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BACKGROUND The design, medicinal chemistry, pharmacokinetics and development of the highly selective α2-adrenoceptor antagonist fluparoxan are reviewed. METHOD The drug's activity and selectivity in vitro, its efficacy in animals and its excellent oral pharmacokinetics and central α2-adrenoceptor antagonist activity in man, are evaluated as well as its ability to increase extracellular levels of noradrenaline, dopamine and acetylcholine in vivo. CONCLUSION Furthermore, its potential for the treatment of central neurodegenerative diseases is highlighted, in particular its improvement of cognitive dysfunction in schizophrenia and in models of Alzheimer's disease.

In cats anaesthetized with pentobarbital sodium, the posterior hypothalamus was superfused and electrically stimulated with a push-pull cannula. The pressor response to stimulation of this hypothalamic area was inhibited when the hypothalamus was superfused with drugs blocking either alpha-adrenoreceptors (piperoxan, tolazoline), or beta-adrenoreceptors--(+/-)-propranolol, (-)-propranolol, practolol, sotalol, metoprolol. (+)-Propranolol and a concentration of procaine equianaesthetic to propranolol were ineffective. During superfusion with tolazoline in the presence of practolol the inhibition was twice as that when the hypothalamus was superfused with either tolazoline or practolol. In another series of experiments the push-pull cannula was inserted into the anterior hypothalamus. The depressor response to stimulation of this area was inhibited by the hypothalamic superfusion with the alpha-adrenoreceptor blocking drugs phentolamine, tolazoline, piperoxan or yohimbine. Hypothalamic superfusion with phenylephrine abolished the inhibitory effect of phentolamine on the depressor response. The results indicate that adrenoreceptors are present in the hypothalamus and that they are involved in blood pressure changes elicited by hypothalamic stimulation.

In vivo microdialysis coupled with HPLC and electrochemical detection was used to monitor extracellular levels of 3,4-dihydroxyphenylacetic acid (DOPAC) of the locus ceruleus (LC) in halothane-anesthetized rats. The identity of DOPAC was confirmed by experiments showing that the chromatographic peak was totally suppressed after inhibition of monoamine oxidase by pargyline. Histological examinations allowed to relate the quantity of DOPAC measured in the dialysates with the localization of the probe implantation site. We found that the DOPAC concentration was inversely proportional to the distance between the probe and the lateral border of the LC. Regardless of the caudorostral level of the nucleus, concentrations were maximal when the axis of the probe was 100 microns from the lateral border of the LC and decreased by 53% when this distance reached 300 microns. Activation of LC noradrenergic neurons by systemic administration of the alpha 2-antagonist piperoxane increased by 100% DOPAC concentrations in LC dialysates. These results suggest that the DOPAC measured by microdialysis could be considered an indicator of the functional state of LC noradrenergic neurons.

The process describes the concise synthesis of (R/S)-enantiomers of doxazosin, an antidepressant drug and α-adrenergic receptor antagonists like prosympal, piperoxan, and dibozane in practical yields from easily available (R)-2,3-O-cyclohexylidene- d -glyceraldehyde and (S)-3-(benzyloxy)propane-1,2-diol.

Starting from commercially available inexpensive optically active diol (I) the synthesis of optically active 2-hydroxymethyl-1,4-benzodioxane (V) is developed and its use as common precursor in the synthesis of the title compounds doxazosin (XI), prosympal (XIIIa), piperoxan (XIIIb), and dibozane (XV) is demonstrated.

Using an in vivo electrophysiological paradigm, venlafaxine and paroxetine displayed similar potency for suppressing the firing activity of dorsal raphe 5-HT neurons (ED50: 233 and 211 μg/kg i.v., respectively), while venlafaxine was three times less potent than desipramine (ED50: 727 and 241 μg/kg i.v., respectively) to suppress the firing activity of locus coeruleus NE neurons. The selective 5-HT1A receptor antagonist WAY 100635 (100 μg/kg, i.v.) reversed the suppressant effect of venlafaxine and paroxetine on the firing activity of 5-HT neurons and the α2-adrenoceptor antagonist piperoxane (1 mg/kg, i.v.) reversed those of venlafaxine and desipramine on the firing activity of NE neurons. The ED50 of venlafaxine on the firing activity of 5-HT neurons was not altered (ED50: 264 μg/kg) in noradrenergic-lesioned rats, while the suppressant effect of venlafaxine on the firing activity of NE neurons was greater in serotonergic-lesioned rats (ED50: 285 μg/kg). Taken together, these results suggest that, in vivo, venlafaxine blocks both reuptake processes, its potency to block the 5-HT reuptake process being greater than that for NE. Since the affinities of venlafaxine for the 5-HT and NE reuptake carriers are not in keeping with its potencies for suppressing the firing activity of 5-HT and NE neurons, the suppressant effect of venlafaxine on the firing activity of 5-HT and NE neurons observed in vivo may not be mediated solely by its action on the [3H]cyanoimipramine and [3H]nisoxetine binding sites. In an attempt to unravel the mechanism responsible for this peculiarity, in vitro superfusion experiments were carried out in rat brain slices to assess a putative monoamine releasing property for venlafaxine. (±)Fenfluramine and tyramine substantially increased the spontaneous outflow of [3H]5-HT and [3H]NE, respectively, while venlafaxine was devoid of such releasing properties. Synapse 32:198–211, 1999. © 1999 Wiley-Liss, Inc.

1. Fluparoxan is an alpha 2-adrenoceptor antagonist that has a relatively planar, tricyclic structure and was considered a potential substrate and inducer of cytochrome P4501A (CYP1A) enzymes. 2. Structure-activity analysis indicated some potential for CYP1A interaction, although its greater log P and molecular depth, compared with many CYP1A inducers, suggested fluparoxan would be a weak ligand for the aryl hydrocarbon (Ah) receptor and only a weak inducer. 3. In vitro, fluparoxan showed little affinity for the CYP1A enzymes. The compound was not metabolized by human CYP1A1 or 1A2 heterologously expressed in yeast and its rate of metabolism in rat and human microsomes was unaffected by the addition of the 1A inhibitor alpha-naphthoflavone. Furthermore, Ki's for fluparoxan against EROD activity were4000-fold higher than those of alpha-naphthoflavone. 4. In vivo, however, fluparoxan did show some capacity for CYP1A induction. In rat, hepatic EROD activity increased approximately 40-fold with seven once-daily oral doses of fluparoxan (50 mg/kg, solution), and immunoblotting studies confirmed induction of CYP1A2, though not of 1A1. In man, administration of 11 twice-daily oral doses of fluparoxan (8 mg tablet) produced some reduction in plasma levels of orally administered phenacetin and in the ratio of phenacetin AUC/urinary paracetamol, consistent with increased O-deethylation.

