Central presynaptic alpha 2-autoreceptors are involved in the blood pressure-lowering effect of moxonidine.

The alpha-adrenoceptor-mediated effects of the newly developed antihypertensive drug moxonidine and of clonidine were compared in four in vitro models and in anesthetized rabbits. Inhibition of the electrically induced twitch response in the isolated rat vas deferens by moxonidine and clonidine (pEC50 values 7.8 and 8.5) was counteracted by yohimbine. The maximum degree of inhibition obtained with both drugs was identical. The contractile response of the rat anococcygeal muscle to moxonidine and clonidine (pEC50 6.2 and 6.9) was antagonized by prazosin. The maximum degree of contraction obtained with moxonidine was similar in degree to that of phenylephrine, whereas that of clonidine was lower. Moxonidine and clonidine inhibited the electrically evoked [3H]norepinephrine (NE) overflow in strips of rabbit pulmonary artery (pEC50 7.1 and 6.6) and in rat brain cortex slices (pEC50 6.9 and 7.7); the effect of moxonidine was counteracted by rauwolscine. After intracisternal injection in anesthetized rabbits, moxonidine lowered blood pressure (BP) more potently than did clonidine. Intracisternal pretreatment of rabbits with 6-hydroxydopamine strongly attenuated the hypotensive effect of moxonidine without affecting that of clonidine. The hypotensive effect of moxonidine was abolished by pretreatment with reserpine and alpha-methyl-p-tyrosine (alpha-MPT). In conclusion, in isolated tissues of the rat, moxonidine is as selective as clonidine as an alpha-adrenoceptor agonist. The hypotensive effect of moxonidine, unlike that of clonidine, appears to involve central presynaptic alpha 2-autoreceptors in large part.     

A comparison of the haemodynamic and behavioural effects of moxonidine and clonidine in normotensive subjects.

1. This randomised double-blind placebo controlled crossover study in healthy normotensive males compared the haemodynamic and behavioural responses following single oral doses of moxonidine (200 micrograms), clonidine (200 micrograms) and placebo. 2. Both active drugs significantly reduced blood pressure as compared with placebo: on average (over the study day) by -5.6/-0.8 with moxonidine and by -13.3/-5.3 mm Hg with clonidine. The hypotensive effect of clonidine was significantly greater (95% CI 3.2-12.2). Heart rate was unchanged by either drug. 3. Psychomotor testing, salivary flow and side effect reporting showed a consistent treatment rank order similar to that of the hypotensive response: clonidine greater than moxonidine greater than placebo. 4. Although moxonidine produced less adverse effects than clonidine, an equivalent hypotensive response was not demonstrated in normal subjects. Further study at comparable antihypertensive doses is required to clarify the relative side effect profile of these agents.     

Antagonism by E. coli endotoxin of some cardiovascular effects induced in the rat by two alpha 2-adrenoceptor agonists

E. coli endotoxin (0.01, 0.1 and 1 microgram/kg i.v.) 1 h before alpha 2-adrenoceptor agonists B-HT 933 and clonidine (i.v.) antagonized their bradycardiac and hypotensive effects in intact rats. This antagonism seems not to depend on the presence of the adrenal glands since similar results were obtained in adrenalectomized rats. Endotoxin at higher doses (1 and 10 micrograms/kg) suppressed the hypotensive and reduced the bradycardiac effect of clonidine injected i.c.v. (5 micrograms/kg). In contrast, endotoxin (up to 100 micrograms/kg) did neither increase arterial pressure nor heart rate in the pithed rat. This suggests the participation of a central site of action for endotoxin. However, E. coli endotoxin (1, 10 or 100 micrograms/kg) did not decrease the inhibition by clonidine of the tachycardia induced by stimulation of the cardioacceleratory nerve. This excludes peripheral presynaptic alpha 2-adrenoceptor blockade by endotoxin. Only 100 micrograms/kg decreased the pressor response to clonidine in the pithed rat. These results show that E. coli endotoxin is a potent modificator of the cardiovascular regulation in the rat. It antagonized central alpha 2-adrenoceptor mediated cardiovascular effects at doses lower than those acting on postsynaptic peripheral alpha-adrenoceptors.     

