Effects Of Idazoxan Research Articles

Differential modulation of (+)-amphetamine-induced rotation in unilateral substantia nigra-lesioned rats byα 1 as compared toα 2 agonists and antagonists

In rats sustaining unilateral 6-hydroxy-dopamine lesions of the substantia nigra (SN), the indirect dopaminergic agonist, (+)-amphetamine (AMPH), dose-dependently induced robust, ipsilateral rotation: this could be dose-dependently abolished by the dopamine (D 2/D 1) antagonist, haloperidol. The selectiveα 1 antagonist, prazosin, dose-dependently attenuated the action of AMPH though rotation was not completely abolished. In the presence of a constant dose of prazosin, the dose-response curve for induction of rotation by AMPH was shifted to the right. The action of prazosin was mimicked by a furtherα 1 antagonist, corynanthine. In contrast, the selectiveα 1 agonist, ST 587, potentiated the rotation evoked by AMPH. The selectiveα 2 antagonist, dose-dependently potentiated the action of AMPH and, in the presence of a constant dose of idazoxan, the dose-response curve for AMPH was shifted to the left. This effect of idazoxan was mimicked by a furtherα 2 antagonist, yohimbine. In distinction, the selectiveα 2 agonist, UK 14,304, dose-dependently attenuated the action of AMPH, an action mimicked by theα 2 partial agonist, clonidine. Upon administration alone, the above mentioned drugs did not induce rotation. The data indicate that activation and antagonism ofα 1 receptors enhance and inhibit rotation, respectively, whereas activation and antagonism ofα 2 receptors inhibit and enhance rotation, respectively. These findings demonstrate an oppositeα 1 andα 2 receptor-mediated control of rotation in this model. They suggest that an increase and decrease in noradrenergic tone, respectively, facilitate and inhibit locomotor activity controlled via the nigro-striatal dopaminergic pathway. The possible relevance of these findings to Parkinson's disease is discussed.

Extracellular brain cortical levels of noradrenaline in ischemia:

Using microdialysis, extracellular noradrenaline (NA) levels in the rat cerebral cortex were studied under isoflurane/N2O anaesthesia before, during and for 6 hours following 10 min of forebrain ischemia in a 2-vessel occlusion model. A microdialysis probe was introduced into the parietal cortex and dorsal hippocampus in anaesthetized rats and continuously perfused with Krebs-Ringer-bicarbonate buffer with or without the NA uptake inhibitor desipramine (DMI, 5 microM). Twenty min fractions were collected and the extracellular NA levels were measured in the dialysates using HPLC with electrochemical detection. The basal NA concentration in the dialysate was 10.5 +/- 1.8 (mean +/- SEM) pg/20 min fraction and increased to 39.3 +/- 4.8 pg/20 min fraction after local administration of DMI. During ischemia, NA increased to 38 times the basal level without DMI, and 6 times with DMI included during two hours' perfusion prior to ischemia. After recirculation NA levels returned to, or even transiently decreased below, preischemic values. With DMI present in the dialysis buffer, administration of idazoxan immediately following ischemia delayed the return to preischemic NA levels in the recirculation phase. In the absence of DMI, no effect of idazoxan on postischemic levels of NA was found. Local administration of DMI increases basal extracellular NA levels and reduces the ischemia-induced NA release. The latter effect may be a due to inhibition of the NA uptake system working in a reversed mode, or as a result of decreased synthesis of NA due to activation of presynaptic alpha 2-receptors by the increased synaptic NA levels. Postischemic treatment with the alpha 2-adrenoceptor antagonist idazoxan in combination with DMI prolongs the period of elevated extracellular NA levels, which may be of importance for the protective properties of idazoxan against ischemic cell injury.