A novel series of tetrahydrobenzodioxinopyrroles has been identified as potent and selective α 2 -adrenoceptor antagonists. Convergent syntheses have been developed that allowed the preparation of analogues and their enantiomers. A compound of particular interest is the 5-fluoro substituted analogue (fluparoxan).

1. The effects of fluparoxan, an alpha 2-adrenoceptor antagonist, on the pharmacodynamic changes induced by clonidine were investigated in this placebo-controlled, double-blind, two-period, cross-over study in 16 healthy male volunteers (aged 19 to 44 years). 2. Subjects received either fluparoxan or placebo, twice-daily for 5 1/2 days (11 doses). One hour after the first and last dose of each treatment period, clonidine (200 micrograms) was infused intravenously over 5 min. 3. Indices of clonidine-mediated pharmacodynamic responses (growth hormone secretion, bradycardia, hypotension, xerostomia and sedation) were taken before and after clonidine infusion. Growth hormone secretion was assessed by quantifying serum growth hormone concentrations; sedation was assessed by both visual analogue scales (VAS) and by a visual psychomotor response meter, measuring critical flicker fusion (CFF). 4. The majority of subjects reported minor adverse events such as lethargy, headache and dry mouth following clonidine infusion. All adverse events were likely to be related to clonidine, as they occurred consistently between treatment groups. Fluparoxan has, however, in previous studies been reported to cause headache and light-headedness. 5. Prior to the clonidine infusion, fluparoxan caused small but statistically significant increases in systolic blood pressure (4 mm Hg) and salivary flow (approximately 30%) after both single and repeated doses. A small increase in heart rate (2 beats min-1) was seen after a single dose which was also statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Locus coeruleus degeneration and reduced central noradrenaline content is an early feature of Alzheimer’s disease. In transgenic mouse models of Alzheimer’s disease-like pathology, lesioning the locus coeruleus exacerbates β-amyloid (Aβ) pathology, neuroinflammation and memory deficits. Here we aimed to determine whether chronic treatment with the α2-adrenoceptor antagonist fluparoxan, that enhances noradrenaline release, can prevent the onset of Alzheimer’s-like pathology and memory deficits in APP/PS1 transgenic mice (TASTPM). Fluparoxan (1 mg/kg/day) was administered to TASTPM and wild type mice from 4 to 8 months of age. Memory was assessed at 4 and 8 months of age using the Morris water maze and contextual fear conditioning and at monthly intervals during the duration of treatment using the object recognition and spontaneous alternation task. Aβ plaque load and astrocytosis were measured at 4 and 8 months of age by immunohistochemistry. Fluparoxan treatment prevented age-related spatial working memory deficits in the spontaneous alternation task but not spatial reference memory deficits in the Morris water maze. Aβ plaque load and astrocytosis were unaltered by fluparoxan treatment in TASTPM mice. The findings suggest that fluparoxan treatment selectively prevent the decline of forms of memory where noradrenaline plays an integral role and that this beneficial effect is not due to altered Aβ plaque pathology or astrocytosis.

1. Achiral reverse-phase h.p.l.c. with semi-automated post-column fraction collection and solid-phase sample reconcentration, has been applied as the purification procedure during the enantiomeric quantification of two widely differing experimental drugs; an HMG-CoA reductase inhibitor (I) and an alpha 2-adrenoceptor antagonist (II). 2. The robust and specific achiral methodologies were available prior to the need for chiral analyses and recovery of drug from the fractions provided clean samples from a variety of biological matrices, without the need to develop compatible achiral/chiral mobile phases. 3. Compared with direct chiral chromatography of plasma extracts, this approach decreased the potential for metabolites and endogenous components to interfere or impair the performance of the chiral stationary phase. 4. The availability of quantitative data from achiral analysis of samples negated the need for internal standardization of the chiral analyses, helped confirm assay specificity and provided potential to determine enantiomeric ratios where only one isomer could be accurately measured. 5. Routine enantiomeric analyses were successfully carried out on samples taken from animals dosed orally with the racemic drugs, providing important data on the possible levels of exposure to individual enantiomers during toxicity testing.

Neuronal metabolic activity was studied by in vivo electrochemistry in two brain areas of the anesthetized rat: the nucleus reticularis lateralis (NRL) region of the ventrolateral medulla oblongata - site of the hypotensive action of clonidine-like imidazolines - and the locus coeruleus (LC), which is involved in the sedative effect of these drugs. Hypotensive doses of i.v. rilmenidine (0.3 and 1.5 mg/kg), which is structurally related to clonidine, induced a dose-related inhibition of the metabolic activity of catecholaminergic neurons in the NRL region whereas higher doses (50-fold) were required to inhibit the activity of the catecholaminergic neurons in the locus coeruleus. On the other hand azepexole, another centrally acting antihypertensive drug that is not structurally related to the imidazolines failed to inhibit the neuronal metabolic activity of the RNL region when administered i.v. in hypotensive doses (1 mg/kg). Taken together, these findings suggest that the central hypotensive action of clonidine-like drugs requires the imidazoline structure or pharmacologically compatible compounds like rilmenidine. Our results also show that rilmenidine is twice as selective as clonidine for the NRL region, which contains imidazoline-preferring receptors, compared with the LC, which contains mainly α 2 -adrenoceptors. In conclusion, this study provides a functional confirmation of the dissociation between the therapeutic (hypotensive) and untoward (sedative) effects of rilmenidine.

