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As the olfactory system is closely connected with the brain areas responsible for the most crucial alterations in psychiatric populations, especially cognitive and emotional impairments, the study of olfactory processing may be a relevant approach to identify specific markers of alcohol dependence. The aim of this study was to propose the probable olfactory markers for alcohol dependence through a study of the olfactory parameters that involve the central olfactory pathway. We recruited the same 41 alcohol-dependent patients in an early (day 8) and late (day 67) stage of abstinence and 41 controls matched for gender, age, and smoking status. The participants underwent clinical assessments and several olfactory evaluations. The results revealed on one hand, the persistence of decreased intensity of positive emotion (happy), increased intensity of negative emotion (sad), and increased citation of surprise in patients, suggesting the presence of probable trait markers of alcohol dependence. On the other hand, we found decreased hedonic score for pleasant and neutral odorants, and decreased odor familiarity judgment only in the early stage of evaluation as probable state markers for alcohol dependence. These results may be underpinned by several neuropsychological alterations specific to this disease and their evolution after weaning. Further studies are needed to replicate these findings and to confirm the specificity and sensitivity of the olfactory tests in a larger sample of patients. The olfactory perception of all controls must be also retested in order to determine the specific state and/or trait markers of alcohol dependence.

LY 186641 is a diarylsulfonylurea with a broad spectrum antitumor activity against both murine and human solid tumors. We report here the results of a phase II trial of LY 186641 in advanced renal cell adenocarcinoma. The drug was administered orally, once daily for 2 weeks, every 21 days at a 700 mg/m2/d dose. Sixteen patients were enrolled in this phase II trial; 12 males, 4 females, with a median age of 58 years. All patients had progressive measurable metastatic disease. The primary tumor was surgically removed in all but one patient. Three patients were previously treated by biologic response modifiers (BRMs). A total of 72 courses were administered. The most common side effects were methemoglobulinemia (MetHgb) and anemia which occurred in 13 and 10 patients respectively. The MetHgb did not exceed 15%, and only 3 patients required blood transfusion for grade 3 (2 patients) and grade 4 (1 patient) anemia. Reversible hepatotoxicity was observed in 3 patients. There were one pathological complete response, seven stable disease and 8 progressive disease.

Unilateral microinjections of quipazine (0.9 μg in 50 nl) into the subretrofacial nucleus produced hypertension and a slight tachycardia associated with an increase in renal sympathetic nerve activity. Microinjections of quipazine lateral, caudal or rostral to this nucleus failed to alter blood pressure and heart rate. Similarly, microinjections of l-glutamate (3 nmol in 15 nl) into the subretrofacial nucleus elicited hypertension, tachycardia and renal sympatho-excitation. The magnitude of the pressor response to quipazine was smaller than the response elicited by l-glutamate but its duration was longer. Microinjections of quipazine into the lateral tegmental field at l-glutamate hypertensive sites failed to alter arterial blood pressure and heart rate. In contrast, microinjections of quipazine into the caudal ventrolateral medulla or into the nucleus tractus solitarii produced hypotension and sympatho-inhibition. These effects were prevented by microinjections of the 5-HT 2 receptor antagonists, LY 53857 or BW 501C. The present results indicate that stimulation of 5-HT 2 receptors of the subretrofacial nucleus produces hypertension and sympatho-excitation whereas stimulation of 5-HT 2 receptors in the caudal ventrolateral medulla and in the nucleus tractus solitarii produces hypotension and sympatho-inhibition.

Quipazine (0.5 mg/kg i.v.) produced a sustained pressor response and an increase in splanchnic nerve activity in intact as well as in baroreceptor-denervated cats without causing a significant change in heart rate. These effects were prevented by the 5-HT2 receptor antagonists, ritanserin (0.5 mg/kg i.v.) or BW 501 C (0.5 mg/kg i.v.). Quipazine induced an hypertensive response and an increase in splanchnic discharge in cats pretreated with prazosin (0.1 mg/kg) or hexamethonium (10 mg/kg i.v.). Bilateral application of quipazine (25 micrograms/side) to the ventrolateral pressor area produced a rapid increase in mean blood pressure and in splanchnic discharge. Pretreatment with prazosin (0.1 mg/kg i.v.) abolished the hypertension but not the sympatho-excitatory effects of quipazine. Local application of the 5-HT2 receptor antagonists, LY53857 (10 micrograms/side) or cyproheptadine (10 micrograms/side), had no effects on blood pressure and splanchnic nerve activity but prevented or reversed the actions of locally applied quipazine. LY 53857 (10 micrograms/side) antagonized the sympatho-excitatory effects of systemically administered quipazine. These results indicate that the cardiovascular changes induced by quipazine in anaesthetized cats are mediated by central 5-HT2 receptors located in the ventrolateral pressor area and by peripheral vascular 5-HT2 receptors.

Quipazine (0.5–2 mg/kg i.v.) produced transient hypotension and bradycardia followed by sustained hypertension and variable effects on heart rate in anaesthetized rats. The hypotension, bradycardia and sympatho-inhibitory effects of quipazine were attenuated by bivagotomy. In bivagotomized rats, the hypertension produced by quipazine was not modified by hexamethonium or prazosin but was abolished by ritanserin (1 mg/kg i.v.). In ritanserin-treated rats, section of the carotid sinus nerves and vagus nerves or ICS 205.930 (0.1 mg/kg i.v.) abolished the hypotensive, bradycardic and sympatho-inhibitory effects of quipazine; the action of quipazine was not reproducible in these rats. Quipazine also inhibited the Bezold-Jarish reflex elicited by 5-HT (20 μg/kg i.v.). In ICS 205.930-treated rats, the hypertension evoked by quipazine was associated with a reduction in splanchnic nerve activity due to stimulation of baroreceptors. The renin-angiotensin system is not involved in the hypertensive response. The increase in heart rate produced by quipazine in bivagotomized rats was reduced by ritanserin and tertatolol (0.1 mg/kg i.v.) and abolished by a combination of both drugs. We conclude that the bradycardic and sympatho-inhibitory effects of quipazine result from activation of 5-HT 3 receptors located in the cardiopulmonary area and of carotid body chemoreceptors. The hypertension and tachycardia are mediated by vascular and myocardial 5-HT 2 receptors. No evidence was obtained for a central sympatho-excitatory effect.