Ventral Horn Neuropeptides Modulate the Release of Noradrenaline from Tissue Slices of Rat Brainstem and Ventral Thoracic Spinal Cord

The release of endogenous noradrenaline (NA) from slices of adult rat brainstem and ventral thoracic spinal cord was investigated using a fixed-volume incubation technique and HPLC with electrochemical detection. Incubation with potassium (15-50 mM) produced a dose-related increase in basal NA release that was calcium dependent. The potassium-evoked release of NA from spinal cord or brainstem slices was potentiated according to dose by preincubation with either (a) the selective alpha 2-adrenoceptor antagonist idazoxan (10(-6)-10(-4) M) or (b) the thyrotrophin-releasing hormone (TRH) analogue RX 77368 (pGlu-His-3,3'-dimethyl ProNH2; 10(-5) and 10(-4) M). Incubation of spinal cord slices with the NA uptake inhibitor maprotiline (1 microM) enhanced the effect of idazoxan but inhibited that of RX 77368. The effects of RX 77368 and potassium alone (15 mM) on NA release from both spinal cord and brainstem slices were reduced to basal levels with tetrodotoxin (10(-7) M). Similarly, preincubation of spinal cord, but not brainstem, slices with the insect neuropeptide proctolin (10(-4) M) significantly attenuated the potassium- or RX 77368-induced release of NA, whereas substance P (3 X 10(-5) and 1 X 10(-4) M) had no effect on either tissue. These results suggest that changes in NA release in the spinal cord and brainstem may mediate some of the actions of neuropeptides in ventral spinal cord, although the peptides may not be acting directly on the noradrenergic nerve terminals in these tissues.

Effects of idazoxan on 5-hydroxytryptamine-mediated behaviour in the mouse and rat

The α(2)-adrenoceptor antagonists idazoxan and RX811059 induced reciprocal forepaw treading, a component of the 5-HT-behavioural syndrome in rats. This response is independent of 'non-α(2)-adrenoceptor idazoxan binding sites' (NAIBS) at which RX811059 is inactive. Idazoxan pre-treatment, in rats, enhanced forepaw treading, head weaving and tremor induced by the 5-HT agonist 5-methoxy-N,N dimethyltryptamine (5-MeODMT), increased head twitches (but decreased hindlimb abduction) induced by the 5-HT releaser p- chloroamphetamine (pCA), but did not clearly alter head twitches induced by the 5-HT precursor L-5-hydroxytryptophan in mice. The α(1)-antagonist prazosin did not alter behaviour induced by either 5-MeODMT or pCA in rats. The α( 2)-agonist, guanoxabenz, did not alter 5-MeODMT-induced behaviour in rats. St587, an α(1)-agonist, selectively potentiated tremor induced by 5-MeODMT, but no other behaviour. A possible mechanism for these interactions could be through enhanced, α(2)-adrenoceptor-mediated, 5-HT release in specific brain areas. Other possibilities, e.g. direct action at subtypes of 5-HT receptors and the importance of these NA-5-HT interactions in the treatment of resistant depression, are discussed.

The effects of the α2-adrenoceptor antagonist idazoxan on sleep in normal volunteers

The effects of idazoxan, a novel antidepressant that is a potent and selective α(2)-adrenoceptor antagonist, were studied on sleep. Twelve normal male volunteers had sleep recordings made using the Oxford ambulatory system (Medilog 9000) with subsequent analysis by automatic sleep staging and visual inspection. Idazoxan was given in a dose of 40 mg three times a day for 21 days. Sleep recording on day 3 demonstrated markedly reduced indices of rapid eye movement (REM) sleep, although other sleep parameters were only minimally affected. The effect on REM persisted unchanged at day 18, however on the second day after withdrawal a rebound in REM measures was observed. These data show that idazoxan has an effect on sleep which is very similar to that of other antidepressants, and emphasize a role for noradrenaline in the regulation of REM sleep.

Evidence for functional separation of alpha-1 and alpha-2 noradrenaline receptors by pre-synaptic terminal re-uptake mechanisms

Information transfer within the central nervous system is predominantly chemical in nature, and occurs both through synaptic specialisations and non-specific diffuse release. The localisation and description of receptors for these two types of neurotransmission is currently a contentious issue. In the present study, the noradrenaline reuptake inhibitor cocaine has been shown to overcome the inhibitory effects of idazoxan, a selective alpha-2 receptor antagonist, but not phentolamine, a non-selective alpha receptor antagonist, on eating following injection of noradrenaline into the rat hypothalamic paraventricular nucleus. Similarly, lesion by 6-hydroxydopamine of noradrenaline terminals in the paraventricular nucleus also reduced the efficacy of idazoxan in blocking eating induced by noradrenaline. These data confirm that postsynaptic alpha-2 receptors are involved in the feeding response to exogenous noradrenaline, but in addition, when taken in conjunction with previously published data, are used to suggest a differential distribution of NA receptors within the hypothalamic paraventricular nucleus. It is proposed that the alpha-2 subtype may be extrasynaptic, the alpha-1 subtype intrasynaptic.

