Central Imidazoline Receptors Research Articles

Adrenergic and imidazoline mechanisms of arterial baroreceptor reflex in the short and long-term regulation of blood pressure

Objective. The purpose of this work was to study how selective activation of сentral adrenergic and imidazoline receptors influence functional state of the blood baroreceptor reflex (BR) in the short and long-term regulation of blood pressure (BP) at rest and under emotional stress. Design and methods. Experiments were conducted on awake Wistar rats. Clonidine (1 and 10 mg/kg) was used for adrenergic receptors activation, moxonidine (10 and 100 mg/kg) was used for imidazoline receptor activation. Emotional stress was caused by sound signal (a ring). Results. Studies demonstrated that the activation of central imidazoline receptors does not change BP level, while alpha 2‑adrenergic systems play a major role in the central regulation of vascular tone and cardiac function. Both imidazoline and alpha 2‑adrenergic systems participate in functioning of baroreceptor reflex. Conclusions. Emotional stress-associated imidazoline receptor activation restores initial BR and reduces BP elevation in rats. Alpha 2‑adrenergic systems do not have a significant impact on cardiovascular manifestations of emotional tension.

Involvement of central α 1-adrenoceptors on renal responses to central moxonidine and α-methylnoradrenaline

Moxonidine (α 2-adrenoceptor/imidazoline receptor agonist) injected into the lateral ventricle induces diuresis, natriuresis and renal vasodilation. Moxonidine-induced diuresis and natriuresis depend on central imidazoline receptors, while central α 1-adrenoceptors are involved in renal vasodilation. However, the involvement of central α 1-adrenoceptors on diuresis and natriuresis to central moxonidine was not investigated yet. In the present study, the effects of moxonidine, α-methylnoradrenaline (α 2-adrenoceptor agonist) or phenylephrine (α 1-adrenoceptor agonist) alone or combined with previous injections of prazosin (α 1-adrenoceptor antagonist), yohimbine or RX 821002 (α 2-adrenoceptor antagonists) intracerebroventricularly (i.c.v.) on urinary sodium, potassium and volume were investigated. Male Holtzman rats ( n = 5–18/group) with stainless steel cannula implanted into the lateral ventricle and submitted to gastric water load (10% of body weight) were used. Injections of moxonidine (20 nmol) or α-methylnoradrenaline (80 nmol) i.c.v. induced natriuresis (196 ± 25 and 171 ± 30, respectively, vs. vehicle: 101 ± 9 µEq/2 h) and diuresis (9.0 ± 0.4 and 12.3 ± 1.6, respectively, vs. vehicle: 5.2 ± 0.5 ml/2 h). Pre-treatment with prazosin (320 nmol) i.c.v. abolished the natriuresis (23 ± 4 and 76 ± 11 µEq/2 h, respectively) and diuresis (5 ± 1 and 7.6 ± 0.8 ml/2 h, respectively) produced by i.c.v. moxonidine or α-methylnoradrenaline. RX 821002 (320 nmol) i.c.v. abolished the natriuretic effect of α-methylnoradrenaline, however, yohimbine (320 nmol) did not change renal responses to moxonidine. Phenylephrine (80 nmol) i.c.v. induced natriuresis and kaliuresis that were blocked by prazosin. Therefore, the present data suggest that moxonidine and α-methylnoradrenaline acting on central imidazoline receptors and α 2-adrenoceptors, respectively, activate central α 1-adrenergic mechanisms to increase renal excretion.

Importance of imidazoline-preferring receptors in the cardiovascular actions of chronically administered moxonidine, rilmenidine and clonidine in conscious rabbits.