A pharmacological analysis of the effects of 5-HT on heart rate has been performed in the pithed rat. 5-HT induced a dose-dependent increase in heart rate whereas 5-HT1 receptor agonists--8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), 5-methoxy-N,N-dimethyl-tryptamine (5-MeODMT), 5-methoxy 3-(1,2,3,6-tetrahydro-4-piridinyl) 1H indole (RU 24969) and 1-(m-trifluoromethylphenyl)-piperazine (TFMPP)--failed to increase heart rate. The increase in heart rate induced by the selective 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodo-phenyl)-2-aminopropane (DOI) was not significant. The dose-response curve to 5-HT for its tachycardic effects was shifted two-fold to the right by ketanserin and LY 53857 and nine-fold to the right by methiothepin. The effects of high doses of 5-HT (higher than 100 micrograms/kg iv) were antagonized by methiothepin, (-)propranolol, 2-(2-[4(O-methoxyphenyl)-piperazine-1-yl]-ethyl)4,4-dimethyl-1,3 (2H-4H) isoquinoline-dione (AR-C 239) and by pretreatment with reserpine. The 5-HT1 receptor antagonists, pindolol and spiroxatrine, the 5-HT3 receptor antagonist MDL 72222 and the alpha 2-adrenoceptor blocking agent idazoxan failed to antagonize the tachycardia induced by 5-HT. It is concluded that in the pithed rat, the tachycardia induced by 5-HT remained unexplained (implication of 5-HT2 receptors probably different from the classical vascular 5-HT2 receptor, or implication of 5-HT1C receptors?). Moreover, at high doses (higher than 100 micrograms/kg iv), 5-HT may increase heart rate by releasing catecholamines.

An attempt to determine the central site of the sympathoinhibitory effects of 8-hydroxy-2-(di-n-propyl-amino)tetralin (8-OH-DPAT), a 5-HT1A receptor agonist, has been made in normotensive anesthetized dogs. Intravenous and central (cisterna magna, vertebral artery) administration of 8-OH-DPAT induced dose-dependent decreases in blood pressure and sympathetic (splanchnic and renal) nerve activity in intact and baroreceptor denervated dogs. In contrast, 8-OH-DPAT was ineffective when injected into the nucleus tractus solitarii or into the raphe nuclei. Administration of 8-OH-DPAT into the ventrolateral pressor area (VLPA) decreased blood pressure and renal sympathetic nerve activity. The sympathoinhibitory effects of 8-OH-DPAT injected into the vertebral artery (v.a.) were antagonized by methiothepin and (+/-)pindolol injected into the v.a. Likewise, the effects of 8-OH-DPAT administered into the VLPA were antagonized by methiothepin injected into the same site. Depletion of central catecholamines and 5-HT content did not change the sympathoinhibitory effects of 8-OH-DPAT. These results suggested that 8-OH-DPAT has a direct effect on 5-HT1A receptors located in the VLPA in dogs.

Central and peripheral hypotensive effects of (+)- and (−)-nicardipine (1–10 μg/kg i.v. or i.c.v.) were investigated in normotensive and SH rats. The results suggest that a stereoselectivity exists for the peripheral and central hypotensive effects of the nicardipine isomers. (+)-Nicardipine was shown to be 3–8 times as potent as the (−) isomer in reducing blood pressure in all the experiments.

In anaesthetized, paralysed and artificially ventilated dogs, activities were recorded from the phrenic nerve and from respiratory units within the nucleus tractus solitarii (nTS), the nucleus ambiguus (nA) and the nucleus retroambigualis (nRA). The respiratory neurons were classified according to their discharge pattern and their response to lung inflation. Fentanyl injected into the vertebral artery (0.5–2 μg/kg) or intravenously (10 μg/kg) produced a depressant effect on the phrenic nerve motoneurons, on inspiratory cells (Iα and Iβ) and on phase-spanning expiratory-inspiratory neurons of the nTS and the nA. The duration of the inspiratory burst increased and the number of spikes and the peak activity were reduced. This pattern of inhibition was followed by complete blockade of spike genesis. Fentanyl also altered expiratory neurons: the duration of the expiratory discharge was enhanced. An increase followed by a decrease in the number of spikes per burst and a reduction in the peak acticity were observed. When the phrenic nerve was silent, continuous discharges appeared. High doses of fentanyl were needed to inhibit these tonic discharges. This pattern of inhibition concerns late peak expiratory units, expiratory units with a constant discharge pattern and the phase-spanning inspiratory-expiratory neurons. Naloxone antagonized these effects but induced the appearance of tonic discharges in fentanyl-treated phase-spanning expiratory-inspiratory neurons. Stimulation of peripheral chemoreceptors with almitrine (0.2 mg/kg i.v.) antagonized the effects of fentanyl. In addition, fentanyl facilitated the lung inflation reflex on respiratory neurons. In conclusion, fentanyl induces respiratory depression through a preferential effect on inspiratory neurons and alters the active inhibitory phase-switching mechanisms maintaining the expiratory periodicity. These experiments support the concept of an inhibitory influence of inspiratory neurons on expiratory cells and also support the idea that respiratory periodicity arises on a background of tonic activity for both inspiratory and expiratory neurons.

L-Glutamine acid and kainic acid injected int o the cisterna magna of dogs, produced a dose-dependent increase in blood pressure and a decrease in heart rate. In contrast, intravenous injection of both compounds was ineeffective. The hypertension was probably due to an increase in sympathetic tone as guanethidine prevented the rise in blood pressure induced by central administration of L-glutamic acid and kainic acid. Kainic acid was 1000 fold more potent than L-glutamic acid.