Idazoxan Inhibits Hyperprolactinaemia in Ovariectomized Estrogen-Treated Rats

The alpha 2-antagonist idazoxan (IDZ) has previously been shown to inhibit hyperprolactinaemia triggered by various stimuli such as lactation, stress, serotonergic agents and morphine (Preziosi, Martire, Navarra, Pistritto and Vacca 1989; Krulich, Jurcovicova and Le 1989). In this study, we investigated the PRL-lowering activity of IDZ in ovariectomized estrogen-treated (OET) rats; since a PRL surge usually occurs in normal cycling rats on the day of proestrus, the effect of IDZ on pulsatile PRL release in intact female rats was also studied. IDZ significantly lowered plasma PRL levels in OET rats; no elevated PRL values were observed in normal cycling rats, indicating that IDZ might inhibit PRL surges in these animals. It is concluded that IDZ is an effective PRL-lowering agent in a number of physiological and pharmacological hyperprolactinaemic models.

Effect of imidazolines on Na + transport and intracellular pH in renal proximal tubule cells

Recently, we characterized an imidazoline-guanidinium receptive site (IGRS) in the renal proximal tubule of rabbit kidney. Although recognized by a series of imidazoline and guanidinium alpha-2 adrenergic compounds, IGRS is insensitive to catecholamines and can be physically separated from alpha-2 adrenergic receptors after solubilization. In the present study, we investigated the effect of imidazoline derivatives on 22Na + uptake and intracellular pH in isolated cells from rabbit renal proximal tubule. After 5 min of preincubation, idazoxan inhibited the total 22Na + influx (−30%) in a dose-dependent manner, with a maximum effect at 10 −5 M. The effect of idazoxan was not competitive as shown by the decrease of the maximal velocity of 22Na + entry (control: 3.80 ± 0.4; idazoxan 10 −5 M: 3.23 ± 0.33 nmol/30 s per mg protein, P < 0.01). A series of imidazoline derivatives inhibited 22Na + entry with an order of potency similar to that previously found for inhibition of [ 3H]idazoxan binding to IGRS (irazoline > idazoxan > UK 14304 > rilmenidine ⪢ cimetidine). The inhibition of 22Na + uptake by these compounds does not appear to be related to interaction with alpha-adrenergic receptors since it was observed in the presence of saturating concentrations of the adrenergic antagonists rauwolscine (alpha-2) or prazosin (alpha-1). When tested on the regulation of intracellular pH by fluorimetric techniques, 10 −5 M cirazoline or idazoxan inhibited by 20% the velocity of the sodium-dependent H + efflux in acidified cells ( P < 0.02). The concomitant inhibition of 22Na + entry and of cell realkalinization suggests that imidazoline derivatives inhibit Na +/H +-exchanger. This effect could be mediated via the renal IGRS and intracellular second messengers that are not yet known.

Idazoxan increases rough-and-tumble play, activity and exploration in juvenile rats

The effects of idazoxan, an alpha-2 noradrenergic antagonist, on play and open field behavior were assessed in juvenile rats. Play was assessed in two separate paradigms. Initially, juvenile rats were housed individually and given a daily 5 min opportunity to play with a responsive partner. Idazoxan (1-8 mg/kg) increased pinning, an indicator variable of play, but did not affect the frequency of dorsal contacts, an index of play solicitation. When rats were tested in a separate test for play solicitation using an unresponsive play partner, idazoxan increased all three measures of play solicitation. Idazoxan increased activity and exploration when rats were tested in an open field, suggesting that the effects of idazoxan on play may be due to an increase in behavioral arousal and/or attention. These data are consistent with a modulatory role for norepinephrine in the control of behavior.