Effects of clonidine and tizanidine, which have antinociceptive and alpha 2-agonistic actions, were studied on the release of substance P from slices of spinal cord from the rat. Veratridine-evoked depolarization induced a 2-3-fold increase in the release of substance P from the slices of spinal cord. Exposure of the cord tissue to 10 microM clonidine and tizanidine significantly reduced the release of substance P. The inhibitory effects of clonidine and tizanidine were attenuated by pre-exposure of the tissue to 10 microM piperoxane, which has alpha 2-antagonistic activity and the inhibitory effect of clonidine was attenuated by 10 microM yohimbine. Moreover, the inhibitory effects of clonidine and tizanidine were also blocked by a small dose of prazosin, an antagonist for alpha 1- and alpha 2B-receptors. None of the antagonists had any effect on release of substance P, when given alone. These results suggest that alpha 2B-adrenoceptors are involved in the inhibitory effects of clonidine and tizanidine on the release of substance P.

1. Respiratory activity was recorded on ventral cervical roots during in vitro experiments performed on superfused newborn rat brain stem-cervical cord preparations. 2. Eliminating the pontine structures by performing a transection at the level of the ponto-medullary junction resulted in a sustained increase in respiratory frequency, which suggests the existence of a pontine inhibitory drive impinging on the medullary rhythm generator. 3. Noradrenaline (NA) and drugs affecting NA efficiency were added to the bathing medium and the resulting changes in respiratory frequency were analysed. NA decreased the respiratory frequency, and this effect was potentiated by pargyline (an inhibitor of the NA degradation by monoamine oxidases) and blocked by yohimbine (an alpha 2-antagonist). 4. Yohimbine or piperoxane (which blocks the alpha 2-adrenoceptors) increased the resting respiratory frequency to the level reached after ponto-medullary transection, whereas pargyline or desipramine (which potentiates NA efficiency) decreased the respiratory rate. Since these effects were no longer observed after elimination of the pons, it is suggested that a permanent release of endogenous NA by pontine areas may modulate the activity of the medullary respiratory rhythm generator. 5. When alpha-methyltyrosine (an inhibitor of NA biosynthesis) was applied to the pons, the respiratory frequency was increased, whereas when tyrosine (a precursor of NA) was applied, the respiratory frequency decreased. This decrease was enhanced by pargyline, suppressed by alpha-methyltyrosine and blocked by piperoxane. 6. To conclude, it is suggested that the mechanisms underlying NA biosynthesis (i) continue to function under these in vitro experimental conditions and (ii) are responsible for a permanent release of endogenous NA, which slows down the respiratory frequency. These results are discussed as regards the possibility that the medullary respiratory rhythm generator may be modulated via the noradrenergic area A5 in the newborn rat.

In connection with the structure of piperoxan 1 and the recently described pharmacological properties of N -(diethylamino-2 ethyl) 2,3-dihydro 1,4-benzodioxin 2-carboximidamide 2a (R = C 2 H 5 , R′ = H) and of idazoxan 3 , different structural analogues have been prepared. These derivatives showed marked antiarrhythmic properties leading to the disappearance of extrasystoles and to a persistent regularization of the cardiac rhythm of rabbits perfused with aconitine. In addition, sedative effects have been detected using classical tests.

The role of descending noradrenergic fibers in the spinal motor systems was investigated using spinal reflexes in acutely spinalized rats. In rats pretreated with the MAO inhibitor clorgyline-HCl (1 mg/kg, i.v.), L-3,4-dihydroxyphenylalanine (L-dopa) (5 mg/kg, i.v.), a precursor of dopamine and noradrenaline, markedly potentiated the mono- (MSR) and polysynaptic reflexes (PSR). Selective blockade of alpha 1-adrenoceptors by pretreatment with prazosin-HCl abolished these facilitatory effects on the MSR and the PSR and revealed the inhibitory effect of L-dopa on the PSR. The depression of PSR was antagonized by the alpha 2-antagonist piperoxan. Clonidine-HCl (0.05 mg/kg, i.v.), a so-called alpha 2-agonist, and tizanidine-HCl (0.1 mg/kg, i.v.) decreased the MSR and the PSR in rats pretreated with prazosin. These inhibitions were antagonized by piperoxan. These results suggest that alpha 1- and alpha 2-adrenoceptors mediate facilitation and attenuation of motor transmission in the rat spinal cord, respectively.

With the recent demonstration of a continuous electrophoretic "moving bed" enantiomer separation at mg/h throughputs, interest has now turned to scaling up the process for use as a benchtop pharmaceutical production tool. To scale the method, a steady-state mathematical model was developed that predicts the process response to changes in input feed rate and counterflow or "moving bed" velocities. The vortex-stabilized apparatus used for the separation was modeled using four regions based on the different hydrodynamic flows in each section. Concentration profiles were then derived on the basis of the properties of the Piperoxan-sulfated beta-cyclodextrin system being studied. The effects of different regional flow rates on the concentration profiles were evaluated and used to predict the maximum processing rate and the hydrodynamic profiles required for a separation. Although the model was able to qualitatively predict the shapes of the concentration profiles and show where the theoretical limits of operation existed, it was not able to quantitatively match the data from actual enantiomer separations to better than 50% accuracy. This is believed to be due to the simplifying assumptions involved, namely, the neglect of electric field variations and the lack of a competitive binding isotherm in the analysis. Although the model cannot accurately predict concentrations from a separation, it provides a good theoretical framework for analyzing how the process responds to changes in counterflow rate, feed rate, and the properties of the molecules being separated.

Continuous free flow electrophoresis was investigated as a tool for the preparative chiral separation of piperoxan enantiomers using sulfated beta-cyclodextrin (sbeta-CD) as the chiral additive. Bulk migration of sbeta-CD was confirmed using LC-MS analysis of the individual fractions collected and visualized with the addition of crystal violet to the separation buffer. In the absence of sbeta-CD, the crystal violet-containing buffer was reddish/purple and the crystal violet was deflected cathodically in the chamber. In the presence of sbeta-CD, the crystal violet-containing buffer was blue and was deflected anodically. However, formation of accumulation and depletion zones was apparent in both cases. The addition of sbeta-CD to the cathodic wash solution allowed for almost complete resolution of the piperoxan enantiomers with a processing rate of 0.45 mg/ h.