The haemodynamic effects of timolol and its inhibiting action on the cardiovascular and bronchial effects of isoproterenol have been studied. Splanchnic nerve activity was recorded. The antiarrhythmic action of timolol was studied on guinea pig isolated atria, using arrhythmias induced by epinephrine, ouabain or coronary ligation in the dog. Timolol is a very potent beta-adrenoceptor blocking agent, without specificity on beta1- or beta2-receptors. No intrinsic beta-stimulating or depressant effects were found. Timolol reduced splanchnic discharges. The antiarrhythmic effect of timolol was limited to epinephrine-induced arrhythmias.

The intravenous injection of loperamide induced an immediate fall in blood pressure and heart rate in anaesthetized rats. Both effects were inhibited by the opiate antagonists naloxone and MRZ 226 BS. Bilateral vagotomy also inhibited both effects whereas atropine only reduced the bradycardia, but the combination of atropine and tertatolol suppressed the bradycardia. A high dose of loperamide induced bradycardia in pithed rats. This effect was prevented by MRZ 2266 BS but not by naloxone. It is concluded that loperamide can elicit a vagally mediated reflex involving vagal and sympathetic mechanisms and could stimulate cardiac opiate receptors, probably κ, both effects leading to bradycardia.

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.

Opiate κ agonists were administered into the cisterna magna of normotensive urethane-anaesthetized artificially ventilated rats: ethylketocyclazocine (78.7 nM) (EKC) and dynorphin-(1–13) (62.3 nM) produced significant and long-lasting decreases in both blood pressure and heart rate. High doses of naloxone (1 mg/kg i.v.) were required to partially antagonize these effects. The central cardiovascular effects of EKC and dynorphin-(1–13) were compared to those of fentanyl (3 nM), [D-Ala 2 , Met 5 ]enkephalinamide (17 nM) and β-endorphin (2.9 nM) which induced increases in blood pressure and heart rate. These results suggest that opposite central cardiovascular effects could be induced by activation of various opiate receptors.

The effects of piribedil on responses to sympathetic stimulation were investigated in anaesthetized dogs. Piribedil (1 mg/kg i.v.) impaired the vasoconstrictor responses to lumbar sympathetic chain stimulation of the perfused hindlimb without changing the effects of noradrenaline. Piribedil (2 mg/kg i.v.) depressed the chronotropic responses to stimulation of the right anterior ansa and the inotropic response to stimulation of the left anterior ansa. Stimulation of the splanchnic nerve induced frequency dependent increases in systemic blood pressure. Piribedil antagonized this effect. Piribedil (1 mg/kg i.v.) attenuated the constrictor responses of the perfused mesenteric artery to postganglionic sympathetic stimulation and reduced the decreases in renal blood flow caused by stimulation of sympathetic renal nerves. The inhibitory efforts of piribedil were preferential on responses induced by low frequency stimulation of nerves. The hypertensive, vasoconstrictor and tachycardic effects of noradrenaline and tyramine were not affected. The effects of piribedil were reversed by haloperidol (0.5 mg/kg i.v.) or pimozide (0.2 mg/kg i.v.).

Dynorphin-(1–13) (i.v.) induced bradycardia and hypotension in artificially ventilated anaesthetized rats. These effects were prevented by MRZ 2266 BS. The bradycardia was inhibited by bilateral vagotomy whereas the fall in blood pressure was not sensitive to bilateral vagotomy and chlorpheniramine treatment. In pithed rats, dynorphin-(1–13) reduced heart rate. This bradycardia was prevented by MRZ 2266 BS but not by tertatolol and cimetidine. It is suggested that the dynorphin-(1–13)-induced effects result from the stimulation of central and cardiac κ-opiate receptors.

Intracerebroventricular injections of nicardipine (10 micrograms/kg) to SHR induced hypotension which was suppressed by pretreatment with 6-OHDA. This hypotension was also inhibited by a previous injection of naloxone (100 micrograms/kg i.c.v.) whereas the hypotension induced by intravenously injected nicardipine (10 micrograms/kg) was not changed. It is suggested that the release of endogenous opioids is involved in the sympatho-inhibitory effect of centrally administered dihydropyridine calcium channel antagonists.

The central cardiovascular effects of the calcium channel blocker nifedipine and the calcium channel activator BAY k 8644 were studied in anesthetized and ventilated normotensive Wistar-Kyoto (WKY) or spontaneously hypertensive rats (SHR). Both drugs were administered in a 1.5-microliter volume into the lateral ventricle of the brain (i.c.v.) or into the cisterna magna (i.c.). The injection of vehicle alone (i.c. or i.c.v.) did not significantly change mean arterial pressure (MAP) or heart rate. Nifedipine (5 and 50 micrograms/kg) and BAY k 8644 (5 and 50 micrograms/kg) induced opposite effects on MAP when centrally injected. Nifedipine decreased MAP and induced a bradycardia (i.c.v.) or no change in heart rate (i.c.), and BAY k 8644 increased MAP without any significant change in heart rate (i.c. or i.c.v.). These effects were more marked with the highest dose of either drug. These effects seemed to be of central origin, since they were suppressed by ganglionic blockade by hexamethonium (100 mg/kg i.v.), whereas after hexamethonium the hypotensive and the hypertensive responses to intravenously injected nifedipine and BAY k 8644, respectively, were preserved. Bilateral vagotomy suppressed the bradycardia induced by i.c.v. administered nifedipine. Previously i.c.v. administered nifedipine (5 micrograms/kg) antagonized the pressor response to BAY k 8644 (5 micrograms/kg i.c.v.). Changes in MAP and heart rate were significantly more marked in SHR than in WKY. These results indicate that a calcium channel inhibitor and a calcium channel activator can modulate in opposite fashion central mechanisms involved in blood pressure control.