To determine the involvement of central imidazoline receptors in the cardiovascular actions of the chronically administered antihypertensive agents moxonidine, rilmenidine and clonidine. In 21 rabbits with implanted fourth-ventricular catheters, we investigated the central effects of three cumulative doses of an I(1)-imidazoline/alpha(2)-adrenoceptor antagonist, efaroxan, and of an alpha(2)-adrenoceptor antagonist, 2-methoxyidazoxan (2-MI), on the changes in blood pressure and heart rate (HR) elicited by chronic subcutaneous administration of moxonidine, rilmenidine and clonidine, after 1 and 3 weeks of treatment. A low, medium and high dose of 2-MI was matched to three doses of efaroxan, such that each produced equal reversal of the hypotension induced by fourth-ventricular alpha-methyldopa and hence produced a similar degree of alpha(2)-adrenoceptor blockade. Clonidine and moxonidine, at doses of 1 mg/kg per day, and rilmenidine at 5 mg/kg per day, produced sustained reductions in mean arterial pressure of 13 +/- 3, 15 +/- 2 and 13 +/- 2 mmHg, respectively over the 3-week treatment period, but did not alter HR. Central administration of efaroxan on day 9 and day 23 of treatment produced a greater increase in blood pressure than did 2-MI with all three antihypertensive agents. Blood pressure reached levels that were significantly above the original control values. By contrast, the alpha(2)-adrenoceptor antagonist 2-MI only induced a rebound blood pressure effect in clonidine- and to a lesser extent in rilmenidine-treated rabbits. Both efaroxan and 2-MI produced a similar degree of tachycardia in moxonidine-, rilmenidine- and clonidine-treated animals.(2) The greater effect of efaroxan compared to the alpha(2)-adrenoceptor antagonist 2-MI suggests that the hypotension induced by chronic subcutaneous administration of moxonidine, rilmenidine and clonidine is mediated predominantly via an action on central imidazoline receptors. Furthermore, all agents showed a propensity to produce rebound hypertension with imidazoline receptor blockade. However, only clonidine showed a rebound phenomenon when challenged by acute central alpha(2)-adrenoceptor blockade

Effects of central sympathetic inhibition on heart rate variability during steady-state exercise in healthy humans.

The profound reduction in heart rate variability (HRV) that occurs during exercise is thought to be, at least in part, the result of sympathetic nervous system activation. Moxonidine is a centrally acting anti-sympathetic drug, which suppresses sympathetic nervous system outflow by stimulation of central imidazoline receptors located in the rostral ventro-lateral medulla. This study was designed to investigate the combined effects of central sympathetic inhibition with moxonidine and steady-dynamic exercise on HRV. Ten normal males participated in a double-blind cross-over study, taking either placebo or 0.4 mg of moxonidine. The subjects were studied at rest and during steady-state exercise. HRV was measured considering both time and frequency domain parameters. As a non-linear measure, the Poincaré scatter-plot was measured and analysed quantitatively. Ventilation and gas exchange were also measured during exercise. In addition, plasma catecholamines were measured at rest and during exercise. The only parameter changed, at rest, by moxonidine was the blood pressure which was reduced. During exercise, moxonidine reduced plasma noradrenaline (NA), compared with the placebo (P<0.01). The only change observed in HRV during exercise was a significant reduction of the continuous long-term standard deviation (SD2) of the Poincaré scatter-plot of the R-R interval (P<0.05). However, the potential and prognostic significance of this result needs to be further assessed.

Central imidazoline (I1) receptors modulate aqueous hydrodynamics

The purpose of this work is to determine the relative contributions of central imidazoline (I 1) receptors to the ocular hydrodynamic action of moxonidine. Moxonidine (MOX), an a 2 and I 1 receptor agonist, and efaroxan (EFA), a relatively selective I 1 antagonist, were utilized to study alterations in intraocular pressure (IOP) and aqueous flow in New Zealand white rabbits subjected to intracerebroventricular (i.c.v.) cannulation and sympathectomy. Intracerebroventricular administration of MOX (0.033, 0.33 and 3.33 µg) to normal rabbits produced dose-dependent, bilateral IOP decreases of 3, 6, and 8 mmHg, respectively. The ocular hypotensive response to MOX was immediate (10 min. post drug), lasted for one hour, and was inhibited by prior administration of efaroxan (3.33 µg icv). In unilaterally sympathectomized (SX) rabbits, the ocular hypotensive response induced by i.c.v MOX in the denervated eye was attenuated approximately 50%, but the duration of ocular hypotension in the surgically altered eye was longer than that of the normal eye. MOX (0.33 µg icv), caused a statistically significant decrease (2.24 to 1.59 ml/min.) in aqueous flow in normal eyes. In SX eyes, there was no change in aqueous flow by MOX, suggesting that IOP effect in icv MOX observed in the SX eye might be mediated by changes in outflow resistance. Sedation was observed in all the rabbits treated with MOX (icv) and was dose-dependent. These in vivo data support the suggestion that centrally located I 1 receptors modulate the early contralateral response to topically administered MOX and are involved in lowering of IOP and aqueous flow in rabbit. In addition, expression of the full ocular hypotensive effect of centrally applied MOX depends on intact sympathetic innervation. Ocular hypotension induced by MOX in the SX eye may involve an effect on uveoscleral outflow.