Different effects of yohimbine and idazoxan in the light-dark choice procedure

In a light-dark choice situation, the alpha(2) adrenoceptor antagonists yohimbine and idazoxan had different effects: idazoxan decreased time spent in the fit box, but yohimbine did not. The effects of idazoxan were not blocked by the alpha(2) adrenoceptor agonist clonidine. The benzodiazepine receptor antagonist Ro 15-1788 itself decreased time spent in the lit box, but in the presence of Ro 15-1788, idazoxan did not cause any further reduction.

α2-adrenoceptor blockade prevents the effect of desipramine in the forced swimming test

The influence of α 2-adrenoceptor blockade on the activity of desipramine in an experimental model of depression was studied by using idazoxan and 1-(pyrimidinyl)piperazine (1-PP). The two drugs antagonists at these receptors, were studied for their ability to modify the effect of repeated treatment with the antidepressant, desipramine in the forced swimming test. Idazoxan (0.03, 0.3 and 3 mg/kg s.c.) and 1-PP (0.3 and 3 mg/kg p.o.) given with the last dose of a 7-day schedule of 10 mg/kg i.p. desipramine significantly reduced the effect of the latter on immobility. On its own neither drug modified the immobility time of rats at any dose. Infusion of various concentrations of idazoxan (1.6, 8 and 40 ng/μl) in the rat locus coeruleus (LC), dose dependently antagonized the effect of desipramine without causing any appreciable change in motor behavior or immobility. The effect of idazoxan (8 ng/μl) infusion in the LC was completely prevented by administering 6 μg 6-hydroxydopamine in the same region 12 days earlier. It thus appears that α 2-adrenoceptor blockade prevents the effect of desipramine in the forced swimming test, presumably by an effect on noradrenaline-containing cells in the LC. The question of how blockade or activation of α 2-adrenoceptors, both in the LC and in other sites, could influence antidepressant activity is discussed.

Involvement of adenylate cyclase and protein kinase C in the ?2-adrenoceptor-mediated inhibition of noradrenaline and 5-hydroxytryptamine release in rat hypothalamic slices

In superfused rat hypothalamic slices prelabelled with [3H]-noradrenaline, the alpha 2-adrenoceptor agonist UK 14304 inhibited in a concentration-dependent manner the electrically-evoked release of tritium. This inhibition was antagonized by the alpha 2-adrenoceptor blocking agent idazoxan, which by itself increased the electrically-evoked tritium overflow. Exposure to forskolin, an adenylate cyclase activator, increased the electrically-evoked release of [3H]-noradrenaline. In the presence of forskolin (1 mumol/l), both the inhibitory effect of UK 14304 and the increasing effect of idazoxan on the electrically-evoked release of [3H]-noradrenaline were less pronounced than in the absence of the adenylate cyclase activator. Exposure to forskolin and to the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine shifted to the right the concentration-effect curve for UK 14304 in a similar manner as that observed in the presence of forskolin alone. Exposure to phorbol-12,13-dibutyrate (0.01-10 mumol/l), a drug which activates protein kinase C, increased the electrically-evoked release of [3H]-noradrenaline. In the presence of phorbol-12,13-dibutyrate (0.1 and 1 mumol/l), the concentration effect curve for UK 14304 on tritium overflow was significantly shifted to the right. The increasing effect of idazoxan on tritium overflow was significantly less pronounced in the presence of 1 mumol/l phorbol-12,13-dibutyrate. In superfused rat hypothalamic slices prelabelled with [3H]-5-hydroxytryptamine, the alpha 2-adrenoceptor agonist UK 14304 significantly inhibited the electrically-evoked release of tritium. Exposure to forskolin increased in a concentration-dependent manner [3H]-5-hydroxytryptamine overflow, but did not modify the UK 14304-mediated inhibition. Exposure to 3-isobutyl-1-methylxanthine enhanced the electrically-evoked release of [3H]-5-hydroxytryptamine. In the presence of both forskolin (1 mumol/l) and 3-isobutyl-1-methylxanthine (1 mmol/l), the concentration-response curve for UK 14304 was significantly shifted to the right. Exposure to phorbol-12,13-dibutyrate (0.01-10 mumol/l) enhanced in a concentration-dependent manner the electrically-evoked overflow of [3H]-5-hydroxytryptamine. In the presence of phorbol-12,13-dibutyrate (0.1 and 1 mumol/l), UK 14304 was significantly less potent to inhibit tritium release than in the absence of the protein kinase C activator. It is concluded that both cyclic AMP and phosphoinositide turnover are involved in the modulation of noradrenaline and 5-hydroxytryptamine release by presynaptic alpha 2-adrenoceptors in rat hypothalamic slices. However, these interactions do not represent definitive proof for a cause-effect relationship for the second messengers mediating the alpha 2-adrenoceptor induced inhibition of transmitter release either as autoreceptor or as heteroreceptor.

