Rilmenidine and alpha-MNA both lowered mean arterial pressure (MAP) by 28% and renal sympathetic nerve activity (RSNA) by 35%, and reduced RSNA upper plateaus and ranges by 30-70%. Rilmenidine decreased both sympathetic burst frequency and amplitude while alpha-MNA reduced amplitude only. Rilmenidine shifted the RSNA baroreflex curve to the left while alpha-MNA shifted the curve to the right Idazoxan (13 nmol) reversed the hypotension and all RSNA effects of rilmenidine, while 2-MI (4 nmol) increased MAP 18% above the control and also reversed all RSNA parameters. By contrast, 2-MI reversed the alpha-MNA-induced hypotension and partially restored RSNA and the upper plateau of the RSNA baroreflex curve. Idazoxan treatment only partially reversed the hypotension after alpha-MNA and had no effect on any of the baroreflex curves. CONCLUSION: Both alpha-MNA and rilmenidine injected into the RVLM of rabbits produce renal sympathetic inhibition, but differences in the location of the baroreflex curve and the pattern of effects on burst amplitude and frequency suggest different mechanisms of action. The effects of idazoxan suggest that rilmenidine acts via imidazoline receptors. Since 2-MI reversed the actions of alpha-MNA and also rilmenidine, this suggests that alpha2-adrenoceptor hypotension can be produced in the rabbit RVLM and that rilmenidine may activate alpha2-adrenoceptors, possibly as a result of activating imidazoline receptors.     

Role of imidazoline receptors in cardiovascular regulation

The involvement of nonadrenergic imidazoline specific receptors in the central control of the vasomotor tone and in the mechanism of action of drugs bearing an imidazoline structure, or analogs, is now well documented. Imidazoline-specific binding sites were found in many tissues and species. Moreover, until now, it is only in the brainstem that such binding sites are associated with a function: the hyportensive effect of imidazoline-like drugs. Rilmenidine, which is an oxazoline structurally related to the reference imidazolines, exerts a central hypotensive effect of central origin involving imidazoline receptors. The selectivity of rilmenidine for the imidazoline receptors compared to ₂-adrenergic receptors could explain the low incidence of sedative side effects observed with this antihypertensive drug. A specific anti-imidazoline radioimmunoassay allowed us to detect the presence of an immunoreactive imidazoline-like substance in human sera. High levels of this immunoreactive substance are associated with high blood pressure in 20–30% of the hypertensive patients. This observation indicates that high levels of this immunoreactive substance in the serum can be associated with some kinds of primary hypertension. The cause-and-effect relation between these 2 phenomena has not yet been determined. This substance is in process of purification; it could be a candidate to be an endogenous ligand of the imidazoline receptors.     

Nitric oxide and central antihypertensive drugs: one more difference between catecholamines and imidazolines

NO is known to be involved in the peripheral and central regulation of the cardiovascular function. It plays a neuromodulatory role via a direct action on presynaptic nerve terminals, stimulating the release of gamma-aminobutyric acid, glutamate, and norepinephrine. Our aim was to study the possible role of NO in the cardiovascular effects of the central antihypertensive drugs clonidine, rilmenidine, and alpha-methyl-norepinephrine (alpha-MNA). Sites and mechanisms of the hypotensive action of these drugs were different; clonidine and rilmenidine acted on imidazoline receptors in the nucleus reticularis lateralis, whereas alpha-MNA acted upon alpha(2)-adrenoceptors in the nucleus tractus solitarius. The influence of N:(G)-nitro-L-arginine, an NO synthase inhibitor, on the central hypotensive effects of these drugs was investigated in pentobarbital-anesthetized rabbits. The intracisternal (IC) administration of alpha-MNA (30 microg/kg) induced hypotension (79+/-2 versus 103+/-4 mm Hg) and bradycardia (222+/-8 versus 278+/-4 bpm) (P:<0.05) (n=5). Clonidine (0.07 microg/kg IC) also induced hypotension (69+/-5 versus 99+/-4 mm Hg) and bradycardia (266+/-7 versus 306+/-10 bpm) (P:<0.05) (n=5). In addition to clonidine, rilmenidine (1 microg/kg IC) induced hypotension (64+/-4 versus 97+/-4 mm Hg) and bradycardia (264+/-11 versus 310+/-4 bpm) (P:<0.05) (n=5). Pretreatment with N:(G)-nitro-L-arginine (900 microg/kg IC) completely prevented the hypotensive effect of alpha-MNA but influenced the cardiovascular effects of neither clonidine nor rilmenidine. These results confirm that imidazoline drugs, such as clonidine, rilmenidine, and the catecholamine alpha(2)-adrenoceptor agonist alpha-MNA, have distinct mechanisms of action.     

The Pharmacology of Prazosin,an Alpha 1-Adrenoceptor Antagonist and the Basis for Its Use in the Treatment of Essential Hypertension

Prazosin was the result of an attempt to find a directly acting vasodilator drug with little or no effect on cardiac output, renin and salt and water metabolism. Clinical studies confirmed that these desirable features were possessed by prazosin in spite of an apparently peripheral mode of action and thus prazosin contrasted strongly with all other agents of this type. Prazosin differs from the classical alpha-adrenoceptor antagonists in possessing marked selectivity for alpha₁-adrenoceptors as opposed to alpha₂-adrenoceptors. This ensures the preservation of the local feedback control of the release of noradrenergic transmitter by the pre-junctional alpha₂-adrenoceptors. This fact appears to be responsible for the therapeutic success of prazosin and why prazosin is the first alpha-adrenoceptor blocking drug to be effective in the treatment of hypertension. The marked selectivity for alpha₁-adrenoceptors makes prazosin invaluable as a research tool, especially as a radioligand for the identification of alpha₁-adrenoceptors.