I1 imidazoline agonists. General clinical pharmacology of imidazoline receptors: implications for the treatment of the elderly.

In recent years evidence has accumulated for the existence of central imidazoline (I1) receptors that influence blood pressure. While there is some controversy, it has been suggested that clonidine exerts its blood pressure-lowering effect mainly by activation of imidazoline I1 receptors in the rostral ventrolateral medulla, while its sedative effect is mediated by activation of central alpha2-receptors. Moxonidine and rilmenidine are 2 imidazoline compounds with 30-fold greater specificity for I1 receptors than for alpha2-receptors. In comparison, clonidine displays a 4-fold specificity for I1 receptors compared with alpha2 receptors. Moxonidine and rilmenidine lower blood pressure by reducing peripheral resistance. They reduce circulating catecholamine levels and moxonidine reportedly reduces sympathetic nerve activity in patients with hypertension. Moxonidine and rilmenidine modestly reduce elevated blood glucose levels and moxonidine has been reported to reduce insulin resistance in hypertensive patients with raised insulin resistance. Small reductions in plasma levels of total cholesterol, low density lipoprotein-cholesterol and triglycerides have been reported with rilmenidine. Both moxonidine and rilmenidine are well absorbed after oral administration and are eliminated unchanged by the kidneys. The elimination half-life (t(1/2)) of rilmenidine and moxonidine is 8 and 2 hours, respectively, but trough/peak plasma concentration ratios indicate that moxonidine can be administered once daily, suggesting possible CNS retention. As would be expected, t(1/2) values are increased in patients with reduced renal function, and in elderly individuals. Both drugs have been compared with established antihypertensive drugs from all the major groups. Studies, almost all of which were of a double-blind, parallel-group design, indicate that blood pressure control with moxonidine or rilmenidine is similar to that with established drugs, i.e. alpha-blocking drugs, calcium antagonists, ACE inhibitors, beta-blocking drugs and diuretic agents. There have been few studies conducted solely in elderly patients. However, evidence clearly suggests that the antihypertensive effect of the imidazoline compounds is not reduced in elderly patients. The overall adverse effect profile of moxonidine and rilmenidine compares reasonably with established agents. In accord with the receptor-binding studies, drowsiness and dry mouth are observed less often with these drugs than with other centrally acting drugs, although the symptoms occur more often than with placebo. An overshoot of blood pressure was seen when treatment with clonidine, but not moxonidine, was abruptly discontinued in conscious, spontaneously hypertensive rats. Clinical evidence of withdrawal reaction with moxonidine or rilmenidine is scant but caution should be observed pending more formal studies.

Imidazoline receptor mediated natriuresis: central and/or peripheral effect?

The ability of imidazoline agonists, such as moxonidine and rilmenidine, to lower blood pressure has been attributed to a central effect resulting in a decrease in peripheral sympathetic nerve activity. A similar decrease in sympathetic nerve activity to the kidney has been proposed to explain the increase in sodium excretion. The observed increase in sodium excretion following an intrarenal infusion of moxonidine or rilmenidine suggested the existence of a direct renal action. We therefore tested the hypothesis that direct renal infusions were acting at a central rather than a peripheral site. Thus, interventions which would decrease the natriuretic effects of central administered moxonidine would also block the effects of intrarenal administered moxonidine. Studies were performed in anesthetized Sprague–Dawley rats (280–320 g) which had undergone unilateral nephrectomy 7 to 10 days prior to the experiment. The interventions utilized resulted in minimal effects on blood pressure and creatinine clearance. Intracerebroventricular (icv) or intrarenal (ir) administration of moxonidine produced a significant increase in urine flow rate and sodium excretion. Intravenous (iv) prazosin was used to block the ability of the sympathetic nerves to alter sodium excretion secondary to α 1-adrenoceptor stimulation. Prazosin prevented the natriuresis following icv moxonidine but only partially antagonized the effects of ir moxonidine. To determine if central imidazoline receptors mediated the effects of moxonidine, animals were pretreated with icv idazoxan. Following icv idazoxan, the effects of icv moxonidine were blocked, whereas the response to intrarenal moxonidine was only partially blocked. Peripheral (iv) administration of idazoxan blocked the actions of intrarenal moxonidine but left the response to icv moxonidine intact. Finally, chemical sympathectomy with reserpine did not alter the response to intrarenal moxonidine suggesting that this effect was independent of the sympathetic nervous system. In conclusion, these studies indicate the ability of central and peripheral moxonidine to increase urine flow rate through sodium excretion at two unique sites of action, one central and the other one peripheral, most conceivably within the kidney.

