Mechanism of ketanserin-induced sympatho-inhibition.

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

Permissive role of spinal alpha 1-adrenoceptors in sudomotor efferents

The electrodermal potential (EDP) recorded in the forepaws of anaesthetized cats in response to stimulation of the cholinergic-sympathetic nervous system at different levels was taken as a measure for sudomotor activity. Electrical stimulation of the hypothalamus with square wave pulses (1 ms duration, 0.5-64 Hz, 2 s train length) at intervals of 1 min induced rate-dependent EDPs which were inhibited at all rates of stimulation by intravenous (i.v.) injection of doses less than 40 micrograms/kg of the alpha 1-adrenoceptor blocking drug prazosin. However, prazosin (50-500 micrograms/kg i.v.) did not impair EDPs induced by preganglionic stimulation (0.5-64 Hz) or by injection of the nicotinic ganglion stimulant DMPP (50 micrograms/kg i.v.). Prazosin (50 micrograms/kg i.v.) inhibited EDPs induced by unilateral electrical stimulation (square wave pulses, 1 ms duration, 16 Hz, 2 s train length, 1 min intervals) of the spinal cord at C 1 in cats with an axotomy at the level of the medulla oblongata, thus indicating a spinal site of prazosin action and suggesting a permissive role of spinal catecholamines by activation of alpha 1-adrenoceptors. In spinal preparations pretreated with 250 micrograms/kg yohimbine i.v. to block inhibition by alpha 2-adrenoceptors of catecholamine reuptake, cocaine 2.5 mg/kg i.v. potentiated EDPs induced by spinal stimulation with 8 Hz. This effect could be antagonized by 50 micrograms/kg prazosin or 1000 micrograms/kg corynanthine i.v. In spinal preparations pretreatment with 5 mg/kg reserpine i.p. for depletion of catecholamines and 250 micrograms/kg yohimbine i.v., EDPs (16 Hz) were smaller than in undepleted preparations. Under these conditions injection of 100 micrograms/kg clonidine i.v. caused amplification of EDPs. This effect was antagonized by 50 micrograms/kg prazosin i.v. After i.v. pretreatment with 250 micrograms/kg yohimbine the i.v. injection of 2.5 mg/kg cocaine also potentiated EDPs which were induced by hypothalamic stimulation in intact cats. The results indicate that catecholaminergic neurons influence sudomotor activity by interaction with efferents of the cholinergic-sympathetic nervous system at the level of the spinal cord. Catecholamines seem to facilitate impulse transmission in non-catecholaminergic synapses by activation of alpha 1-adrenoceptors.     

Effect of prazosin on spontaneous sympathetic-cholinergic activity

Tonic sympathetic-cholinergic electrodermal (sudomotor) activity was measured in intact anesthetized and unanesthetized decerebrate and decerebrate-spinalized cats. Prazosin (3-100 micrograms/kg i.v.) depressed spontaneous electrodermal activity in intact anesthetized cats in a dose-dependent fashion (ED50 4.8 micrograms/kg). Prazosin's action was almost totally abolished by monoamine depletion with reserpine and a synthesis inhibitor. The alpha 2-adrenoceptor blocker, yohimbine (0.5 mg/kg i.v.) also antagonized prazosin-induced sympatho-inhibition. Prazosin reduced tonic sudomotor activity in unanesthetized decerebrate cats in a dose-dependent fashion (ED50 5.5 micrograms/kg i.v.) but was without effect in spinalized preparations. These results support the hypothesis that, in this system, prazosin produces sympatho-inhibition indirectly by means of an alpha 2-adrenoceptor-mediated mechanism, an effect which appears to be prejunctional. It is proposed that prazosin acts at the level of the spinal cord to facilitate ongoing alpha 2-adrenergic inhibition arising from supra-spinal loci.     