Piperoxan (50-100 micrograms/kg) injected into the cisterna magna of anaesthetized dogs increased blood pressure, heart rate and resting rate of sympathetic nerve discharge. The baroreflex curve was shifted to the right with an elevation of the upper plateau (when blood pressure was lowered below resting values, renal sympathetic nerve activity rose to an upper plateau) and with no change in baroreflex sensitivity. Catecholamine depletion, produced by reserpine and alpha-methyl-p-tyrosine, did not change the effects of piperoxan on resting sympathetic nerve activity and on the baroreflex curve. Piperoxan (50 micrograms/kg i.c.) enhanced the rate of renal sympathetic nerve discharge in baroreceptor-denervated dogs. Piperoxan (5 micrograms) injected bilaterally into the nucleus tractus solitarii (NTS) increased blood pressure and resting sympathetic nerve activity with a shift of the sympathetic baroreflex curve to the right and no change in baroreflex sensitivity. Piperoxan (5 micrograms) injected bilaterally into the ventrolateral pressor area did not change blood pressure or the rate of sympathetic discharge. However, the baroreflex curve was shifted to the right with an elevation of the upper plateau level and the baroreflex sensitivity was increased. The present findings suggest that tonically active alpha 2-adrenergic mechanisms located within the NTS regulate resting and reflex sympathetic activity. An alpha 2-adrenergic mechanism in the rostral ventrolateral medulla modulates reflex sympathetic activity but has no influence on resting activity.

SUMMARY 1. AR-C 239, a new α-adrenoceptor blocking drug, appears to act selectively on α1 sites in rats. At peripheral sites, this drug did not change the tachycardia induced by spinal sympathetic outflow stimulation in pithed rats, and did not antagonize the inhibitory effects of clonidine on this preparation. In addition, AR-C 239 showed predominant α1-adrenoceptor blocking properties in the bisected rat vas deferens preparation. AR-C 239 did not prevent or reverse the centrally mediated hypotensive and bradycardic actions induced by clonidine, in intact animals. 2. In conclusion, AR-C 239 seems to be a very useful tool for the characterization of peripheral and central α1-adrenoceptors, in this animal species.

Intracisternal (i. cist.) administration of d-tubocurarine (0.025-0. 100 mg. kg-1) in alpha-chloralose-anaesthetized dogs caused a dose-related increase in blood pressure associated with seizures. When injected in dogs pretreated with guanethidine (15 mg. i.v.), d-tubocurarine elicited the same effect while bilateral adrenalectomy abolished the pressor response. The hypotensive effect of clonidine (0.003 mg. kg-1 i. cist.) was reversed when clonidine was given after the alkaloid. These results suggest possbile interactions of the drugs at central GABA-ergic, glycinergic or cholinergic synapses.

Morphinomimetic peptides were injected into the cisterna magna of chloralosed dogs. Methionine enkepalin (500 microgram/kg i.c.) was found ineffective but beta-endorphin (50 microgram/kg i.c.) induced an initial and transient increase in blood pressure and heart rate followed by a delayed hypotension and bradycardia. The synthetic pentapeptides, [d-ala2]met-enkephalin (500 microgram/kg i.c.), [d-ala2]met-enkephalinamide 500 microgram/kg i.c.) also induced a marked hypotensive, bradycardic and sympatho-inhibitory effect. High doses of naloxone (100 microgram/kg i.v.) were required to antagonize these effects transiently.

ET 495 and apomorphine, injected in small doses (0.1--1 microng/kg) into the femoral artery, induced a dose-dependent increase in femoral blood flow. This dilator effect was abolished by section of the ipsilateral femoral nerve and sciatic nerve, transection of the spinal cord, alpha-adrenoceptor blockade, ganglionic blockade and guanethidine. In addition, the increase in blood flow was inhibited by intravenous administration of haloperiol (2 mg/kg i.v.) or pimozide (2 mg/kg i.v.) and by injection of small doses (10--50 microng/kg) of these drugs into the femoral artery. It was concluded that a dopaminergic component located in the femoral vascular bed of the dog may be involved in the local vasodilator and sympathoinhibitory effect of apomorphine and ET 495.

In the vas deferens of the rat, (-)-170 150 (imidazolinyl-2)-benzodioxane-1-4 or 2-(2-(1,4-benzodioxanyl))-2-imidazoline appeared to be more selective than (+)-170 150 for antagonizing the inhibitory effects of clonidine on the twitch response. In contrast, (+)-170 150 was the most potent of the two isomers for antagonizing the centrally mediated clonidine- or azepexole-induced sleep in chickens. These unexpected results seem to indicate that there are several subpopulations of alpha 2-adrenoceptors.

In anesthetized, normotensive beta-blocked rats, the alpha 1-adrenoceptor blocking drug, AR-C 239 (300 micrograms/kg, i.v.) induced a bradycardic effect related to a central increase in the vagal tone. This bradycardia was inhibited by previous administration of naloxone, intravenously (1 mg/kg) or centrally (100 micrograms/kg, i.c.) injected. Naloxone, by itself did not change the heart rate. In brainstem membranes from normotensive rats, AR-C 239 did not influence the stereoselective binding of [3H]naloxone. In spontaneously hypertensive (SH) rats, naloxone peripherally or centrally administered did not influence the activation of the vagal tone induced by AR-C 239, in beta-blocked animals. These results suggest the possible involvement of opiate release in the AR-C 239-induced vagal bradycardia, in normotensive rats. They also afford new arguments for the existence of close interactions between central alpha-adrenergic and opiate systems in the cardiovascular regulation. The possible participation of kappa-receptors in this effect is discussed. In addition, such an opiate mechanism triggered by central alpha 1-adrenoceptor blockade seems to be either absent or inactive in SH rats.

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.