Arterial pressure lability in hypotensive effects of clonidine in barodenervated spontaneously hypertensive rats

Hypotensive effect of clonidine and its effect on arterial pressure lability as the main index of stability of background blood pressure are studied in intact spontaneously hypertensive rats (SHR) and rats with chronic sinoaortic denervation. Barodenervation potentiates hypotensive and negative cardiochronotropic effects of clonidine, which is accompanied by reduced blood pressure lability. This indicates an increased sensitivity of central α2-and imidazoline receptors, which mediate the depressor effect of clonidine, against the background of chronic inhibition of the baroreceptor reflex.

Central imidazoline (I1) receptors as targets of centrally acting antihypertensives: moxonidine and rilmenidine.

Clonidine, guanfacine, guanabenz and alpha-methyl-dioxyphenylalanine (DOPA), the prototypes of centrally acting antihypertensives, are assumed to induce peripheral sympathoinhibition and a reduction in blood pressure via the stimulation of alpha2-adrenoceptors in the brain stem. More recently, central imidazoline (I1)-receptors have been recognized to be another target of centrally acting antihypertensive drugs. Clonidine is considered to be a mixed agonist that stimulates both alpha2- and I1-receptors. Moxonidine and rilmenidine are considered to be moderately selective I1-receptor stimulants, although it still remains unknown whether these agents act directly on the receptor as genuine agonists. A survey is given on the location, characteristics and functional aspects of imidazoline I1-receptors as targets of centrally acting antihypertensives. Furthermore, the pharmacology and clinical potential of selective I1-receptor agonists such as moxonidine and rilmenidine are discussed. Although far from perfect, these compounds have shown that it may potentially be possible to develop agents with which the well-known side effects caused by alpha2-receptor agonists can be separated from the central antihypertensive mechanism.

Central Imidazoline Receptors and Centrally Acting Anti-Hypertensive Agents

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 α2-adrenoceptor antagonist 2-methoxy-idazoxan), suggesting that IR are important in the sympatho-inhibition produced by these agents. Clonidine was not preferentially reversed by the IR antagonists suggesting an action via aadrenoceptors.In anaesthetised rabbits, the rostral ventrolateral medulla(RVLM) was the most potent site for rilmenidine to produce the sympathoinhibition and modulation of sympathetic baroreflexes. a-Methylnoradrenalhe was also sympatholytic suggesting a-adrenoceptors are also present in this site. Microinjection of the IR and a-adrenoceptor antagonists showed that rilmenidine activates IR in the RVLM but that a-adrenoceptors are also activated as a consequence. These studies suggest that rilmenidine acts primarily via IR in the RVLM to reduce sympathetic tone but also imply an important association of a-adrenoceptors and IR in the region.

Relative importance of central imidazoline receptors for the antihypertensive effects of moxonidine and rilmenidine.