A quantitative assessment of CNS sympatho-inhibition produced by psychotropic drugs

As one index of sympathetic reactivity, electrodermal responses (EDR) were evoked from central (hypothalamic) and peripheral (ulnar nerve) sites in pentobarbital-anesthetized cats. When compared with intravenous chlorpromazine (ED₅₀ ～ 1.0 mg/kg), only thioridazine, trifluoperazine and pimozide were less potent than chlorpromazine in reducing the amplitude of these centrally-evoked sympathetic-cholinergic responses. Perphenazine and methotrimeprazine (a non-neuroleptic phenothiazine) were about twice as potent as chlorpromazine. Haloperidol and triflupromazine were about 5 times as potent and chlorprothixine was more than 10 times as potent. None of these agents reduced the peripherally-evoked electrodermal response, indicating a CNS mode of action. Diazepam was without effect at either site. In addition, pretreatment with yohimbine (0.5 mg/kg, i.v.) did not significantly alter the ED₅₀ for any of the above drugs. These results demonstrate that all of the phenothiazines and non-phenothiazine neuroleptics tested produced a dose-dependent central sympatho-inhibition and that diazepam does not. The results also suggest that there is no significant correlation between central symphatho-inhibition and the antipsychotic potency of these compounds and that their depression of central sympathetic outflow is independent of α-adrenergic mechanisms in the CNS.     

Studies on the mechanism of clonidine-induced mydriasis in the rat

Intravenous administration of clonidine hydrochloride (3-100 micrograms/kg) produced a dose-dependent pupillary dilation in anaesthetized rats. All experiments were carried out in rats in which vagosympathetic nerve trunks were sectioned bilaterally at the cervical level. Clonidine-induced mydriasis was present only in those preparations having intact parasympathetic neural tone to the iris. Depletion of CNS monoamines by more than 95% with reserpine (5 mg/kg) and alpha-methyl-para-tyrosine (2 X 300 mg/kg) failed to alter the dose-response relation to clonidine. Pretreatment with the alpha-2-adrenoceptor antagonist, yohimbine hydrochloride (1.5 mg/kg), produced about a 10-fold shift to the right in the pupillary dose-response curve to clonidine. Yohimbine administered after the highest dose of clonidine also antagonized the mydriatic response. The above results suggest that clonidine acts on CNS post-synaptic alpha-2-adrenoceptors to produce mydriasis by withdrawal of parasympathetic neural tone to the iris. In an attempt to assess the physiological substrate(s) involved, mydriatic responses, due to parasympatho-inhibition, were evoked by electrical stimulation of ascending (sciatic nerve and medullary) and descending (hypothalamic) pathways. Yohimbine (0.3 and 1.0 mg/kg) produced a dose-dependent inhibition of the pupillary dilation evoked by stimulation of the sciatic nerve and medullary loci, whereas these doses of yohimbine failed to alter the dilation in response to hypothalamic stimulation. Similarly, monoamine depletion greatly antagonized the pupillary dilation elicited by sciatic nerve and medullary stimulation without significantly affecting mydriasis due to hypothalamic stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition of a peripheral sympathetic-cholinergic system by presynaptic α2-adrenoceptors

Summary Intravenous administration of catecholamines produced dose-related inhibition of electrodermal responses (EDRs) evoked by electrical stimulation of the post-ganglionic sciatic nerve in anaesthetized rats, with relative potencies being (–)-adrenaline > (±)-adrenaline > (–)-noradrenaline = (+)-adrenaline. The suppression of EDRs by (±)-adrenaline and (–)-noradrenaline was blocked by pretreatment with yohimbine (0.75 mg/kg i.v.) but not by prazosin (0.3 mg/kg i. v.). The selective ₂-adrenoceptor agonist B-HT 920 also inhibited neurally evoked skin potential responses. This effect of B-HT 920 was antagonized by the selective ₂-adrenoceptor antagonist idazoxan (0.1 mg/kg i. v.) but was insensitive to prazosin. Idazoxan was more potent than yohimbine in blocking (±)-adrenaline-induced suppression of EDRs. Methacholine administered into the femoral artery evoked EDRs by an atropine-sensitive mechanism. Methacholine-induced EDRs were not suppressed by intravenous administration of (–)-adrenaline (1 g/kg or 3 g/ kg) whereas EDRs evoked by the sciatic nerve stimulation on the other hindpaw were inhibited. Increase in the endogenous catecholamines by asphyxia strongly inhibited EDRs by a mechanism which was also sensitive to yohimbine but not to prazosin. These results suggest that peripheral presynaptic ₂-adrenergic mechanisms are involved in inhibition of transmitter release in this sympatheticcholinergic system. Send offprint requests to M. C. Koss     