Continuous free flow electrophoresis was investigated as a tool for the preparative chiral separation of piperoxan using a sulfated cyclodextrin chiral additive. In the absence of chiral additive, the sample stream was deflected cathodically. However, the presence of sulfated cyclodextrin in the run buffer caused anodic deflection and splitting of the sample stream into two streams, each enriched in one enantiomer. Although the sulfated cyclodextrin used was comprised of a mixture of homologues and isomers, this polydispersity did not seem to significantly impact band dispersion. Sample introduction rates ranged from approximately 0.9-7.2 mg h-1. Maximum resolution was 0.53, using an applied voltage of 220 V, buffer composition of 0.075% sulfated cyclodextrin, 7.6 mM citrate (pH 3), 4.5 degrees C.

Herein, we evaluate the interaction of the alpha(2)-AR antagonist, yohimbine, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. Yohimbine displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, yohimbine exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), h5-HT(1D), and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of yohimbine at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of yohimbine at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to yohimbine, fluparoxan shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, yohimbine also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, yohimbine decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, yohimbine enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. Yohimbine likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of yohimbine increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the 5-HT(1A) agonist actions of yohimbine suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels.

Capillary electrophoresis (CE) was used to optimize the buffer pH, ionic strength and sulfated cyclodextrin concentrations for enantiomeric separation of piperoxan. These enantioseparation conditions were then applied to a classical gel electrophoresis system. Binding constants of the sulfated beta-cyclodextrin-piperoxan couple were approximated using CE and the effects of organic solvents on the system were also investigated.

We have previously shown that the release of acetylcholine (ACh) in the medial prefrontal cortex of the conscious rat, as measured by microdialysis, is increased following intraperitoneal injection of the selective alpha 2-adrenoceptor antagonist (+)-efaroxan. To characterize further the receptor pharmacology of this response, the effects of other selective alpha 2-adrenoceptor ligands were examined. The alpha 2-adrenoceptor antagonists idazoxan (2.5 and 20 mg/kg), atipamezole (2.5 mg/kg), and fluparoxan (10 mg/kg) increased ACh outflow by up to 250-325% of basal levels over a 3-h period following intraperitoneal injection. The alpha 2-adrenoceptor agonists UK-14304 (2.5 mg/kg) and guanabenz (2.5 mg/kg) reduced ACh outflow by 80 and 60%, respectively. Clonidine (0.00063-0.16 mg/kg) had no significant depressant effect and at 2.5 mg/kg increased ACh outflow to 233% of basal levels. These results indicate a modulatory role for alpha 2-adrenoceptors on the release of ACh in the rat prefrontal cortex in vivo. Based on the facilitatory effects produced by the antagonists alone, this alpha 2-adrenoceptor modulation appears to be tonic and inhibitory. The ability of alpha 2-adrenoceptor antagonists to enhance ACh outflow suggests a therapeutic usefulness in disorders where cortical ACh release deficits have been implicated.

Although amphetamine has profound cardiovascular actions, the role of the sympathetic nervous system in these responses is largely unknown. The purpose of this study was to characterize the sympathetic nerve responses to amphetamine and to determine whether these neural responses involve an action of amphetamine in the rostral ventrolateral medulla (RVLM). In sinoaortically denervated (SAD) and sham-SAD rats, amphetamine dose-dependently increased mean arterial pressure (MAP) and heart rate (HR), while decreasing (-87 +/- 5%, max) renal sympathetic nerve discharge (SND) for 57 +/- 5 min. Comparison of the SND responses in SAD and sham-SAD rats revealed a small but significant contribution of the baroreceptor reflex to the sympathoinhibitory response. In separate studies, the bilateral microinjection of amphetamine into RVLM decreased HR, MAP, and SND. The magnitude and duration of the decrease in SND elicited by amphetamine were significantly attenuated by the prior intravenous (i.v.) administration of idazoxan (alpha 2-adrenergic antagonist). The prior bilateral microinjection of idazoxan or piperoxan into RVLM significantly attenuated the duration of the sympathoinhibitory responses elicited by i.v. amphetamine. Idazoxan and piperoxan also tended to decrease the magnitude of the SND response; however, this reduction was significant at only the highest doses. The MAP and HR responses were unaffected by idazoxan treatment. The microinjection of terazosin (alpha 1-adrenergic antagonist) or propranolol (beta-adrenergic antagonist) into RVLM did not alter the HR, MAP, or SND responses to i.v. amphetamine. We conclude that i.v. amphetamine decreases SND in anesthetized rats, in large part, by a mechanism involving the activation of alpha 2-adrenergic receptors in RVLM.

Piperoxane is an α2-noradrenergic antagonist with demonstrated excitatory effects on neurons in the locus coeruleus, causing a corresponding increase in norepinephrine in many forebrain areas. 16 male Fischer-344 rats approximately 16 months of age were injected with 3 mg/kg of piperoxane or .09% saline. The piperoxane-treated rats lived an average of 127.1 days longer than the saline-treated rats. The results are discussed in terms of the effects of strategies designed to enhance brain levels of catecholamine and their effect on the aging process. A discussion of further research is also presented.