To determine the involvement of central imidazoline receptors in the cardiovascular actions of the antihypertensive agents moxonidine, rilmenidine and clonidine administered systemically. We determined the relative potency of these drugs with respect to their effects on mean arterial pressure and heart rate by performing cumulative intravenous dose-response relationship studies in six conscious rabbits. In another eight rabbits with implanted fourth-ventricular catheters, we investigated the central effects of three cumulative doses of an l1-imidazoline/ alpha 2-adrenoceptor antagonist, efaroxan, and of an alpha 2-adrenoceptor antagonist, 2-methoxyidazoxan (2-Ml), on the hypotension and bradycardia elicited by a single intravenous dose of the above agents. The doses of antagonists were matched for an equal reversal of the hypotension induced by fourth-ventricular alpha-methyldopa (an alpha 2-adrenoceptor agonist) and hence for similar alpha 2-adrenoceptor blockade. Moxonidine and rilmenidine were sevenfold and eightfold less potent, respectively, than was clonidine in eliciting hypotension. By comparison, moxonidine and clonidine were more potent than was rilmenidine in producing bradycardia. Efaroxan and 2-Ml reversed the hypotension and bradycardia induced by a single dose of all three agents dose-dependently. However, efaroxan was more effective than was 2-Ml at reversing the effects of rilmenidine and moxonidine. Complete reversal of their hypotensive effect was observed with the highest dose of efaroxan but the highest dose of 2-Ml reversed approximately 50% of that effect. In contrast, the two antagonists were equally effective at reversing the responses to clonidine. These results suggest that the hypotension and bradycardia induced by intravenous administration of moxonidine and rilmenidine were mediated mainly by actions on central imidazoline receptors whereas clonidine appears to act predominantly on central alpha 2-adrenoceptors.

Modulation of sympathetic outflow by centrally acting antihypertensive drugs.

The modulation of peripheral sympathetic activity by the central nervous system (CNS) has been intensely investigated as a potential target of antihypertensive drugs. In particular, clonidine, guanfacine, and alpha-methyl-DOPA (acting via its metabolite alpha-methylnoradrenaline) have been developed as antihypertensives with a predominantly CNS site of action. Initially these drugs have been assumed to reduce elevated blood pressure via the stimulation of central alpha2-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 the 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: alpha-methyl-DOPA, alpha2 (through alpha-methylnoradrenaline); clonidine alpha2 + I1 (mixed agonist); and moxonidine, rilmenidine, I1 > alpha2. The various compounds mentioned will thus cause peripheral sympathoinhibition, initiated by different receptor targets in the CNS. Finally, the peripheral alpha1-blocker, urapidil, has been demonstrated to possess an additional central mechanism, mediated by the stimulation of serotonergic 5HT1A-receptors located in the rostral ventrolateral medulla. The stimulation of these 5HT1A-receptors appears to suppress, via the autonomic nervous system, the reflex tachycardia triggered by vasodilation.

Antiarrhythmic action of rilmenidine on adrenaline‐induced arrhythmia via central imidazoline receptors in halothane‐anaesthetized dogs

1. To elucidate the role of central imidazoline receptors in the genesis of adrenaline-induced arrhythmias under halothane anaesthesia, we investigated the effects of rilmenidine, a selective agonist at imidazoline receptors, on this type of arrhythmia in dogs. Rilmenidine (1, 3, 10 micrograms kg-1, i.v.) did not affect basal haemodynamic parameters (heart rate and blood pressure), but dose-dependently inhibited adrenaline-induced arrhythmias under halothane anaesthesia. 2. Although, rilmenidine has a weak affinity for alpha(2)-adrenoceptors, pretreatment with idazoxan (10 micrograms kg-1, intracisternally i.c.), an imidazoline receptor antagonist which has also alpha(2)-adrenoceptor blocking potency, blocked the antiarrhythmic effect of rilmenidine (10 micrograms kg-1, i.v.). In contrast, pretreatment with rauwolscine (20 micrograms kg-1, i.c.), a classical alpha(2)-adrenoceptor antagonist with little affinity for imidazoline receptors, did not affect the effect of rilmenidine (10 micrograms kg-1, i.v.). Furthermore, bilateral vagotomy completely blocked the antiarrhythmic action of rilmenidine (10 micrograms kg-1, i.v.). 3. It is suggested that the antiarrhythmic action of rilmenidine is due to the activation of central imidazoline receptors and that vagal tone is critical for this action of rilmenidine.