Clonidine (15 μg/kg, i.v.) induced an increase followed by a long-lasting decrease in blood pressure and reduced heart rate and cardiac output of dogs. All the indices of myocardial performance were decreased: maximal rate of rise in left ventricular pressure, max dP/dt/I.P. (I.P. = ventricular pressure at max dP/dt), pressure time index. The left ventricular end diastolic pressure was increased even when stroke work was decreased. The curve relating dP/dt to the developed pressure was flattened. These facts indicate that clonidine decreased myocardial contractility. Ventricular volumes were not altered. Pacing of the heart after clonidine did not lead to a recovery of cardiac output and myocardial contractility. To analyze the role of the sympathetic and vagal tones on these factors, 5 groups of dogs were used: (1) reserpinized, (2) reserpinized with both vagus nerves cut, (3) with β-adrenoceptor (S 2395, 50 μg/kg) and muscarinic receptor (atropine, 50 μg/kg) blockade, (4) with both vagus nerves cut, and (5)_with both carotid sinus nerves cut. Heart rate was markedly reduced in group 1 but not change in group 2 and 3 3; in groups 4 and 5, heart rate was decreased but to a smaller extent than in control dogs. Therefore the decrease in sympathetic tone and the increase in vagal tone were responsible for the bradycardia. The increase in the vagal tone was apparently due to potentiation of the influence of baroreceptor impulses. The maximal rate of rise in left ventricular pressure did not change in groups 1,2, and 3, but was decreased in groups 4 and 5, indicating that the loss of the sympathetic tone was responsible for the reduction in myocardial contractility. Cardiac output was not changed significantly in groups 2,3 and 4, but decreased in groups 1,3 and 5. The loss of the sympathetic tone and the bradycardia when very marked appear to reduce cardiac output. Left ventricular end diastolic pressure rose in groups 1 and 2, and was increased only transiently in groups 4 and 5. The decrease in myocardial contractility, the changes in blood pressure, the bradycardia and possibly the reduced venous return appear to be the factors influencing this parameter. Blood pressure shows the usual biphasic changes, an increase followed by a decrease in groups 3,4 and 5, did not change in group 1, and was only increased in group 2. The loss of the sympathetic tone was therefore responsible for this effect.

Clonidine and l-dopa (after M.K. 486) reduced pressor responses evoked by submaximal high frequency stimulation of the sciatic nerve, and medullary and hypotahalamic pressor areas. Low frequency stimulation at these sites and in the cervical spinal cord evoked responses in the splanchnic nerve consiting of early and late components which were inhibited by clonidine and l-dopa. Piperoxan or yohimbine reversed these effects. It is suggested that α-adrenoreceptor activation at medullary and spinal sites exerts sympatho-inhibitory effects.

Administration of tubocurarine, pancuronium, gallamine, or decamethonium into the cisterna magna of chloralosed dogs induced a rise in blood pressure. Clonidine (3 micrograms/kg) administered into the cisterna magna after tubocurarine, pancuronium, or gallamine significantly increased blood pressure; no significant change was found after decamethonium. The pressor response to clonidine after tubocurarine was antagonized by injection of the alpha 1-adrenoceptor-blocking agents AR-C 239 or prazosin into the cisterna magna at low doses prior to injection of clonidine. Yohimbine, a preferential alpha 2-adrenoceptor-blocking agent was ineffective. It is suggested that the pressor response to intracisternal clonidine after intracisternal tubocurarine is due to stimulation of alpha 1-adrenoceptor stimulation.

Anaesthetized guinea-pigs were intoxicated with an intravenous infusion of ouabain. This infusion induced a marked pressor response which was reduced in bilaterally adrenalectomized or pithed animals. Ouabain produced initial bradyarrhythmias in 60% of guinea-pigs. Bilateral vagotomy or pretreatment with atropine abolished the bradyarrhythmias and sensitized the animals to the arrhythmic effects of ouabain. Pithing or beta-adrenoceptor blockade reduced the potency of ouabain for producing arrhythmias, but bilateral adrenalectomy did not give protection. Preferential alpha 2-adrenoceptor stimulation with clonidine (10-300 micrograms . kg-1 i.v.) also reduced the arrhythmogenic effects of ouabain, whereas no protection was found with St 91, a clonidine related compound which does not cross the blood-brain barrier. The effect of clonidine was antagonized by piperoxan. Preferential alpha 2-adrenoceptor blockade with piperoxan (6 mg . kg-1 i.v.) did not change the pressor response to ouabain, but sensitized the animals to the arrhythmogenic effects of ouabain. In contrast, the preferential alpha 1-antagonistic agent AR-C 239 (0.3 mg . kg-1 i.v.) abolished the pressor response to ouabain and in addition increased the dose of ouabain required to produced ventricular premature beats and ventricular fibrillation. These experiments indicate: (i) that ouabain produces in guinea-pigs a pressor response which seems to be due to catecholamine release from the adrenal medulla probably by an action on the central nervous system; (ii) that the ventricular arrhythmias induced by ouabain are due in part to stimulation of the central nervous system leading to an increase in beta-adrenoceptor activity; (iii) that central alpha-adrenoceptors appear to be involved in the arrhythmogenic effects of ouabain, as clonidine reduced these effects. On the other hand piperoxan, a preferential alpha 2-adrenoceptor antagonist did not change the pressor response to ouabain and increased the arrhythmogenic effects whereas AR-C 239 had opposite effects.

Intracerebroventricular (i.c.v.) injection of the 1,4-dihydropyridine (DHP) calcium channel agonist, Bay K8644 (30 micrograms/kg) increased mean blood pressure and the K+-evoked release of [3H]acetylcholine ([3H]ACh) from hippocampal slices in spontaneously hypertensive rats (SHR). The Bay K8644-induced hypertension was inhibited by a pretreatment with methylatropine (80 micrograms/kg i.c.v.). In SHR, nicardipine, a DHP calcium channel antagonist, reduced mean blood pressure when i.c.v. injected (10 micrograms/kg). The nicardipine-induced hypotension was reduced by a pretreatment with hemicholinium-3 (20 micrograms, i.c.v.). Nicardipine (1 microM) did not modify, in SHR, the K+-evoked release of [3H]ACh, but inhibited the Bay K8644-induced increase in the ACh release. In normotensive rats, neither Bay K8644 nor nicardipine modify blood pressure, when centrally injected, or the stimulated release of [3H]ACh from hippocampal slices. The participation of central DHP sites in the cholinergic transmission in genetic hypertension is discussed.

The stereoselectivity of central α 2 -adrenoceptors involved in sleep induced in chicks by clonidine, suggested by the results observed with the stereoisomers of idazoxan, was further investigated with the stereoisomers of(imidazolinyl-2)-2-dihydro-2,3-benzofurane (S9871) and those of (imidazolinyl-2)-2-benzocyclobutane (S 10089). As for the stereoisomers of idazoxan, there was not a good separation between the effects of the stereoisomers of S10089. In contrast, there was a clearcut separation between the effects of(+)S9871 (antagonist) and (−)S9871 (no effect against the action of clonidine). Therefore, these results strongly support the view that central α 2 -adrenoceptors which mediate sedation are stereoselective for α 2 -antagonists.