1. The effects of alpha 2-adrenoceptor agonists and antagonists on rat tail skin temperature (tts), an indicator of local cutaneous blood flow, were studied in conscious and anaesthetized rats and in the isolated, Krebs perfused, vascular bed of the rat tail. 2. In conscious rats, at an ambient temperature of 18.5-20 degrees C, tts was 21.0 +/- 0.2 degrees C and core (rectal) temperature (tc) was 38.2 +/- 0.04 degrees C (n = 126). The alpha 2-adrenoceptor antagonist, delequamine (RS-15385-197; 1 mg kg-1, s.c., n = 6), produced a rapid elevation in tts to 29.1 +/- 0.7 degrees C (P0.001 vs. saline-treated control group), attained 10 min after injection. tc fell slightly, by 1.0 +/- 0.1 degrees C. The tts response was dose-related over the dose-range tested (0.01-1 mg kg-1, s.c.), with an ED50 of 17 micrograms kg-1, s.c. (n = 6 per dose). 3. The maximum increases in tts in response to a dose of 1 mg kg-1, s.c. of alpha 2-adrenoceptor antagonists were as follows (n = 6 per drug): delequamine (+9.6 +/- 0.8 degrees C)yohimbine (+9.0 +/- 1.0 degrees C)WY-26703 (+7.9 +/- 1.3 degrees C)piperoxan (+5.6 +/- 1.7 degrees C)idazoxan (+4.6 +/- 1.3 degrees C)imiloxan (+4.1 +/- 1.3 degrees C)SKF 104078 (+2.0 +/- 1.9 degrees C)BDF-6143 (+1.3 +/- 0.8 degrees C). 4. Prazosin (0.3 mg kg-1, s.c.), hydralazine (10 mg kg-1, s.c.) and nifedipine (3 mg kg-1, s.c.) did not increase tts, whereas propranolol (10 mg kg-1, s.c.) evoked a small increase in tts (+2.9 +/- 1.0 degrees C). Pentolinium (2-10 mg kg-1, s.c.) elicited a dose-related increase in tts, which was elevated by 4.4 +/- 1.3 degrees C after a dose of 10 mg kg-1; tc was reduced in a dose-related manner. Drug vehicles (1 ml kg-1, s.c.) had no effect on tts or tc. 5. In anaesthetized rats, idazoxan (300 microg, i.v.) produced a rapid increase in tts which was detectable 2 min after beginning the injection, reaching a peak after 7 min. When the same dose was administered i.c.v., tts also rose, but more slowly. The peak response (+ 3.6 +/- 0.70C, n = 5) was significantly smaller than when idazoxan was administered intravenously (+ 6.3 +/- 1.2 C, n = 5), which suggests that the increase in tts following systemic administration of M2-adrenoceptor antagonists is not due to a central effect. The change in tts was not secondary to changes in blood pressure.6. In the isolated, Krebs perfused, tail vascular bed of the rat, at an ambient temperature of 20-21C,under constant flow conditions (3.5-4.0 ml min-1; n = 4), baseline perfusion pressure was 57 +/- 4 mmHg.5-Hydroxytryptamine (5-HT; 70-150 nM) increased perfusion pressure by 56+/- 9 mmHg. The alpha2-adrenoceptor agonist, UK-14,304 (10 nmol), elicited a further increase in perfusion pressure by27.5 +/- 15 mmHg but had no effect in the absence of 5-HT; this response to UK-14,304 was abolished by rauwolscine (1 microM).7. Under constant pressure conditions (-100 mmHg; n = 9), baseline mean perfusion flow was 2.1 +/- 0.2 ml min-1, and mean tail skin temperature was 31.6 +/- 0.6C. 5-HT (119 +/- 28 nM) decreased tts.by 3.3 +/- 2.0 C and reduced flow by 1.2 +/- 0.3 ml min-1. UK-14,304 (10 nmol) further reduced tts by 3.0 +/- 0.3 C without significant effect on flow; this effect was also abolished by 1 microM rauwolscine.8. We conclude that post-junctional M2-adrenoceptors in the vasculature of the rat tail have a major vasoconstrictor role, controlling both the flow and distribution of blood within the tail and thereby thermoregulatory heat loss from its surface.

The direct effect of alpha 2-autoreceptors was studied by measuring the effects of piperoxan, an alpha 2-autoreceptor antagonist, and clonidine, an agonist on catecholamine exocytosis, from single bovine chromaffin cells in culture. Catecholamine release was elicited by stimulation with 100 microM nicotine and was monitored electrochemically with a carbon-fiber microelectrode placed adjacent to the cell. These electrodes allowed the number of exocytotic release events to be monitored and reported as total charge for release following a specific stimulus. Repeated stimulation with 100 microM nicotine showed that total release caused by the second exposure to nicotine was 32% of the first, and release caused by the third exposure to nicotine was 80% of the second. Total release of catecholamine increased significantly after application of 20 microM piperoxan relative to a control application of balanced salt solution. Application of 20 microM piperoxan alone did not cause release. After the cells were incubated in culture medium containing 20 microM clonidine, a significant decrease in nicotine-stimulated catecholamine release was observed. These results confirm that there are autoreceptors on chromaffin cells and, when relatively high levels of catecholamine are released, the catecholamine stimulates the alpha 2- autoreceptors, which inhibits subsequent release through a negative feedback mechanism. In addition to piperoxan, the sympathomimetic drug amphetamine also increases quantal release after application of nicotine. Amphetamine increases the extracellular concentration of catecholamine, and these data appear to indicate that at least part of the pharmacology of amphetamine might involve blocking catecholamine autoreceptors.

The alpha 2 agonist clonidine has been shown to be anxiolytic in a number of preclinical anxiety models. Interestingly, intravenous infusion of the alpha 2 antagonists idazoxan at 10 mg/kg and rauwolscine at 2.24 mg/kg significantly disinhibited lick-shock conflict responding in rats similar to the alpha 2 agonist clonidine (0.022 mg/kg) and the benzodiazepine diazepam (0.5 mg/kg). However, the alpha 2 antagonists yohimbine and piperoxan, the alpha 2 agonists medetomidine, guanfacine, and guanabenz, the non-specific alpha antagonist phentolamine, and the alpha 1 antagonist prazosin did not disinhibit conflict responding in the Vogel lick-shock paradigm. In fact, yohimbine has been shown to be anxiogenic in both animals and man. This may be due to yohimbine's lack of specificity and its ability to inhibit GABAergic release. In addition, all of these agents, except idazoxan, did not increase water consumption in water deprived rats. Idazoxan (10 mg/kg) significantly decreased water consumption by 45%. Therefore, idazoxan increased conflict responding for water reward at a dose (10 mg/kg) which also decreased water consumption in a non-conflict paradigm. These data suggest that agents with selective antagonism at the alpha 2 receptor site may be anxiolytic while agents with less specificity at this site such as yohimbine, piperoxan, and phentolamine are not anxiolytic.