Unique presynaptic alpha 2-receptor selectivity and specificity of the antihypertensive agent moxonidine

The characteristics of the alpha-receptor activating property of the new antihypertensive agent moxonidine (4-chloro-N-(4, 5-dihydro-1H-imidazol-2-yl)-6-methyl-2-methyl-5-pyrimidinamine, BDF 5895) was studied using peripheral vasculature and brain membranes of various animals. Moxonidine exerted a full agonist effect in elevating diastolic blood pressure in the pithed rat. Activation of postsynaptic alpha 1- and alpha 2-receptors contribute to the vasoconstrictory effect in rats. In the vasculature of the rabbit, moxonidine was a full agonist at presynaptic alpha 2-receptors in inhibiting transmitter release induced by electrical stimulation of pulmonary artery strips. At postsynaptic sites, exogenously applied moxonidine was a full agonist at alpha 1-receptors in the isolated aorta, pulmonary artery and vena cava of the rabbit. Selectivity for alpha 2-receptors in the pulmonary artery was 106-fold. In rat brain membranes, moxonidine showed 288-fold greater selectivity for alpha 2-receptors, when the displacement of [3H]-rauwolscine was compared with the displacement of [3H]-prazosin. On the whole, clonidine exhibited greater potency than moxonidine on both alpha-receptor subtypes, but moxonidine consistently showed greater alpha 2-receptor selectivity than clonidine. In the guinea pig myocardium, moxonidine caused neither bradycardia nor tachycardia in the isolated right atrium and produced a negligible positive inotropic effect at 100 mumol/l in the isolated papillary muscle.     

Effects of imidazoline antihypertensive drugs on sympathetic tone and noradrenaline release in the prefrontal cortex

1. The aim of the present study was to compare the effects of the centrally acting antihypertensive drugs rilmenidine, moxonidine, clonidine and guanabenz on sympathetic tone with their effects on noradrenaline release in the cerebral cortex. In particular, the hypothesis was tested that rilmenidine and moxonidine, due to their high affinity for sympatho-inhibitory imidazoline I(1) receptors and low affinity for alpha(2)-adrenoceptors, lower sympathetic tone without causing an alpha(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 microg kg(-1)), moxonidine (10, 30, 100 and 300 microg kg(-1)), clonidine (1, 3, 10 and 30 microg kg(-1)) and guanabenz (1, 3, 10 and 30 microg kg(-1)) 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 effect was probably due to an alpha(2)-adrenoceptor-mediated inhibition of the firing 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.     

The alpha 1- and alpha 2-adrenoceptor involvement in the central cardiovascular action of clonidine in the conscious renal hypertensive cat

An attempt has been made to characterise the alpha-adrenoceptor subtype (alpha 1 or alpha 2) mediating the hypotensive and bradycardic action of clonidine in conscious renal hypertensive cats. The relatively selective alpha 2-adrenoceptor agonists clonidine, UK-14,304, guanfacine and lofexidine caused significant hypotension and bradycardia when given intracerebroventricularly (i.c.v.). This suggests that alpha 2-adrenoceptors can mediate hypotension and bradycardia. However, both alpha 1- and alpha 2-adrenoceptor antagonists, prazosin, UK-33,274, corynanthine, yohimbine, rauwolscine and RS21361 blocked the hypotensive effect of clonidine. These results suggest an alpha 1-adrenoceptor may also mediate the central hypotensive action of clonidine, or possibly that the central alpha-adrenoceptors in which clonidine acts, may show pharmacological differences to peripheral alpha 1- and alpha 2-subtypes.     

The interaction between prazosin and clonidine at alpha-adrenoceptors in rats and cats.