From α and β to I1

There is no doubt that the sympathetic nervous system (SNS) plays an important role in the pathogenesis and maintenance of hypertensive disease, although many details concerning this association remain to be clarified. Over the years, several types of antihypertensive drugs have been developed that can impair SNS activity at virtually all levels of the system. Alpha and beta-adrenoceptor antagonists, postganglionic sympathetic neuron blockers and ganglioplegic agents are well-known examples of drugs with a predominantly peripheral activity. The CNS regulation of peripheral sympathetic activity offers a further possibility to counteract the influence of SNS activity. In particular, central catecholaminergic neurons and alpha-adrenoceptors have been analyzed in detail and are recognized as important targets for the classic centrally acting antihypertensives clonidine, guanfacine, and alpha-methyldopa. Initially, these drugs were assumed to reduce elevated blood pressure via the stimulation of central alpha-adrenoceptors in the brainstem, 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 may also be involved in the central regulation of peripheral sympathetic activity and that they act as a target for centrally acting antihypertensives. Moxonidine and rilmenidine are the prototypes of such agents. Accordingly, the receptor profile of the various types of centrally acting antihypertensives can be characterized as follows: alpha-methyl-DOPA (through alpha-methyl-norepinephrine) alpha 2; clonidine (mixed agonist), alpha 2 + I1; moxonidine, rilmenidine, I1 > alpha 2. The various compounds mentioned will thus cause peripheral sympathoinhibition, initiated by different receptor targets in the CNS. Because most of the adverse reactions to clonidine and related drugs are mediated by central alpha-adrenoceptors, is is hoped that the imidazoline receptor agonists (moxonidine, rilmenidine) will show a more favorable pattern of side effects.

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 alpha-adrenoceptors have been analysed in detail, and they are recognized as important targets of the classic centrally acting antihypertensives clonidine, guanfacine and alpha-methyl-DOPA. Initially these drugs have been assumed to reduce elevated blood pressure via the stimulation of central alpha 2-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: [formula: see text] The various compounds mentioned will thus cause peripheral sympathoinhibition, initiated by different receptor targets in the CNS. Finally, the peripheral alpha 1-blocker urapidil has been demonstrated to possess an additional central mechanism, mediated by the stimulation of serotonergic 5HT1A-receptors located in the rostral ventrolateral medulla.

Excess catecholamines and the metabolic syndrome: Should central imidazoline receptors be a therapeutic target?

A sympathetic overactivity plays a major role in the pathogenesis of cardiovascular diseases in Westernized affluent societies. Of importance is an increased caloric intake and psychosocial stress which are associated with a raised central sympathetic outflow and unfavourable changes in metabolic parameters. Normalization of central sympathetic outflow could thus be a major therapeutic target. The newly developed anti hypertensive drugs moxonidine and rilmenidine reduce the excitatory activity of neurons of the rostral ventrolateral medulla (RVLM) via binding to imidazoline receptors. Using radio telemetry, it is shown that, in contrast to the first generation centrally acting drug clonidine, moxonidine did not result in rebound of blood pressure after drug withdrawal in rats with spontaneous hypertension. In accordance, moxonidine is characterized by a low affinity for a-adrenoceptors and exhibits few side-effects. It is proposed that normalization of central sympathetic outflow represents a causal approach for improving crucial features of the metabolic syndrome.

Effects of immidazoline and guanidinium compounds on the cardiovascular system

The ability of imidazoline agonists, such as moxonidine and rilmenidine, to lower blood pressure has been attributed to a central effect resulting in a decrease in peripheral sympathetic nerve activity. A similar decrease in sympathetic nerve activity to the kidney has been proposed to explain the increase in sodium excretion. The observed increase in sodium excretion following an intrarenal infusion of moxonidine or rilmenidine suggested the existence of a direct renal action. We therefore tested the hypothesis that direct renal infusions were acting at a central rather than a peripheral site. Thus, interventions which would decrease the natriuretic effects of central administered moxonidine would also block the effects of intrarenal administered moxonidine. Studies were performed in anesthetized Sprague–Dawley rats (280–320 g) which had undergone unilateral nephrectomy 7 to 10 days prior to the experiment. The interventions utilized resulted in minimal effects on blood pressure and creatinine clearance. Intracerebroventricular (icv) or intrarenal (ir) administration of moxonidine produced a significant increase in urine flow rate and sodium excretion. Intravenous (iv) prazosin was used to block the ability of the sympathetic nerves to alter sodium excretion secondary to α1-adrenoceptor stimulation. Prazosin prevented the natriuresis following icv moxonidine but only partially antagonized the effects of ir moxonidine. To determine if central imidazoline receptors mediated the effects of moxonidine, animals were pretreated with icv idazoxan. Following icv idazoxan, the effects of icv moxonidine were blocked, whereas the response to intrarenal moxonidine was only partially blocked. Peripheral (iv) administration of idazoxan blocked the actions of intrarenal moxonidine but left the response to icv moxonidine intact. Finally, chemical sympathectomy with reserpine did not alter the response to intrarenal moxonidine suggesting that this effect was independent of the sympathetic nervous system. In conclusion, these studies indicate the ability of central and peripheral moxonidine to increase urine flow rate through sodium excretion at two unique sites of action, one central and the other one peripheral, most conceivably within the kidney.