Bulbospinal barosensitive neurons of the rostral ventrolateral medulla (RVLM cells; presumed sympathetic vasomotor premotor neurons) were recorded with iontophoretic electrodes in urethan-anesthetized rats. The majority of these cells were insensitive to intravenous clonidine (Clo; up to 20 micrograms/kg) and insensitive to iontophoretically applied Clo or alpha-methylnorepinephrine (alpha-MNE). These cells (n = 47 of 76) had a spinal conduction velocity of 4.1 +/- 0.2 m/s and a mean firing rate of 20 +/- 1 spikes/s. A second population (n = 29) was powerfully inhibited by intravenous Clo (5-10 micrograms/kg, activity decreased by 83 +/- 11%), iontophoretically applied Clo (decreased by 51 +/- 7%), and iontophoresis of alpha-MNE (decreased by 69 +/- 3%). These cells had a slower conduction velocity (2.0 +/- 0.3 m/s) and a much slower discharge rate (6 +/- 1 spikes/s). Both populations were pulse synchronous at resting arterial pressure. The inhibitory effects produced by iontophoresis of alpha-MNE or Clo were reduced to the same degree (86-98%) by iontophoresis of idazoxan (an alpha 2-adrenergic antagonist with imidazoline structure) and by iontophoresis of piperoxan (65-77%, a nonimidazoline alpha 2-antagonist). The inhibition of RVLM cells by intravenous Clo was reversed by iontophoresis of idazoxan and by intravenous injection of yohimbine (nonimidazoline alpha 2-antagonists). These data suggest that 1) intravenous Clo only inhibits a subpopulation of RVLM sympathetic premotoneurons, possibly the C1 adrenergic cells, 2) this effect of Clo is due to activation of alpha 2-adrenergic receptors rather than nonadrenergic imidazoline binding sites, and 3) these alpha 2-receptors are located on or close to the Clo-sensitive cells and may be continuously activated by endogenously released catecholamines.

It has been previously reported that the adrenergic system is involved in the control of feeding behavior and LH release. In the present study, the role of the adrenergic receptors in the suppression of LH release during acute fasting are examined by injecting the alpha 1-antagonist (prazosin), alpha 2-antagonists (idazoxan, SKF 86466-A, piperoxan), or beta-antagonist (propranolol) into the third ventricle of unfasted and 48 h fasted ovariectomized estradiol-treated rats. Blood samples were collected every 6 min for 3 h and the drugs were administered after the first hour of the sampling period. Prazosin caused a significant suppression of LH release in the unfasted animals while idazoxan and propranolol had no significant effects. In contrast, all alpha 2-antagonists blocked the inhibitory effect of fasting on LH release and significantly reinstated the suppressed LH release while prazosin and propranolol had no significant effects. We conclude from these results that the suppression of LH release during acute fasting is mediated by alpha 2-adrenergic receptors but not alpha 1- or beta-adrenergic receptors.

The pharmacological characteristics of hindlimb scratching induced by serotonergic compounds were studied. We conclude that hindlimb scratching induced by serotonergic compounds is mediated by a serootonin 1D (5-HT 1D ) or 5-HT 1D -like receptor outside the blood-brain barrier because hindlimb scratching could be induced by s.c. injection of 5-methoxytryptamine (5-MeOT), 5-carboxamidotryptamine (5-CT), bufotenine, 5-hydroxytryptamine (5-HT) and tryptamine. These compounds have high affinity for 5-HT 1A and 5-HT 1D receptors. The 5-HT 1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), the 5-HT 1C receptor agonist MK 212, and the mixed 5-HT 1C /5-HT 2 receptor agonists (dl)-1-(2,5 dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and quipazine did not induce hindlimb scratching. Rather, the latter compounds attenuated 5-MeOT-induced hindlimb scratching. The 5-HT releasing compounds fenfluramine and p-chloroamphetamine (PCA) inhibited whereas the 5-HT re-uptake inhibitors fluvoxamine and indalpine potentiated 5-MeOT-induced hindlimb scatching, 5-MeOT-induced hindlimb scratching could be inhibited dose dependently by the α- 2 -adrenoceptor blockers yohimbine and rauwolsince, which also have high affinity for 5-HT 1D receptors, whereas the α 2 -adrenoceptor blocker piperoxan only weakly counteracted hindlimb scratching. Haloperidol, apomorphine, morphine, clonidine and methiothepin strongly attenuated hindlimb scratching, atropine, naloxone and ICS 205930 attenuated it weakly whereas domperidone, methylatropine and mepyramine were inactive in doses up to 10 mg/kg. Hindlimb scratching induced by 5-MeOT was potentiated by the 5-HT receptor antagonists metergoline, methysergide, mesulergine, mianserin, ritanserin and xylamidine. Hindlimb scratching was not induced by i.c.v. injection of 5-MeOT. This lack of i.c.v. activity of 5-MeOT and the effect of xylamidine suggests that the site of action for induction of hindlimb scratching is outside the blood-brain barrier.

International audience; We have studied the effect of modafinil and amphetamine, two waking drugs, on the electrical activity of central dopaminergic and noradrenergic neurons in the rat. Modafinil (128 mg/kg, i.p.) was unable to modify the firing pattern of these neurons, while amphetamine (2 or 5 mg/kg, i.p.) consistently inhibited their activity. A pretreatment with modafinil did not change thereafter the effect of amphetamine. Contrary to amphetamine, the waking effect of modafinil does not seem to be mediated by the catecholaminergic neuron activity per se.

Antagonism of pressor responses to sympathetic outflow stimulation and alpha-adrenoceptor agonists in pithed spontaneously hypertensive rats was used to estimate postsynaptic alpha-adrenoceptor blocking activity of mianserin, phentolamine, phenoxybenzamine, piperoxan and yohimbine. Estimation of presynaptic alpha-adrenoceptor blocking activity of these drugs was obtained by studying their ability to antagonize clonidine-induced suppression of positive chronotropic responses to sympathetic outflow stimulation. In this manner, evidence was obtained that mianserin causes selective presynaptic alpha-adrenoceptor blockade. Mianserin, piperoxan and yohimbine antagonized clonidine-induced avoidance blockade or hypotension in spontaneously hypertensive rats, but methysergide, phenoxybenzamine and phentolamine were ineffective. These results suggest that mianserin may antagonize the central effects of clonidine by blockade of noradrenergic presynaptic or autoreceptors and possibly explain the antidepressant effect of mianserin as due to indirect activation of central noradrenergic neurons.