Intracerebroventricular (i.c.v.) injections of AR-C 239 (30 micrograms/kg), a selective alpha 1-adrenoceptor blocking drug, did not modify the heart rate in normotensive control (without pretreatment), bilaterally vagotomized and beta blocked rats and in spontaneously hypertensive (SH) bilaterally vagotomized rats. Intracisternal (i.c.) administrations of AR-C 239 (30 micrograms/kg) however decreased the heart rate in normotensive beta blocked and in SH bilaterally vagotomized rats. The differential effect on heart rate of i.c.v. versus i.c. administration of AR-C 239 suggests a brainstem localization of the alpha 1-adrenoceptors involved. The binding of [3H]prazosin was significantly higher in homogenates from whole brain and in membranes from the cerebral cortex and hypothalamus of SH rats as compared to normotensive rats. In addition, the binding of [125I]BE 2254, a new iodinated radioligand of high specific radioactivity used to characterize alpha 1-adrenoceptors, was significantly increased in membranes from the NTS of SH rats. These results suggest that central alpha 1-adrenoceptors localized in the brainstem and in the hypothalamus and the cortex play a role in the control of vagal tone in normotensive rats and of sympathetic activity in SH animals. Thus, it is postulated that central alpha 1-adrenoceptors may participate in either the genesis or the maintenance of genetic hypertension.

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.

Intracisternal administration of noradrenaline (10, 20, 150 μg) decreased blood pressure, heart rate and spontaneous and evoked splanchnic nerve discharges in anaesthetized intact and ‘de-buffered’ cats. I.v. administration of lower dose of noradrenaline (4 μg/kg) increased blood pressure and reduced heart rate and splanchnic discharges; de-afferentation prevented the decrease in heart rate and in splanchnic discharges. Higher doses induced a delayed phase of hypotension, bradycardia and decreased spontaneous and evoked splanchnic discharges in intact and ‘de-buffered’ cats, indicating a central sympatho-inhibitory effect.

1. The cardiovascular effects of morphine, fentanyl, [D-Ala2]-met-enkephalinamide were analyzed after intracisternal injection in anaesthetized rats. PaO2 was measured as an index of respiratory function. 2. At low doses in spontaneously breathing rats, morphine, fentanyl and [D-Ala2]-met-enkephalinamide induced a pressor response with slight tachycardia and no significant change in PaO2. 3. The pressor response appeared to be due to activation of opiate receptors and mediated through the sympathetic nervous system. 4. High doses of morphine and [D-Ala2]-met-enkephalinamide induced a biphasic effect with a secondary hypotension associated with bradycardia in spontaneously breathing rats. A marked reduction in PaO2 was found during the depressor phase. 5. High doses of [D-Ala2]-met-enkephalinamide produced only a pressor response in artificially-ventilated rats with no signs of secondary hypotension. 6. Our data support the idea that morphinomimetic agents are centrally pressor at low doses in the rat. The respiratory depression observed with high doses may be the cause of hypotension.

Microinjections of putative enkephalin releasors, veratridine (0.2 micrograms), L-Tyr-D-Arg (1 microgram) and physostigmine (1 microgram) into the nucleus ambiguus (NA) induced naloxone-reversible bradycardia in chloralosed dogs. In addition, microinjections of compounds known to inhibit enkephalin degradation: D-phenylalanine (10 micrograms), puromycin (20 ng), Gly-Gly-Phe-Met (0.5 micrograms), and captopril (20 ng) induced a naloxone-reversible bradycardia. These results are compatible with the view that an enkephalinergic mechanism is involved in the central vagal control of the heart. These experiments provide evidence that enkephalins are tonically released from nerve terminals located in the NA and that enkephalinase, amino-peptidase and possibly angiotensin I-converting enzyme, could be involved in their catabolism in vivo.

The present experiments served to compare the effects of the 3 5-HT1 agonists, 8-OH-DPAT, 5-MeODMT and TFMPP on the blood pressure and heart rate of normotensive anaesthetized rats. All the agonists induced, after i.v. injection, a decrease in blood pressure and heart rate. The hypotensive effects of 5-MeODMT and TFMPP were preceded by an increase, suppressed by both ketanserin and methysergide. The decrease in blood pressure induced by 5-MeODMT and 8-OH-DPAT was not antagonized by ketanserin, cocaine (and methysergide for 8-OH-DPAT) but was antagonized by methysergide (for 5-MeODMT) and spiroxatrine (for both). Bradycardia was not susceptible to ketanserin and cocaine (for 5-MeODMT) or to ketanserin and methysergide (for 8-OH-DPAT) but to methysergide and spiroxatrine (for 5-MeODMT) and cocaine and spiroxatrine (for 8-OH-DPAT). These results suggested that the hypotension and bradycardia induced by 5-MeODMT and 8-OH-DPAT are due to the stimulation of ‘5-HT1-like’ receptors and probably to the 5-HT1A subtype; the 5-MeODMT-induced hypertension being ascribed to the stimulation of 5-HT2 receptors.

Yohimbine (100 micrograms/kg), an alpha 2-adrenoceptor blocking agent when injected into the vertebral artery of anaesthetized dogs decreased the vagally mediated bradycardia induced by carotid sinus nerve stimulation. Intracisternal administration of phenylephrine (30 micrograms/kg) an alpha 1-adrenoceptor agonist decreased, whereas AR-C 239 (5 micrograms/kg) and prazosin (5 micrograms/kg) two potent alpha 1-adrenoceptor antagonists injected into the vertebral artery, potentiated the bradycardiac response. These results suggest the presence of two types of alpha-adrenoceptors to modulate the baroreceptor pathway: alpha 1-adrenoceptors inhibit and alpha 2-adrenoceptors facilitate the transmission of baroreceptor impulses.