In pithed rats prazosin (10μg/kg, i.v.) caused a prolonged antagonism of the hypertensive response to clonidine and (?)-noradrenaline, probably due to inhibition of vascular, postsynaptic α-adrenoceptors. The clonidine-induced reduction of the tachycardia evoked in pithed rats by electrical stimulation of cardiac sympathetic nerve fibres was antagonized by piperoxan and less effectively by prazosin, thus suggesting that prazosin displays a modest degree of cardiac presynaptic α-adrenoceptor blocking activity apart from its predominantly postsynaptic affinity. Prazosin (1 mg/kg, i.p.) significantly affected the hypotensive effect of clinidine (2 and 6 μg/kg, i.v.), but not the bradycardia induced by clonidine in pentobarbitone-anaesthetized, normotensive rats. Prazosin proved to be an effective hypotensive drug in anaesthetized cats. This action was peripheral as no central nervous origin could be demonstrated. Prazosin in low doses significantly reduced the central hypotensive effect of clonidine (1 μg/kg), injected into the left vertebral artery of chloralose-anaesthethized cats. Since the intravenous pretreatment with low doses of prazosin did not alter the central hypotensive response to clonidine, the interaction was likely to have occured within the brain-stem. Presumably, postsynaptic α-adrenoceptors in the brain, similarly to those in the periphery are inhibited by prazpsin, thereby preventing the central hypotensive effect of clonidine. It is submitted that clonidine and prazosin should not be combined in antihypertensive therapy in patients.     

Cardiovascular effects of rilmenidine, moxonidine and clonidine in conscious wild-type and D79N alpha2A-adrenoceptor transgenic mice

1. We investigated the cardiovascular effects of rilmenidine, moxonidine and clonidine in conscious wild-type and D79N alpha2A-adrenoceptor mice. The in vitro pharmacology of these agonists was determined at recombinant (human) alpha2-adrenoceptors and at endogenous (dog) alpha2A-adrenoceptors. 2. In wild-type mice, rilmenidine, moxonidine (100, 300 and 1000 microg kg(-1), i.v.) and clonidine (30, 100 and 300 microg kg(-1), i.v.) dose-dependently decreased blood pressure and heart rate. 3. In D79N alpha2A-adrenoceptor mice, responses to rilmenidine and moxonidine did not differ from vehicle control. Clonidine-induced hypotension was absent, but dose-dependent hypertension and bradycardia were observed. 4. In wild-type mice, responses to moxonidine (1 mg kg(-1), i.v.) were antagonized by the non-selective, non-imidazoline alpha2-adrenoceptor antagonist, RS-79948-197 (1 mg kg(-1), i.v.). 5. Affinity estimates (pKi) at human alpha2A-, alpha2B- and alpha2C-adrenoceptors, respectively, were: rilmenidine (5.80, 5.76 and 5.33), moxonidine (5.37, <5 and <5) and clonidine (7.21, 7.16 and 6.87). In a [35S]-GTPgammaS incorporation assay, moxonidine and clonidine were alpha2A-adrenoceptor agonists (pEC50/intrinsic activity relative to noradrenaline): moxonidine (5.74/0.85) and clonidine (7.57/0.32). 6. In dog saphenous vein, concentration-dependent contractions were observed (pEC50/intrinsic activity relative to noradrenaline): rilmenidine (5.83/0.70), moxonidine (6.48/0.98) and clonidine (7.22/0.83). Agonist-independent affinities were obtained with RS-79948-197. 7. Thus, expression of alpha2A-adrenoceptors is a prerequisite for the cardiovascular effects of moxonidine and rilmenidine in conscious mice. There was no evidence of I1-imidazoline receptor-mediated effects. The ability of these compounds to act as alpha2A-adrenoceptor agonists in vitro supports this conclusion.     