To determine whether the hyperactivity of noradrenergic neurons that occurs during opiate withdrawal might be associated with a reciprocal alteration in noradrenergic receptor response, isoproterenol-stimulated adenylate cyclase activity was examined in the cerebella of morphine-addicted monkeys at two time periods: a) prior to withdrawal, and b) during late withdrawal. Compared to controls, the chronically-addicted group showed a significant increase in maximal enzyme velocity, a finding consistent with the observed hypoactivity of noradrenergic neurons which occurs during opiate administration. In contrast, the morphine withdrawal group demonstrated a significant decrease in enzyme activity. Piperoxan, known to mimic the effects of withdrawal in causing noradrenergic hyperactivity, also decreased enzyme activity. In no group was there a change in Ka for isoproterenol. These findings, indicating that opiate withdrawal is associated with a subsensitivity of noradrenergic receptor response, suggest a possible etiology for certain of the physiological changes of noradrenergic hypoactivity seen during the secondary (or protracted) abstinence syndrome.

Measurements were taken for the acetylcholine content of animal and human pelviureteral muscle and for the release of acetylcholine at rest and during field stimulation of the isolated renal pelvis and ureter. Release was frequency-dependent, with the maximum output obtained at 10 Hz. The release of acetylcholine from reserpine-pretreated and piperoxan-treated tissues remained unchanged, but tetrodotoxin (1.10(-6) g/ml) and noradrenaline (2.10(-6) g/ml) significantly reduced the output.

The acute hypotensive and bradycardic effects of the new compound B-HT 933 (2-amino-6-ethyl-4,5,7,8-tetrahydro-6H-oxazolo-[5,4-d]-azepin-dihydrochloride) were investigated in anaesthetized cats and rats. In spite of the molecular structure of B-HT 933, which differs considerably from that of clonidine, its cardiovascular reaction pattern is comparable, although the former is much less potent. B-HT 933 showed a central nervous origin for its acute hypotensive action in anaesthetized cats, since its effects on blood pressure after infusion via the left vertebral artery were much greater than after intravenous application of the same amounts. Pretreatment with the alpha-adrenoceptor-blocking drug, piperoxan (100 micrograms/kg), completely abolished the hypotensive response to B-HT 933 (30 micrograms/kg) injected subsequently via the left vertebral artery. It is concluded that B-HT 933 is a centrally acting hypotensive drug. Central alpha-adrenoceptors are involved in a similar manner as the mechanism of clonidine.

Clonidine (150 Μg/kg s. c.) depressed avoidance conditioned reflexes in Long-Evans rats. Some α-adrenoceptor blocking agents piperoxan, tolazoline, phentolamine, dibenamine and phenoxybenzamine also depressed these reflexes. Yohimbine (1–2 mg/kg) was found to have no significant effect. Atropine (10 to 15 mg/kg i. p.) antagonized the depression of conditioned avoidance reflexes induced by α-adrenoceptor blocking agents as well as the depression produced by clonidine. Yohimbine (1–2 mg/kg) reduced the depressing effects of clonidine on avoidance conditioned reflexes. In rats treated with piperoxan (10 mg/kg) the effects of clonidine were reduced. In these rats the depression of conditioned reflexes was less than in rats treated with clonidine or piperoxan alone. These experiments suggest that clonidine depressed avoidance conditioned reflexes in rats by activating central α-adrenoceptors. It is proposed that α-adrenoceptor blocking agents might act as partial agonists.

Dextromoramide (0.01−0.2 mg/kg i.v.) and fentanyl (0.005−0.05 mg/kg) induced a dose dependent decrease in blood pressure and heart rate in dogs. These effects appear to be to a centrally mediated decrease in sympathetic tone, (i) Both drugs are 10−20 times more potent when injected into the vertebral artery or the cisterna magna than when they were injected intravanously, (ii) Both drugs reduced splanchnic nerve activity in intact animals. The effect appears to be localized to the medulla oblongata as suggested by central injections; transection of the brain stem at midpoint levels did not change the effects on blood pressure and heart rate induced by dextromoramide in intact bivagotomized dogs. After transection of the spinal cord at C1, dextromoramide induced a strong decrease in heart rate and a hypertension. Cutting of both vagus nerves abolished the decrease in heart rate and blood pressure. The hypotensive effect was therefore due to the bradycardia reducing cardiac output. In contrast in intact and midpontine dogs, a reduction in sympathetic tone contributes to the hypothensive effect. Nalorphine prevented and reversed the hypotensive, bradycardic and sympatho-inhibitory effects of dextromoramide. Piperoxan and yohimbine, two potent peripheral and central α-adrenoceptor blocking agents did not change the effects of dextromoramide. However oxotremorine or acetylcholine administered into the cisterna magna and vertebral artery administration of physostigmine abolished or reversed the haemodynamic effects of dextromoramide. A tropine abolished the antagonistic effects of cholinomimetic agents on the central cardiovascular effects of dextromoramide. Muscarinic mechanism appear to be involved in the haemodynamic effects of analgesic agents.

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.

Acute noradrenergic stimulation has previously been shown to stimulate brain (Na + , K + )- adenosine triphosphatase activity. Effects of repeated stimulation with piperoxane were examined in the present study. Daily piperoxane increased ouabain binding, measured 24 h after the last dose, after 4 days or 3 weeks treatment; K + -p-nitrophenylphosphatase was increased after 3 weeks. Prazosin, which, like piperoxane, activates presynaptic noraadrenergic neurons but, unlike piperoxane, blocks postsynaptic receptors, did not increase K + -p-nitrophenylphosphatase , and decreased ouabain binding after 3 weeks.