In dogs, anaesthetized with chloralose, fentanyl (5 mug/kg i.v.) augmented the bradycardia produced by electrical stimulation of the carotid sinus nerves. In contrast, the same dose of the drug did not change the bradycardic response to stimulation of the nucleus of the solitary tract (NTS) indicating that a central facilitation of baroreceptor impulses occurs within the NTS, probably at the first synapse of baroreceptor reflex fibres. Bilateral destruction of the NTS caused a fulminating hypertension and tachycardia similar to that after cutting the baroreceptor afferent fibres. After both procedures, fentanyl (20 mug/kg i.v.) produced marked hypotension and bradycardia. The bradycardic effect was abolished by cutting both vagal nerves when the dogs were pretreated with a beta-adrenoceptor blocking agent (S 2395, 50 mug/kg i.v.). The results provide evidence that the NTS is not the main site of action either for the hypotensive effect or for the vagally mediated bradycardia of fentanyl. Since the dorsal nucleus of the vagal nerve was destroyed together with the NTS, this nucleus does also not appear to be a major site of the action of fentanyl. Blockade of dopamine receptors by haloperidol or pimozide or of serotonin receptors by methysergide did not change the hypotensive, bradycardic and sympathoinhibitory effects of fentanyl.

DOI (1–100 μg/kg i.v.) induced an increase in mean blood pressure in the anaesthetized rat. Similarly, in the pithed rat, DOI (1–100 μg/kg i.v.) induced a dose-dependent increase in mean blood pressure, as did 5-HT. However, in contrast to 5-HT, DOI did not change the heart rate in either intact or pithed rats. In the pithed rat, the dose-pressor response curves to both 5-HT and DOI were unaffected by MDL 72222 (5-HT 3 receptor antagonist), spiroxatrine or (±)-pindolol) (5-HT 1A receptor antagonists), idazoxan ( α 2 -adrenoceptor blocking agent) and AR-C 239 ( α 1 -adrenoceptor blocking agent). Only the selective 5-HT 2 receptor antagonist, LY 53857, significantly and dose dependently shifted to the right the dose-response curves to both 5-HT and DOI. These results indicated that DOI possesses 5-HT 2 agonistic properties and that the pressor response induced by DOI in the pithed rat is mediated via 5-HT 2 receptors.

Injections of 8-OH-DPAT (0.1-6 micrograms/kg) into the vertebral artery or into the cisterna magna (5 micrograms/kg) produced a dose-dependent decrease in blood pressure, heart rate and renal sympathetic nerve activity in intact anaesthetized dogs and baroreceptor-denervated dogs. 8-OH-DPAT reduced the renal sympathetic nerve activity without changing the blood pressure or heart rate in catecholamine-depleted animals. Methiothepin (0.2 mg/kg) injected into the vertebral artery reduced the blood pressure without changing the heart rate or renal sympathetic nerve activity in baroreceptor-denervated dogs. The pressor response to i.v. phenylephrine was largely attenuated. Subsequent administration of 8-OH-DPAT (3 micrograms/kg) into the vertebral artery failed to alter the sympathetic discharge. Methiothepin (0.2 mg/kg) injected into the vertebral artery reversed the sympatho-inhibitory effect of 8-OH-DPAT (3 micrograms/kg) injected by the same route without changing the blood pressure. (+/-)Pindolol (0.2 mg/kg) injected into the vertebral artery of baroreceptor-denervated dogs reduced the blood pressure and heart rate without changing renal sympathetic activity. Subsequent administration of 8-OH-DPAT (3 micrograms/kg) failed to alter the sympathetic discharge. Bilateral microinjection of 8-OH-DPAT (1 microgram) into the nucleus tractus solitarii or into the medullary raphe nuclei failed to alter the blood pressure, heart rate or renal sympathetic activity. In contrast, bilateral microinjections of 8-OH-DPAT into the ventrolateral pressor area (VLPA) (0.2 microgram) produced a marked decrease in blood pressure, heart rate and renal sympathetic nerve activity. These effects were prevented or reversed by microinjections of methiothepin (10 micrograms) at the same sites. These results indicate that the central sympatho-inhibitory effects of 8-OH-DPAT were due to the stimulation of 5-HT1A receptors located in the ventrolateral pressor area. 5-HT autoreceptors did not seem to be involved.

In anaesthetized and bilaterally vagotomized dogs, reflex bradycardia elicited by intravenous injection of noradrenaline was facilitated by AR-C 239, a new alpha 1-adrenoceptor blocking drug and inhibited by the alpha 2-adrenoceptor antagonist, yohimbine. Both alpha-blocking drugs were administered into the vertebral artery. In another group of bilaterally vagotomized dogs, unilateral electrical stimulation of the carotid sinus nerve induced a frequency-dependent decrease in mean blood pressure solely mediated through the sympatho-inhibitory component of the baroreflex. Administration of the alpha 1-adrenoceptor blocking drugs, AR-C 239 and prazosin (5 micrograms/kg) into the vertebral artery decreased basal mean blood pressure and increased depressor responses to the carotid sinus nerve stimulation, whereas the intracisternal injection of phenylephrine (30 micrograms/kg), a preferential alpha 1-agonist, increased mean blood pressure but inhibited the hypotension resulting from electrical stimulation. In addition, the injection into the vertebral artery of yohimbine (100 micrograms/kg), an alpha 2-adrenoceptor blocking agent which caused no change in mean arterial pressure, inhibited the decrease in the sympathetic component. In conclusion, these results suggest the possible participation of the two types of alpha-adrenoceptors in the modulation of the sympathetic component of the baroreflex: alpha 1-adrenoceptor stimulation could inhibit, whereas alpha 2-adrenoceptor activation facilitates the reflex activity in the sympathetic fibres.