Effects of clonidine and chlorpromazine on a sympathetic-cholinergic reflex

Intravenous administration of clonidine and chlorpromazine resulted in a dose-dependent inhibition of the amplitude of reflexly evoked electrodermal responses in intact and spinal cats. Yohimbine pretreatment (0.5 mg/kg, i.v.) antagonized the effects of clonidine but not chlorpromazine in both preparations. These findings confirm and expand previous observations that both clonidine and chlorpromazine inhibit the amplitude of centrally evoked responses in this sympathetic-cholinergic system. In addition, both drugs appeared to have a spinal site of action. The antagonism of the effects of clonidine by yohimbine suggests that the mechanism of the action of clonidine may be a result of activation of central inhibitory alpha-adrenergic receptors. The failure of yohimbine to antagonize the effects of chlorpromazine suggests that clonidine and chlorpromazine may depress these sympathetic reflexes by different mechanisms.     

PRESYNAPTIC DOPAMINE RECEPTORS MEDIATE THE INHIBITORY ACTION OF DOPAMINE AGONISTS ON STIMULATION-EVOKED PRESSOR RESPONSES IN THE RAT

1 The effects of the dopamine agonists TL-99, M-7 (N, N-dimethyl analogues of aminotetralins) and N, N-din propyldopamine (NNPD) on stimulation-evoked pressor responses and tachycardia in pithed Sprague-Dawley rats were investigated when pressor responses to the compounds per se had subsided. Various antagonists were used to characterise the effects of the dopamine agonists. 2 M-7 (3 μg/kg i.v.) and NNPD (1 mg/kg i.v.), but not TL-99 (1–30 μg/kg i.v.), inhibited pressor responses evoked by low frequency electrical stimulation of the spinal cord in the pithed rat. 3 M-7 (3 μg/kg i.v.), but neither NNPD (1 mg/kg i.v.) nor TL-99 (1–30 μg/kg), inhibited tachycardia evoked by low frequency electrical stimulation of the spinal cord in the pithed rat. 4 The inhibition of stimulation-evoked pressor responses by M-7 and NNPD was prevented by pimozide, metoclopramide and sulpiride but not by yohimbine, atropine, cimetidine or propranolol. 5 The inhibition of stimulation-evoked tachycardia by M-7 was prevented by yohimbine (and to a certain extent by sulpiride) but not pimozide, metoclopramide, atropine or cimetidine. 6 Pressor responses elicited by TL-99, M-7 and NNPD were selectively antagonised by yohimbine, but not by prazosin, indicating that these responses were mediated by stimulation of vascular postsynaptic α₂-adrenoreceptors. 7 This study demonstrates that, in the rat, presynaptic dopamine receptors exist on sympathetic pre- or postganglionic nerve endings to blood vessels, but not on sympathetic pre- or postganglionic nerve endings to the heart, where inhibition by M-7 of stimulation-evoked tachycardia is mediated by stimulation of presynaptic α₂-adrenoreceptors.     