Protection of focal ischemic infarction by rilmenidine in the animal: Evidence that interactions with central imidazoline receptors may be neuroprotective

Rilmenidine and idazoxan reduce the volume of focal ischemic infarctions produced by occlusion of the middle cerebral artery in the rat by 33% and 29%, respectively, by preserving neurons within the ischemic penumbra. In contrast, the α 2-selective antagonist SKF-86466 is without effect. The neuroprotective action of rilmenidine is dose dependent and parallels its antihypertensive actions. Neuroprotection cannot be attributed to changes in cerebral blood flow. We conclude that the neuroprotection produced by rilmenidine is attributable to an interaction with imidazoline receptors (IRs). However, the mechanism of action is not obvious. If it results from an action within the penumbra (direct), it is mediated by mitochondrial I-2 receptors on astrocytes, since cortical neurons are devoid of IRs. Neuroprotection might occur by selectively stimulating Ca 2+ uptake into astrocytes, and thereby reducing Ca 2+ uptake into neurons. Alternatively, rilmenidine may act indirectly to activate pathways in the brain that are neuroprotective. Neuroprotection may be a therapeutic target for rilmenidine and allied agents that act at central IRs.

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

The central regulation of blood pressure and other cardiovascular parameters may involve the baroreceptor reflex are, 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 alpha-methyl-DOPA. The central components of the hybrid drugs urapidil and ketanserin also involve serotonergic pathways and receptors. For urapidil the stimulation of 5-HT1A-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.

Natriuretic effect of rilmenidine in anesthetized rats

Rilmenidine binds to α 2-adrenoceptors and imidazoline receptors in the central nervous system and the kidney. To test the hypothesis that rilmenidine would increase sodium excretion, renal function was studied in rats with innervated and denervated kidneys to distinguish between indirect (via renal sympathetic nerves) and direct effects of rilmenidine on the kidney. Standard clearance techniques were used in Wistar rats anesthetized with thiobutabarbital to measure renal function during 80 minutes of infusion of 0.9% NaCl or rilmenidine (20 or 50 μg · kg −1 · min −1 intravenously). Snares on abdominal arteries were used to offset hypotension induced by rilmenidine. Heart rate decreased by 80–120 beats/min with either dose of rilmenidine. At 20 μg · kg −1 · min −1, rilmenidine increased total and fractional excretion of sodium and clearance of osmoles while decreasing free water clearance from innervated kidneys. There were no changes in these variables in chronically denervated kidneys. Direct recording of renal sympathetic nerve activity showed a progressive, marked decrease in nerve activity during the low-dose infusion of rilmenidine. At 50 μg · kg −1 · min −1, rilmenidine produced a differential effect on the clearance of osmoles by innervated and denervated kidneys but both kidneys had an increase in free water clearance. The data indicate that rilmenidine increases sodium excretion indirectly in anesthetized rats by decreasing renal sympathetic nerve activity. At doses and infusion periods used in these studies, there was no evidence for a direct effect of rilmenidine on sodium excretion. The increase in free water clearance seen with the high dose of rilmenidine suggests that the inhibitory effect of α 2-adrenoceptor activation on vasopressin is involved at this dose. On the other hand, the effect of rilmenidine on sodium excretion may involve central imidazoline receptors.