Involvement of alpha 2-adrenoceptors in the activation of kininogenesis by clonidine

The effects of clonidine and alpha 2-adrenoceptor blocking agents, yohimbine and tolazoline on kininogen and prekallikrein levels in plasma and on blood pressure were investigated in male Wistar rats. Clonidine (0.5 mg/kg) decreased concentration of kininogen. Yohimbine (3 mg/kg) and tolazoline (5 mg/kg) counteracted this effect of clonidine and increased the kininogen level in plasma. Clonidine did not change the level of prekallikrein, however in rats receiving alpha 2-adrenoceptor blockers alone or together with clonidine kallikrein utilization was reduced, which indicated indirectly that the level of prekallikrein in plasma augmented. Yohimbine and tolazoline in the same doses (3 mg/kg and 5 mg/kg resp.) increased the blood pressure and counteracted the hypotensive action of clonidine, which indicated the presynaptic alpha 2-adrenoceptor blocking effect of the doses used. The data indicate that clonidine-induced activation of kininogenesis as well as its hypotensive effect are counteracted by yohimbine and tolazoline in doses blocking specifically presynaptic alpha 2-adrenoceptors. It can be suggested that alpha 2-adrenoceptors are involved in the kininogenesis-activating effect of clonidine.     

Participation of central and peripheral I1-imidazollinovykh and alpha2-adrenergic receptors in realizing the effects of moxonidine

The role of the central and peripheral I1-imidazoline and alpha 2-adrenergic receptors in the development of hypotension and bradycardia induced by the intravenous injections of moxonidine was studied, in stroke-prone spontaneously hypertensive (SHR-SP) rats. The intravenous and local injections of I1--alpha 2 antagonist efaroxan (Efa) into the rostral ventrolateral medula (RVLM) abolished the moxonidine-induced fall of blood pressure, but did not eliminate bradycardia. The alpha 2 antagonist yohimbine (Yoh) injected into RVLM did not influence the moxonidine effects, whereas the intravenous Yoh injections fully blocked these effects. Thus the hypotensive action of moxonidine is mediated predominantly by the I1-imidazoline RVMM receptors, while the heart rate decrease is partly realized via the alpha 2 adrenoreceptors of peripheral innervation.     

Contribution of alpha 2-adrenoceptors to the central cardiovascular effects of clonidine and S 8350 in anaesthetized rats.

1. The alpha 2-adrenoceptor agonist clonidine elicits centrally mediated effects through an interaction with both alpha 2-adrenoceptors and imidazoline binding sites. 2. We selected a new oxazoline derivative, S 8350, which competes with [3H]-yohimbine for binding to cerebral alpha 2-adrenoceptors (IC50, 67 +/= 17 nmol/L) and displays a higher affinity (35-fold) for alpha 2- than for alpha 1-adrenoceptors. 3. As observed for clonidine, intravenous (i.v.) administration of S 8350 resulted in a brief pressor effect followed by a prolonged hypotension. When S 8350 was administered i.v. to spinally pithed rats, only a rise in blood pressure was observed. 4. In order to discriminate the cardiovascular effects related to the central imidazoline receptor or alpha 2-adrenoceptor activation, the effects of intracisternal (i.c.) administration of clonidine and S 8350 were investigated in the rat. 5. In the anaesthetized rat, both clonidine and S 8350 displayed a profound central (i.c. route) hypotensive effect associated with a bradycardia. 6. The cardiovascular effects of S 8350 were abolished by the central administration of the selective alpha 2-adrenoceptor antagonist rauwolscine. Conversely, rauwolscine completely prevented bradycardia but it induced only a partial reversion of the hypotension elicited by clonidine. 7. These results suggest that central alpha 2-adrenoceptors are responsible for hypotension and bradycardia while imidazoline binding sites do not apparently contribute to heart rate control.     