Analysis of CNS sympatho-inhibition produced by guanabenz

The effects of guanabenz on several autonomic systems were observed in vagotomized, anesthetized cats with the aim of determining, in a quantitative sense, the degree to which guanabenz produces a clonidine-like central nervous system action. Guanabenz given as a single dose (50 μg/kg i.v.) produced a transient hypertension associated with a more sustained bradycardia and depression of centrally (hypothalamic) evoked electrodermal responses (EDR). Increasing cumulative doses of guanabenz (3–1000 μg/kg i.v.) also resulted in a dose-related depression of EDR amplitude, transient hypertension followed by hypotension, sustained bradycardia, and mydriasis. All responses were antagonized by pretreatment with yohimbine (0.5 mg/kg i.v.). The ED₅₀ for depression of the centrally evoked EDR was in the range of 50–100 μg/kg i.v. in the non-pretreated preparations. Guanabenz (100 μg/kg i.v.) was shown to be devoid of significant ganglionic blocking properties. These experiments suggest that guanabenz acts like clonidine in the CNS and that an α₂-adrenergic inhibitory mechanism is involved in its myriad of central autonomic effects.     

Possible role of alpha 1- and alpha 2-adrenoceptors in the modulation of the sympathetic component of the baroreflex

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.     

Spinal facilitation in cholinergic-sympathetic efferents by desipramine

Summary Electrodermal potentials (EDPs) evoked by electrical stimulation of the cholinergic-sympathetic system at different levels were recorded in the forepaws of anaesthetized cats and used as a measure of sudomotor activity. After pretreatment with yohimbine (0.25 mg/kg i.v.) to block ₂-adrenoceptors, unilateral electrical stimulation of the hypothalamus (square wave pulses 1 ms duration, 16 Hz, 2 s train length at intervals of 1 min) induced EDPs in both forepaws. Injection of the inhibitor of neuronal catecholamine reuptake, desipramine (1 mg/kg i.v.), facilitated the EDPs in both forepaws, even though access of the drug to the sweat glands was prevented by application of a tourniquet to one paw. The facilitation was abolished by injection of the specific ₁-adrenoceptor antagonist, prazosin (0.5 mg/kg i.v.). An equal enhancement of this effect by desipramine (1 mg/kg i.v.) and its abolition by prazosin (0.5 mg/kg i.v.) was obtained in cats with the brain stem transected at the level of the medulla oblongata and electrical stimulation of the spinal cord at C1. EDPs evoked in the right forepaw by preganglionic electrical stimulation of the right stellate ganglion were inhibited by desipramine (1 mg/kg i.v.).From these and previous results it is concluded that inhibition of neuronal reuptake of catecholamines results in facilitation of activity in sudomotor efferents. This effect is mediated by spinal ₁-adrenoceptors and provides an explanation of the occasional occurrence of excessive sweating in psychiatric patients treated with tricyclic antidepressants.     

Use of a sympathetic-cholinergic system in the analysis of sympatho-inhibition produced by clonidine and some congeneric derivatives of clonidine

The effects of clonidine and five analogs of clonidine were tested with regard to their ability to depress centrally and peripherally evoked electrodermal responses (EDR) in control cats, as well as in animals pretreated with yohimbine hydrochloride. With the exception of St-91, all of the clonidine-like substances selectively reduced the amplitude of centrally (hypothalamic) evoked responses in a dose-dependent fashion. Clonidine was found to have no significant inhibitory effect at the level of the sympathetic ganglion. The order of central nervous system sympatho-inhibitory potency of these compounds was clonidine (St-155) greater than St-375 greater than St-606 greater than St-600 greater than St-608 much much greater than St-91. Prior treatment with yohimbine hydrochloride (0.5 mg/kg i.v.) antagonized the depressant effect of all of these drugs. These results indicate that clonidine and the clonidine congeners tested (with the exception of St-91) all produce sympatho-inhibition by an action on a CNS alpha-adrenergic mechanism and demonstrate the usefulness of this electrodermal model system for the analysis of drugs affecting central sympathetic reactivity.     

Vasoactive responses of a human cystic artery: adrenoceptor characterization.