Effect of idazoxan on evening melatonin plasma concentrations in healthy volunteers

Robin A, Binnie CD, Copas JB (1985): Electrophysiological and hormonal responses to three types of electroconvulsive therapy. Br J Psychiatry 147:707-712. Rudorfer MV, Potter WZ (1987): ECT alters monoamines in humans differently than do antidepressant drugs. Presented at the American College of Neuropsychopharmacology Meeting. Sackeim HA, Mukherjee S (1986): Neurophysiological variability in the effects of the ECT stimulus. Convulsive Ther 2:267-276. Sackeim HA, Decina P, Kanzler M, Kerr B, Malitz S (1987): Effects of electrode placement on the efficacy of titrated, low-dose ECT. Am J Psychiatry 144:1449-1455.

α-Adrenergic regulation of androgen receptor concentration in the preoptic area of the rat

We examined the effect of the pharmacological disruption of the catecholaminergic system on the concentration of nuclear androgen receptor, as measured by the in vitro binding of methyltrienolone ([ 3H]R1881) to salt extracts of anterior pituitary (AP), preoptic are (POA) and medial basal hypothalamus (MBH). Treatment of gonadectomized male and female rats with the dopamine-ß-hydroxylase inhibitor, diethyldithiocarbamate (400 mg/kg b. wt.), 30 min before treatment with dihydrotestosterone (1 mg/animal) produced a decrease in the number of nuclear androgen receptor compared with saline-treated controls ( P<0.05). This effect was specific for the POA and was not present 15 h after DHT treatment. There was no effect on cytosolic androgen receptor nor was there a drug effect on the apparent dissociation constant ( K d) of [ 3H]R1881 binding to hypothalamus-preoptic area cytosols. Treatment of intact males and castrated, testosterone-treated males with the a 1- and a 2-adrenergic antagonists, prazosin (5 mg/kg b. wt.) and yohimbine (2 mg/kg b. wt.), respectively, resulted in a significant decrease in the number of nuclear AR 2 h following drug treatment ( P<0.05). There was no effect of the ß-adrenergic receptor antagonist propranolol (10 mg/kg b. wt.) when given to intact animals, nor was there an effect of idazoxan (5 mg/kg) when given to testosterone-treated animals. The effects of yohimbine and prazosin were restricted to the POA. None of the drugs competed with the binding of [ 3H]R1881 for the androgen receptor nor did they alter the K d of cytosol or nuclear androgen receptor. These data provide evidence for an adrenergic interaction with the POA androgen receptor and suggest a role for catecholamines in modulating androgen sensitivity in the rat brain.

Long-term suppression of the cerebral spread of a memory: Effects of idazoxan and clonidine

Bitemporal injections of puromycin consistently induce amnesia of aversive maze-learning in mice when administered within 3 days of training. These bitemporal puromycin injections lose their amnestic effectiveness if the latency between training and injection is extended beyond 6 days. Consistent with other evidence, we believe that memory (in our task) “spreads” during the 6 days following training. Since previous experiments have indicated that the central noradrenergic system is involved in this process of “memory spread”, we have examined the effect of stimulation or blockade of the α 2-receptor. To this end, we adminstered a single dose of the α 2-adrenoceptor antagonist, idazoxan, or the α 2-agonist, clonidine. Idazoxan (1 mg/kg, SC) had no effect on engram spread. Clonidine (25 μg–125 ng/kg, SC), by contrast, suppressed engram spread for at least 30 days after treatment. When mice were tested at 60 and 90 days after treatment, spontaneous recovery (i.e., engram spread) was evident in only about 50% of the clonidine treated mice. Coadministration of idazoxan with clonidine blocked the effects of clonidine on “memory spread.”