Involvement of central dopamine receptors in the hypotensive action of pergolide

The involvement of central dopamine receptors in the hypotensive action of the dopaminergic ergoline, pergolide was determined in anesthetized rats. Intravenous (i.v.) or intracerebroventricular (i.v.t.) administration of pergolide (12.5, 25 and 50 micrograms/kg) produced dose-dependent decreases in blood pressure. The magnitude of hypotension seen following either i.v. or i.v.t. administration of pergolide was similar. However, while both sulpiride (1 mg/kg, i.v.) as well as phentolamine (1 mg/kg, i.v.) antagonized the hypotensive action of i.v. pergolide, only sulpiride (1 mg/kg, i.v.t.) was able to antagonize the hypotension seen following i.v.t. administration of pergolide. Phentolamine (1 mg/kg, i.v.t.) did not alter the central hypotensive action of pergolide. In a separate group of rats, clonidine (25 micrograms/kg, i.v.t.) also produced a decrease in blood pressure. While phentolamine (i.v.t.) antagonized the central hypotensive action of clonidine, sulpiride (i.v.t.) did not have any effect on the action of clonidine. These results show that selective activation of central dopamine receptors was responsible for the hypotensive action of centrally-administered pergolide. In a separate group of rats greater splanchnic sympathetic nerve activity was measured. Intravenous pergolide produced similar hypotensive response as seen in previous groups, and this was accompanied by a concomitant decrease in the sympathetic nerve activity. The maximum fall in blood pressure (26 +/- 6 mm Hg) was correlated with a 40% reduction in sympathetic nerve activity. The return of blood pressure to control levels occurred after 60-70 min and was also associated with the return of sympathetic nerve activity to control levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Rilmenidine lowers arterial pressure via imidazole receptors in brainstem C1 area.

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 alter the dose dependent reductions in arterial pressure and heart rate elicited by i.v. drug. Rilmenidine microinjected bilaterally into the C1 area of the rostral 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 C1 area of the selective alpha 2-adrenoceptor antagonist SKF-86466, even at high doses, failed to modify the hypotension to i.v. rilmenidine. However, microinjection of 3- to 10-fold lower doses of idazoxan, a ligand for imidazole as well as alpha 2-adrenoceptors, blocked the effects. Rilmenidine also competed with the clonidine analogue [3H]p-aminoclonidine ([3H]PAC) at specific binding sites in membranes of bovine ventrolateral medulla and frontal cortex. In RVL rilmenidine competed with binding to imidazole and alpha 2-adrenergic binding sites with a 30-fold selectivity for the imidazole binding sites. In frontal cortex binding was of lower affinity and restricted to alpha 2-adrenergic sites. We conclude that rilmenidine, like clonidine, acts to lower arterial pressure by an action on imidazole receptors in the C1 area of RVL. The higher selectivity of rilmenidine for imidazole to alpha 2-adrenoceptors as compared to clonidine may explain the lower sedative effects of rilmenidine.     

PHARMACOLOGICAL ACTIVITIES OF THE ANTIHYPERTENSIVE DRUG URAPIDIL IN THE RAT

Urapidil had blocking activity on alpha 1-adrenoceptors in the rat isolated caudal artery (pA2 congruent to 7) and in the anaesthetized rat. Urapidil had no clonidine like agonistic activity on alpha 2-adrenoceptors in preparations of the guinea-pig ileum (prejunctional) or dog saphenous vein (post-junctional). Urapidil (0.01-0.1 mg/kg i.v.) had a hypotensive effect in the anaesthetized rat. In a dose of 0.1 mg/kg, the depressor response was accompanied by bradycardia. Vagotomy abolished the bradycardia and attenuated the depressor response. The results indicate that the antihypertensive effect of urapidil may be due partly to blockade of postjunctional alpha 1-adrenoceptors, but in addition there is a central component of action.     

A comparative study of the reversal by different alpha 2-adrenoceptor antagonists of the central sympatho-inhibitory effect of clonidine.