1. The pharmacology of various agonists and antagonists was studied in the human isolated cystic artery. 2. The estimated pA2s for the alpha 1-adrenoceptor antagonist prazosin against the alpha-adrenoceptor agonists phenylephrine, alpha-methylnoradrenaline and noradrenaline were not significantly different. Similar results were seen for estimated pA2s of the alpha 2-adrenoceptor antagonist yohimbine against these same agonists. Equivalent responses to exogenous noradrenaline and to transmural electrical stimulation were blocked to the same degree by an antagonist with alpha 1-adrenoceptor blocking properties (prazosin). Responses to transmural electrical stimulation, however, tended to be more resistant than equivalent responses to exogenous noradrenaline to blockade by antagonists with alpha 2-adrenoceptor blocking properties (phentolamine, yohimbine). 3. Relaxation to isoprenaline was observed in partially contracted arterial strips using isoprenaline concentrations of up to 10(-6) M, but cumulative addition of higher concentrations of isoprenaline sometimes then evoked a contraction from the relaxation nadir. The relaxation effect of isoprenaline was antagonized by propranolol (10(-5) M). 4. These findings suggest the human cystic artery has almost exclusively alpha 1-adrenoceptors postjunctionally, although prejunctional alpha 2-adrenoceptors may be present; and, it also has some postjunctional beta-adrenoceptors which mediate relaxation.     

The antinociceptive effect of FR140423 in mice: involvement of spinal alpha(2)-adrenoceptors

We investigated the role of the spinal noradrenergic system in the antinociceptive effect of FR140423, 3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)phenyl]py razole, by using the tail-pinch test in mice and various adrenoceptor antagonists. The antinociceptive effect of FR140423 injected i.t. was completely abolished by co-administration of the non-selective alpha-adrenoceptor antagonist phentolamine and the alpha(2)-adrenoceptor antagonist yohimbine but not by the alpha(1)-adrenoceptor antagonist prazosin or the beta-adrenoceptor antagonist propranolol. Oral administration of FR140423, at doses of 5-80 mg/kg, produced a dose-dependent antinociceptive effect with an ED(50) value of 19 mg/kg. This antinociception was abolished by i.t., but not i.c.v., injection of phentolamine and yohimbine (10 microg/mouse). These results suggest that alpha(2)-adrenoceptors in the spinal cord are involved in the antinociceptive effect of FR140423 against mechanical noxious stimulus as they are in the effect of morphine and clonidine.     

Alpha-1A adrenoceptors modulate potentiation of spinal nociceptive pathways in the rat spinal cord in vitro.

The rat hemisected spinal cord preparation was used to assess the role of different adrenoceptor subtypes on the modulation of nociceptive reflexes. These were elicited by trains of high intensity electrical stimuli delivered to a lumbar dorsal root. Responses were recorded from the corresponding ventral root in AC- and DC-amplification modes simultaneously.Superfusion of noradrenaline produced a potentiation of action potential firing (AC channel) as well as a depression of the cumulative depolarisation (DC channel) in responses to repetitive afferent stimulation.Noradrenaline-induced potentiation of firing was mimicked by the alpha1A-adrenoceptor agonist A 61603 and the alpha1-adrenoceptor agonist methoxamine in a reversible and concentration-dependent manner. The order of potency of these agonists was A61603>noradrenaline>methoxamine. The alpha(1A)-adrenoceptor antagonist 5-methyl-urapidil and the alpha1-adrenoceptor antagonist corynanthyne blocked the excitatory effects of noradrenaline. In contrast, the alpha(1B/D)-adrenoceptor antagonists chloroethylclonidine and BMY 7378 failed to block this effect.Noradrenaline-induced depression of cumulative depolarisation was mimicked by the alpha2-adrenoceptor agonist UK 14,304. In addition, this compound produced inhibition of firing in responses to afferent stimulation.These results show that noradrenaline has bi-directional modulatory effects on nociceptive reflexes and indicate that selective activation of alpha1A- but not alpha1B/D-adrenoceptors mediate potentiation of spinal nociceptive reflexes.     