Idazoxan blocks the action of noradrenaline but not spinal inhibition from electrical stimulation of the locus coeruleus and nucleus Kolliker-Fuse of the cat

The effects of idazoxan, a specificα 2-adrenoceptor antagonist, on spinal inhibition by administration of noradrenaline and from electrical stimulation of the dorsolateral pons were studied in 26 cats anaesthetized with sodium pentobarbitone. The excitation of dorsal horn neurons of the spinal cord by noxious heating of the skin or by impulses in unmyelinated primary afferent fibres was markedly reduced when noradrenaline was administered microelectrophoretically in the substantia gelatinosa or near cell bodies. Electrical stimulation of the region of the locus coeruleus selectively inhibited spinal nociceptive transmission when dorsal horn neurons were excited by noxious and non-noxious stimuli. In contrast to stimulation of the locus coeruleus, stimulation of the nucleus Kolliker-Fuse produced non-selective inhibition of both nociceptive and non-nociceptive responses of dorsal horn neurons of the spinal cord. Microelectrophoretic ejection of idazoxan reduced or abolished noradrenaline-induced inhibition with 19 of 20 neurons. This antagonist did not alter inhibition from stimulation of the locus coeruleus and the nucleus Kolliker-Fuse, regardless of whether it was administered microelectrophoretically (11 neurons), systemically (3 neurons) or topically (4 neurons). The results suggest thatα 2-adrenoceptors do not mediate inhibiton of spinal nociceptive transmission from electrical stimulation of the locus coeruleus and the nucleus Kolliker-Fuse. Other possibilities for the failure of idazoxan to modify inhibition from such stimulation are discussed.

α1-Adrenoceptor-Mediated Contraction of Rabbit Mesenteric Artery

The alpha-adrenoceptors that mediate contraction to exogenous and endogenous noradrenaline in rabbit isolated mesenteric artery were investigated. Prazosin (10(-9)-10(-7) M) antagonised contractions to noradrenaline, methoxamine, and, in particular, contractions to neuronal noradrenaline released by field stimulation. Only a high concentration (10(-5) M) of idazoxan was able to markedly antagonise the three contractile stimuli. The effects of idazoxan (at high concentrations) and prazosin were studied upon noradrenaline-evoked contractions attributable to intracellular Ca2+ release using Ca2+ -deplete medium, and, on readministration of Ca2+, upon Ca2+ influx. Both components of the response were inhibited by the two antagonists, but the contraction associated with intracellular Ca2+ release was preferentially inhibited in each case. The results demonstrate that only alpha 1-adrenoceptors are involved in the contraction of this tissue to exogenous and endogenous noradrenaline. This receptor type is linked to both extracellular and intracellular Ca2+ sources, although the latter is more sensitive to inhibition by alpha-adrenoceptor blocking drugs.

Possible involvement of presynaptic alpha 1-adrenoceptors in the effects of idazoxan and prazosin on 3H-noradrenaline release from tail arteries of SHR.

The effects of several alpha-adrenoceptor antagonists have been examined on tritium release elicited by electrical stimulation from isolated perfused SHR tail artery preparations prelabelled with 3H-noradrenaline (3H-NA). Phentolamine and yohimbine potently facilitated the stimulation evoked release of tritium at low frequencies of stimulation, but the alpha 2-adrenoceptor antagonist idazoxan was only weakly active at 1 mumol/l, despite antagonising the clonidine-evoked inhibition of 3H-release at a lower concentration of 0.1 mumol/l. The alpha 1-adrenoceptor antagonists prazosin and corynanthine also increased stimulation evoked tritium release in this preparation, suggesting the presence of prejunctional alpha 1-adrenoceptors. Furthermore, the alpha 1-adrenoceptor agonist methoxamine (3 mumol/l) caused a significant inhibition of tritium-evoked release, an effect which was blocked by prazosin (10 nmol/l). When alpha 1-adrenoceptors were blocked in the presence of prazosin, idazoxan (0.1 mumol/l) produced a significant facilitatory effect on the electrically-evoked release of 3H-transmitter. On the other hand, when alpha 2-adrenoceptors were blocked in the presence of yohimbine, exposure to idazoxan (0.1 mumol/l) reduced significantly the stimulation-evoked release of tritium elicited by electrical stimulation. The results indicate that in the SHR tail arteries, idazoxan has a partial agonist inhibitory activity on transmitter release, which can mask the facilitatory effects due to blockade of presynaptic alpha 2-adrenoceptors. The inhibitory effects of idazoxan appear to involve presynaptic alpha 1-adrenoceptors, which when stimulated, reduce 3H-NA release in SHR tail arteries.