1. The recovery of the clonidine-induced hypotension, bradycardia and sympatho-inhibition produced by several putative alpha 2-adrenoceptor antagonists was investigated in pentobarbitone anaesthetized rats. The activity of four substances containing an imidazoline structure: idazoxan, methoxy-idazoxan, BRL44408 and atipamezole was compared with the effect of fluparoxan, yohimbine and L-657,743; in addition the effect of the alpha 1-adrenoceptor antagonist, prazosin, was also studied. 2. Prazosin (0.03-1 mg kg-1, i.v.) failed to alter the sympatho-inhibitory and hypotensive effects of clonidine (10 micrograms kg-1, i.v.). L-657,743 (0.01-1 mg kg-1, i.v.) induced a recovery of blood pressure, heart rate and renal sympathetic nerve activity. Yohimbine (0.03-3 mg kg-1, i.v.) completely reversed the sympatho-inhibitory effect of clonidine but did not alter its hypotensive effect. 3. The four imidazoline drugs: idazoxan (10-300 micrograms kg-1, i.v.), methoxy-idazoxan (1-100 micrograms kg-1, i.v.), BRL44408 (0.1-3 mg kg-1, i.v.) and atipamezole (0.03-1 mg kg-1, i.v.) and fluparoxan (10-300 micrograms kg-1, i.v.) reversed the clonidine-induced hypotension but produced only a partial recovery of the renal sympathetic nerve activity and of the heart rate. After pretreatment with prazosin (0.1 mg kg-1, i.v.), the recovery of the sympathetic nerve activity elicited by these compounds was significantly higher. In hexamethonium (10 mg kg-1, i.v.) pretreated rats, these five drugs induced dose-related hypertension which was reduced by pretreatment with prazosin (0.1 mg kg-1, i.v.). 4. Our results indicate that the putative alpha 2-adrenoceptor antagonists idazoxan, methoxy-idazoxan, BRL44408, atipamezole and fluparoxan also have a peripheral hypertensive effect which is mediated through activation of vascular alpha 1-adrenoceptors; this property of the compounds may be partly responsible for the reversal of the hypotensive action of clonidine. Considering the structure and the affinities of the drugs tested, our data indirectly suggest that alpha 2A-adrenoceptors may be implicated in the central sympatho-inhibitory effects of clonidine.     

Mechanism of ketanserin-induced sympatho-inhibition.

Experiments were undertaken to determine if sympatho-inhibition produced by ketanserin is due to antagonism of central nervous system alpha 1-adrenoceptors rather than central 5-HT2 receptors and if (like prazosin) it produces sympatho-inhibition indirectly via a central (presynaptic) alpha 2-adrenoceptor mechanism. Administration of ketanserin (0.03-3.0 mg/kg i.v.) caused a dose-related depression of sympathetic-cholinergic electrodermal responses evoked by electrical stimulation of the hypothalamus in pentobarbital anesthetized cats. No effect of ketanserin was observed on electrodermal responses evoked by preganglionic sympathetic nerve stimulation nor did the more specific 5-HT2 receptor antagonist, cinanserin, produce a central sympatholytic effect at dosages up to 3 mg/kg i.v. Pretreatment with alpha 2-adrenoceptor blockers yohimbine, idazoxan, or rauwolscine significantly antagonized ketanserin-induced sympatho-inhibition. Depletion of central nervous system (CNS) monoamines totally prevented ketanserin-induced sympatho-inhibition although clonidine (30 micrograms/kg i.v.) continued to be effective. These results suggest that ketanserin acts in the CNS to reduce sympathetic reactivity by blocking alpha 1-adrenoceptors and not 5-HT2 receptors. In this regard, ketanserin appears to act in a manner similar to other alpha 1-adrenoceptor antagonists (e.g. prazosin and indoramin) by an apparent presynaptic facilitation of alpha 2-adrenoceptor mediated tonic inhibition descending from the lower brainstem.     

Effects of clonidine on the experimental hypertension by abdominal aortic coarctation in rats.