Characterization of alpha-adrenoceptors mediating sympathetic vasoconstriction in rat autoperfused hindlimb: effects of SK&F 104078

In the autoperfused hindlimb of pithed rats, vasoconstrictor responses to intra-arterial infusions of the selective alpha 2-adrenoceptor agonist, B-HT 933, were antagonized by the alpha 2-adrenoceptor antagonist, rauwolscine (1 mg/kg i.v.), and by the selective postjunctional alpha 2-adrenoceptor antagonist, SK&F 104078 (1 mg/kg), but not by the selective alpha 1-adrenoceptor antagonist, prazosin (0.1 mg/kg). In contrast, responses to the selective alpha 1-adrenoceptor agonist, methoxamine, were antagonized by prazosin, but not by rauwolscine or SK&F 104078. Vasopressor responses to stimulation of sympathetic nerves were inhibited by prazosin, increased by rauwolscine, and not affected by SK&F 104078. The results indicate that vascular neuroeffector transmission in rat hindlimb is mediated by postjunctional alpha 1-adrenoceptors, and that SK&F 104078 is a selective antagonist of postjunctional alpha 2-adrenoceptor, and lacks the prejunctional alpha 2-adrenoceptor antagonist action of rauwolscine.     

Vascular actions of MDMA involve alpha1 and alpha2-adrenoceptors in the anaesthetized rat

We have investigated the effects of methylenedioxymethamphetamine (MDMA, 'ecstasy'), i.v., on diastolic blood pressure (DBP) in pithed and pentobarbitone anaesthetized rats. In pithed rats, the non-selective 5-HT receptor antagonist methiothepin (0.1 mg kg(-1)) and the alpha2-adrenoceptor antagonists methoxyidazoxan and yohimbine (1 mg kg(-1)) showed significant alpha1-adrenoceptor antagonist potency, but methiothepin did not show alpha2-adrenoceptor antagonist potency. MDMA (1 and 5 mg kg(-1)) produced pressor responses which were significantly reduced by the alpha(1)-adrenoceptor antagonist prazosin (0.1 mg kg(-1)), yohimbine (1 mg kg(-1)) or methiothepin (0.1 mg kg(-1)), but not by the 5-HT2 receptor antagonist ritanserin (1 mg kg(-1)). In anaesthetized rats, antagonists revealed two phases with three components to the effects of MDMA (5 mg kg(-1)) on DBP: an initial pressor response, a later pressor component at 1 min, the sustained depressor response. Methoxyidazoxan, methiothepin or the combination ritanserin/prazosin significantly reduced the initial pressor response, although neither of the latter compounds alone had any effect. The pressor response to MDMA (5 mg kg(-1)) at 1 min was converted to a depressor response by prazosin and to a lesser extent methiothepin and methoxyidazoxan. The depressor response to MDMA (5 mg kg(-1)) was significantly reduced by methoxyidazoxan (0.1 mg kg(-1)), and by the noradrenaline re-uptake blocker cocaine 10 mg kg(-1) but not 1 mg kg(-1). However, the most marked reduction in the depressor response was produced by the combination of methoxyidazoxan and cocaine. It is concluded that the initial pressor response to MDMA (5 mg kg(-1)) in anaesthetized rats involves alpha2- and possibly alpha1-adrenoceptors and 5-HT2 receptors, the pressor component at 1 min is largely alpha1-adrenoceptor mediated, and the sustained depressor response involves alpha2-adrenoceptors.     

alpha-Adrenoceptor blocking properties of raubasine in pithed rats.