In anaesthetized dogs, clonidien (10 μg/kg i.v.) increased the spontaneous firing of the carotid sinus nerve and decreased blood pressure and heart rate. After transection of the spinal cord, clonidine decreased heart rate and this bradycardia was abolished by selective baroreceptor denervation. Clonidine (1 μg/kg) injected into the vertebral artery of anaesthetized dorgs, pretreated with a β-adrenoceptor blocking agent (S 2395: 50 μg/kg i.v) potentiated the bradycardia induced by stimulation of the carotid sinus nerve but did not change the hypotension and bradycardia produced by stimulation of the nucleus tractus solitarius or of the nucleus ambiguus. In anaesthetized cats with bilateral destruction of nuclei tractus solitarii, clinidine (10 μg/kg i.v.) decreased blood pressure and heart rate. Clonidine (2 μg/kg), injected into the vertebral artery of anaesthetized dogs pretreated with a β-adrenergic blocking agent (S 2395: 50 μg/kg i.v.) or guanethidine, induced a bradycardia but the discharges of the carotid sinus nerve were not increased. Selective baroreceptor denervation abolished this bradycardia. In conclusion, these experiments provide direct evidence that the central facilitory effect of clonidine on baroreceptor impulses plays a role in the bradycardic effect of the drug. This facilitation is likely localised in the nucleus tractus solatrius at the first synapse of baroreceptor fibres. The vagally mediated bradycardia can be explained by an increased in baroreceptor discharges and by the central facilitation of baroreceptor impulses. The site of the hypotensive effect of clonidien did not seem to be localized in the nucleus tractus solitarius.

A technique for recording splanchnic discharges chronically, in conscious dogs is described. Two small stainless steel electrodes were inserted into the splanchnic nerves and secured with dental cement. The wires were passed under the skin and attached to plugs. With this technique intravenous clonidine was shown to decrease splanchnic discharges, to induce bradycardia and biphasic changes in blood pressure: an increase followed by a decrease. By peroral route the effects were the same, except that the initial hypertension did not occur. No tolerance to this effect of clonidine was seen during the 10 days treatment. The method appears to be valuable in disclosing centrally or reflexly mediated decreases in the sympathetic tone.

SUMMARY 1. Clonidine and three α-adrenoreceptor blocking agents were injected into the cisterna magna of rats, rabbits and dogs. Clonidine (1 μg. kg−1) induced a fall in blood pressure in the three species. 2. Phentolamine, tolazoline and phenoxybenzamine (100 μg. kg−1) induced a fall in blood pressure in rats, but only phentolamine was effective in rabbits, and none of these drugs significantly altered blood pressure in dogs when given intracisternally. 3. A subsequent administration of clonidine after recovery of blood pressure no longer decreased blood pressure in rats and rabbits. 4. In dogs the effects of clonidine were antagonized by tolazoline and phentolamine, but not by phenoxybenzamine. 5. These results indicate that clonidine stimulates central α-adrenoreceptors to produce a decrease in blood pressure, but the structure of these receptors may vary according to animal species.

In vagotomized dogs, lesions of the lateral reticular nucleus (LRN) region did not change arterial blood pressure and sympathetic nerve activity. The hypertensive and tachycardic responses elicited by section of both carotid sinus nerves and both vagus nerves were not altered. However the sympathoinhibitory component of the baroreflex arc was attenuated. These lesions also abolished the hypotensive and sympathoinhibitory effects of fentanyl (10 micrograms/kg i.v.). In debuffered dogs, bilateral lesions of the LRN regions attenuated the effects of fentanyl (20 micrograms/kg i.v.) on arterial blood pressure and splanchnic discharges. Microinfusion of naloxone into the LRN reduced the effects of fentanyl (10 micrograms/kg) administered intravenously. Microinfusion of [D-Ala2,Met5]enkephalinamide (0.1-1 microgram) into the LRN region produced a dose dependent decrease in arterial blood pressure and sympathetic nerve activity. Lesions of the nucleus ambiguus (NA) region also reduced the effects of fentanyl. In contrast, lesions placed in the ventral median reticular formation or above the NA were ineffective in changing the sympathoinhibitory effect of fentanyl. These results indicate that the lateral reticular formation ventral to the nucleus ambiguus including the lateral reticular nucleus region is involved in the sympathoinhibitory effect of morphinomimetic agents.

The purpose of the present study was to characterize the effects of mianserin at alpha 2-adrenoceptors. Firstly, the action of mianserin on postganglionic sympathetic fibres has been studied using the tachycardia induced by stimulation of the cardiac nerve in dogs. Mianserin increased this tachycardia, but could not prevent the inhibitory effect of clonidine in this model. However, an antagonistic effect of mianserin against clonidine was observed when animals were pretreated with desipramine. Secondly, mianserin antagonized the inhibitory effect of clonidine on the electrically stimulated guinea-pig ileum. In high concentrations, mianserin reduced both electrically and acetylcholine induced contractions. Thirdly, mianserin antagonised the sleep induced by clonidine in chickens. These results are consistent with alpha 2-adrenoceptor blocking properties of mianserin in peripheral noradrenergic fibres in dogs, in cholinergic fibres in guinea-pig ileum and in the central nervous system in chickens.

The alpha-adrenoceptor blocking properties of the two enantiomers of idazoxan have been investigated in rats, dogs and chicks, as well as their agonistic effects in pithed rats. At peripheral sites, (+) idazoxan was equipotent for blocking both postsynaptic alpha-1 and alpha-2 adrenoceptors of the rat and revealed to be a potent antagonist at presynaptic sites of rats and dogs. (-) Idazoxan revealed to be selective for postsynaptic alpha-2 adrenoceptors with an apparent selectivity ratio of about 10. This selectivity of (-) idazoxan was greater in vitro. (-) Idazoxan also antagonized presynaptic alpha-2 adrenoceptors of rats and dogs. At central sites, (+) and (-) idazoxan antagonized the hypotension, bradycardia, inhibition of sympathetic nerve activity induced by clonidine in rats and dogs and sedation induced by clonidine and azepexole in chicks. Although (+) idazoxan was more potent than (-) idazoxan, binding studies revealed (-) idazoxan to be more selective than (+) idazoxan at central sites. It is concluded that (+) idazoxan antagonizes both alpha-1 and alpha-2 adrenoceptors and (-) idazoxan is selective for alpha-2 adrenoceptors. In the pithed rat, only (-) idazoxan possesses both alpha-1 and alpha-2 agonistic effects. These results show little differences between the two enantiomers of idazoxan as for those of imidazoline derivatives.