Earlier investigations of sympathomimetic drugs overcoming the amnesic action of cycloheximide (CXM) in day-old chickens were extended to biochemical studies in vitro. The effects of amphetamine, norepinephrine, α and β noradrenergic stimulants and receptor blockers on Na + /K + ATP'ase activity in total homogenate of chicken forebrain were investigated. Norepinephrine and the β stimulant, isoprenaline significantly stimulated the activity of this enzyme, while the β blocker, propranolol inhibited activity. Amphetamine, the α stimulant, methoxamine and the α receptor blocker, piperoxane had no effect on Na + /K + ATP'ase activity in total homogenate. In a purified synaptosomal preparation, both amphetamine (5 × 10 −5 M) and norepinephrine (1 × 10 −4 M) produced a slight stimulation of Na + /K + ATP'ase activity. A similar concentration of amphetamine (1.12 × 10 −4 M) did not inhibit 1 4 C-leucine uptake or incorporation into protein in the synaptosomal fraction. Nor was it able to alleviate CXM inhibition of 1 4 C-leucine incorporation into synaptosomal protein. The results are interpreted in terms of amphetamine (via release of norepinephrine) norepinephrine and isoprenaline stimulating and maintaining the labile, sodium pump-dependent, phase of memory formation for a sufficient length of time until protein synthesis inhibition by CXM wears off.

The effects of intravenous (i.v.) cocaine HCl on single identified spontaneously firing noradrenergic neurons in the nucleus locus coeruleus (LC) were studied in rats in vivo . Cocaine (0.25–1 mg/kg) produced inhibition of spontaneously firing LC neurons, which was reversed by the administration of the selective alpha2-adrenoceptor antagonist, piperoxane (250 ug/kg, i.v.). Procaine, a local anesthetic that is structurally related to cocaine, did not inhibit LC neurons in doses up to 4 mg/kg, i.v. These results suggest that cocaine in low doses has significant central sympathomimetic effects at the single noradrenergic neuron level and that the inhibition of spontaneous activity may be mediated by alpha2-adrenoceptors. Our results also indicate that cocaine in pharmacologically relevant doses, can significantly affect central alpha2-adrenoceptor regulatory processes.

Cats were anaesthetized with pentobarbital sodium and the anterior hypothalamus was superfused with artificial cerebrospinal fluid through a push-pull cannula. Electrical stimulation of the superfused area with the tip of the cannula elicited a fall of the arterial blood pressure which was dependent on frequency and voltage. Maximal depressor response was obtained at 60 Hz with 2-4V; further increase of the voltage often led to a rise of the arterial blood pressure. Superfusion of the anterior hypothalamus with the alpha-adrenoreceptor blocking drugs tolazoline, piperoxan, yohimbine or phentolamine caused a dose-dependent inhibition of the depressor response to hypothalamic stimulation. Tolazoline was less effective than the other drugs. Superfusion of the anterior hypothalamus with the alpha-sympathomimetic drug phenylephrine prior to and during superfusion with phentolamine abolished the inhibitory action of the latter drug. It is concluded that alphaadrenoreceptors are present in the anterior hypothalamus and involved in the depressor response to electrical stimulation of this hypothalamic area.

Bilateral injections of adrenaline (0.01-10.0 microgram) into the anterior hypothalamic (AH) region, in urethane-anaesthetised spontaneous hypertensive (SH) rats, elicited dose-dependent falls in blood pressure and heart rate. The bradycardia was immediately in onset while the hypotension was preceded by a short-lasting rise in blood pressure. Bilateral injections of adrenaline into the anterior preoptic area (POA) and areas surrounding the AH had little or no effect on blood pressure and heart rate, while injections into the posterior hypothalamus (PH) induced tachycardia and hypertension followed by a smaller fall in blood pressure. Pretreatment with dl-propranolol (25-100 microgram bilat. AH) appeared to potentiate the hypotension induced by adrenaline (1 microgram bilat. AH) in a dose-dependent manner, but did not affect the falls in heart rate. On the other hand, pretreatment with metoprolol (25-100 microgram bilat. AH) effected a dose-dependent antagonism of the adrenaline-induced hypotension and bradycardia. Pretreatment with 1-propranolol (25 microgram bilat. AH) also antagonised the adrenaline-induced cardiovascular depressor effects, while pretreatment with d-propranolol (25 microgram bilat. AH) abolished the initial hypertensive effect. Pretreatment with piperoxan (25-100 microgram bilat. AH) antagonised adrenaline (1 microgram bilat. AH) induced hypotension and bradycardia only at the highest dose used. The results give further support to the concept that hypothalamic adrenaline receptors may be involved in the central regulation of blood pressure and heart rate. Furthermore, while an involvement of hypothalamic alpha-adrenoceptors cannot be ruled out, it is suggested that hypothalamic beta-adrenoceptors may be involved in mediating the cardiovascular depressor effects of adrenaline injected into the AH.

1. Intraventricular clonidine and BAY 1470, administered in small doses to conscious renal hypertensive cats, produced a fall in mean blood pressure lasting for a period of 3 h. This fall in blood pressure was accompanied by a marked bradycardia. 2. Pretreatment with intraventricular phentolamine (0.3–6 μmol), piperoxan (0.18–0.74 μmol) or tolazoline (0.35–1 μmol) abolished the hypotensive effects of intraventricular clonidine (74 nmol), whereas pretreatment with haloperidol (2.6 μmol/kg, intraperitoneally), or desmethylimipramine (3.3 μmol/kg, intraperitoneally, or 1.7 μmol, intraventricularly) did not modify the cardiovascular responses to clonidine. 3. Emesis was observed 1 min after intraventricular administration of clonidine (18–112 nmol) or BAY 1470 (0.07–0.14 μmol), which always preceded the cardiovascular actions and was still observed after pretreatment with haloperidol, desmethylimipramine, phentolamine, piperoxan or tolazoline. 4. In conscious hypertensive rats clonidine (0.6 μmol/kg, intraperitoneally) produced a marked fall in blood pressure that was antagonized by centrally acting α-adrenoreceptor blocking agents but not modified by pretreatment with either 6-hydroxydopamine (three doses of 1 μmol, intraventricularly) or 5,6-dihydroxytryptamine (0.1 μmol). 5. It is concluded that the anti-hypertensive responses to clonidine are mediated via stimulation of central α-adrenoreceptors and are independent of central dopaminergic receptors, intact central serotonergic neurons and intact adrenergic uptake mechanisms.