1 Raubasine was compared with yohimbine and corynanthine in pithed rats. Antagonist activity at alpha 1-adrenoceptors was evaluated on the pressor response to electrical stimulation of the spinal sympathetic outflow and to phenylephrine administration, both being reduced by raubasine in the dose range 1 to 4 mg/kg. Corynanthine was quantitatively similar, but yohimbine was not only less potent but also in doses of 0.125 to 0.5 mg/kg enhanced the effects of electrical stimulation. 2 Antagonist activity at alpha 2-adrenoceptors was determined against the inhibitory effects of clonidine on tachycardia induced by electrical stimulation of cardiac sympathetic nerves and against the pressor responses to B-HT-933 injection. Raubasine up to 4 mg/kg, like corynanthine, did not affect the pressor responses to B-HT-933 nor did it reduce the inhibitory effect of clonidine. By contrast yohimbine reduced the response to BHT-933 and antagonized clonidine as well as enhancing the tachycardia caused by electrical stimulation. 3 The results indicate that, in vivo, raubasine, like corynanthine, is a selective antagonist at alpha 1-adrenoceptors and that yohimbine is more potent in blocking alpha 2-than alpha 1-adrenoceptors.     

The alpha 2-adrenoceptor selectivities and haemodynamic effects of WY26392 and yohimbine in the anaesthetised dog

The selectivities of WY26392 and yohimbine for prejunctional alpha 2-adrenoceptors have been evaluated in the anaesthetised dog. Clonidine inhibited the tachycardia evoked by cardiac sympathetic nerve stimulation, WY26392 and yohimbine reversed this effect by 50% at doses of 3.3-12 and 7.5-69.5 micrograms/kg respectively, depending upon the frequency of nerve stimulation. The alpha 1-adrenoceptor agonist phenylephrine evoked a pressor response which was reduced by 50% following approximately 1.0 mg/kg of either antagonists. Due to its greater potency at alpha 2-adrenoceptors, WY26392 consistently exhibited a greater selectivity than yohimbine for this receptor. The haemodynamic evaluation of WY26392 and yohimbine revealed that low doses of these compounds (0.03-0.1 mg/kg i.v.) increased systolic blood pressure, heart rate and dp/dtmax. WY26392 evoked a small rise in diastolic blood pressure over this dose range. These increases may be due to an increase in sympathetic nerve activity resulting from alpha 2-adrenoceptor blockade. Higher doses of these compounds reduced these cardiovascular parameters, possibly as a result of alpha 1-adrenoceptor blockade.     

Alpha 1-adrenoceptor antagonist activity of novel pyrimidine derivatives (SHI437 and IK29) in rabbit aorta and trigone of the bladder.

1. In the rabbit isolated aorta and trigone of the bladder, noradrenaline, phenylephrine and clonidine elicited concentration-dependent contractions, which may be caused through activation of postsynaptic alpha 1-adrenoceptors. 2. SHI437, IK29, prazosin and yohimbine competitively antagonized the contractile responses induced by noradrenaline in the aorta and trigone. The pA2 values of SHI437, IK29, prazosin and yohimbine were 7.35 +/- 0.09, 7.47 +/- 0.10, 8.55 +/- 0.02 and 6.28 +/- 0.05 in the aorta, and 8.07 +/- 0.04, 8.30 +/- 0.03, 8.22 +/- 0.04 and 6.46 +/- 0.04 in the trigone, respectively. 3. SHI437, IK29, prazosin and yohimbine also possessed competitive alpha 2-adrenoceptor blocking properties, judging from their antagonism of the clonidine-induced inhibitory effect on the twitch responses in the electrically stimulated vas deferens of the rat. The pA2 values of SHI437, IK29, prazosin and yohimbine were determined to be 4.76 +/- 0.02, 4.74 +/- 0.02, 5.06 +/- 0.03 and 7.86 +/- 0.04, respectively. 4. SHI437, IK29 and prazosin inhibited the contractile responses elicited by transmural electrical stimulation without affecting the evoked 3H-overflow from the [3H]-noradrenaline-preloaded rabbit aorta. Yohimbine augmented the contractile responses and 3H-overflow. 5. SHI437 and IK29 at a concentration sufficient to inhibit noradrenaline-induced contraction failed to attenuate the contractile responses of aorta to KCl, 5-hydroxytryptamine and prostaglandin F2 alpha, and of the trigone to acetylcholine and histamine. 6. The present results suggest that SHI437 and IK29 are highly selective alpha 1-adrenoceptor antagonists, especially in the trigone of the bladder.