Cardiovascular baroreflex mechanisms and sympathetic tone could be involved in the arterial hypertension by coarctation of abdominal aorta artery (CoA). The present work analyzes the effect on the arterial pressure and heart rate (HR) of the clonidine, an alpha(2)-adrenergic central acting antihypertensive agent, after intravenous (i.v.), intracerebroventricular (i.c.v.) and intrathecal (i.t.) administration in rats anesthetized with pentobarbital (40 mg/kg i.p.).Wistar rats of both sexes (240-270 g) were used to the 7 days of the CoA or a sham operation (SO). Values of mean arterial pressure (MAP) and of HR were calculated from intraarterial recordings of blood pressure.The MAP of the CoA rats (161.5+/-5.3 mmHg, n=20) was significantly higher (P<0.01) than that of the SO rats (101.6+/-3.3 mmHg, n=20).The i.v. injection of clonidine (3-30 microg/kg) produced an increase of blood pressure in the rats SO and in the CoA animals, followed by a fall of arterial pressure in both groups of rats. Clonidine showed a small pressor effect but also a great depressor action in the hypertensive rats. Except for with the dose of 10 microg/kg, differences in cardiac response to clonidine were not seen in both groups of rats.Injection of clonidine by the i.c.v. via (10 microg) like by the i.t. (3 microg) also produced a greater fallen of the MAP in the hypertensive rats than in the controls SO animals.In conclusion, these hypertensive animals would be sensitive to the antihypertensive action of central acting alpha(2)-adrenoceptor agonist clonidine administered by different ways, suggesting a great sensitivity of the post-synaptic alpha(2)-adrenoceptor of central nervous system.     

Cardiovascular and sedative alpha-adrenoceptor effects of detomidine-like arylalkyl imidazoles and associated derivatives

The effects of detomidine (4-[(2,3-dimethylphenyl)methyl]-1H-imidazole, Domosedan) and its congeners, MPV compounds, are evaluated in the cardiovascular system and related to their sedative action using clonidine and xylazine for reference purposes. The structure of the MPV compounds had been modified with methyl substituents in the phenyl ring, with differing lengths in the alkyl bridge, and with variations in the imidazole terminus. The lipophilicity of the test compounds had been estimated in terms of apparent partition coefficients in the octanol/buffer (pH 7.4, 24-26 degrees C) using the HPLC technique. The lipophilicity of the MPV compounds was found to be higher than for either clonidine or xylazine, suggesting a more rapid penetration into the central nervous system. Some of these 21 MPV compounds were hypotensive and bradycardic in anaesthetized rats. Interestingly a number of these MPV compounds were only bradycardic but not clearly hypotensive after i.v. administration to anaesthetized rats, this being most obvious in the case of the 2,5-dimethylphenyl derivative MPV 867. A further characteristic distinguishing between the central and peripheral alpha-adrenoceptors regulating cardiovascular tone was a distinct inability of some derivatives active at peripheral cardiac presynaptic (pithed rats) and central (young chicks) alpha 2-adrenoceptors to reduce blood pressure in anaesthetized rats. The sedative action of the compounds after i.m. injection into 2- to 5-day-old chicks was in general related to their central hypotensive and bradycardic effect in anaesthetized rats, and with peripheral vasopressor and sympatho-inhibitory activity in pithed rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evidence for a noradrenergic component in the antinociceptive effect of the analgesic agent tramadol in an animal model of clinical pain, the arthritic rat.

The analgesic agent tramadol has a potent antinociceptive effect in arthritic rats. In the present study, the actions of the selective alpha 2-adrenoceptor antagonists yohimbine and idazoxan on this antinociceptive effect were tested in arthritic rats, using vocalization thresholds to paw pressure as a nociceptive test. The antagonists were administered 30 min before tramadol, at doses (0.5 and 1 mg/kg i.v.) without action per se, but which prevented the antinociceptive action of the prototypic alpha 2-adrenoceptor agonist clonidine (0.1 mg/kg i.v.) in these animals. The potent antinociceptive effect of tramadol (1 mg/kg i.v.) was significantly decreased (mean total effect reduced about 2-fold) by yohimbine and idazoxan. In alpha 2-adrenoceptor antagonists-pretreated arthritic rats, the effect of tramadol was almost abolished when tramadol was coinjected with the opioid antagonist naloxone. In addition to the involvement of opioid receptors, these results provide evidence for a noradrenergic component to the antinociceptive action of tramadol in this model of clinical pain.