Influence of neuronal uptake on the contribution of smooth muscle alpha 2-adrenoceptors to vasoconstrictor responses to noradrenaline in SHR and WKY isolated tail arteries.

The effects of the selective alpha-adrenoceptor antagonists idazoxan (alpha 2) and prazosin (alpha 1) were examined on responses to exogenous noradrenaline and to sympathetic nerve stimulation in SHR and WKY rat isolated perfused proximal tail artery segments. The influence of inhibition of neuronal uptake with cocaine on the effects of these antagonists was also determined. The following results were obtained: Prazosin (10 nmol/l) was equieffective in antagonising responses to exogenous noradrenaline and sympathetic nerve stimulation in both SHR and WKY arteries and the degree of antagonism was similar in either the presence or the absence of neuronal uptake inhibition. In contrast to prazosin, the effects of idazoxan (100 nmol/l), on both exogenous noradrenaline and sympathetic nerve stimulation were dependent on the degree of inhibition of neuronal uptake. In SHR arteries, the degree of antagonism of responses to exogenous noradrenaline by idazoxan (100 nmol/l) decreased progressively as the concentration of cocaine was increased to 4 and 40 mumol/l; in WKY arteries, even in the absence of cocaine, idazoxan (100 nmol/l) did not antagonise responses to exogenous noradrenaline. In SHR arteries, the responses to sympathetic nerve stimulation were reduced to a lesser extent by idazoxan (100 nmol/l) when the concentration of cocaine was increased to 4 mumol/l than in the absence of cocaine. In WKY arteries, idazoxan (100 nmol/l) reduced the responses to sympathetic nerve stimulation in the absence of cocaine. However, this concentration of idazoxan increased the responses to nerve stimulation in the presence of cocaine. Our results indicate that smooth muscle alpha 2-adrenoceptors are present in SHR tail arteries, both intra- and extrajunctionally.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of idazoxan on catecholamine systems in rat brain

Experiments have been performed to assess the potency of idazoxan (RX 781094) at α and β-adrenoceptors and dopamine receptors and on catecholamine uptake processes in rat brain. The effects of idazoxan on the turnover rates of noradrenaline and dopamine have been determined. Radioligand binding studies with cerebral cortex membranes have demonstrated that idazoxan exhibits 46-fold selectivity for α 2-adrenoceptors labelled by ( 3H)-idazoxan (Mean K i ± S.E.M. = 3.1 ± 0.4 nM) compared with α 1-adrenoceptors labelled by ( 3H)-prazosin (Mean K i ± S.E.M. = 142 ± 27 nM). Under the same conditions, yohimbine showed 6-fold selectivity for α 2-adrenoceptors. Idazoxan had low affinity for β-adrenoceptors labelled by ( 3H)-dihydroalprenolol ( ic 50 value > 10 μ M ), for dopamine receptors labelled by ( 3H)-domperidone ( ic 50 value > 20μ M ), for the ( 3H)-noradrenaline uptake site in rat hypothalamus ( ic 50 = 31μ M ) and for the ( 3H)-dopamine uptake site in rat striatum ( ic 50 value ∼ 800 μ M ). In rats treated with α-methyl- p-tyrosine, idazoxan (10–80 mg/kg, po) produced a marked increase (63% at 10, 217% at 20 mg/kg, po) in the apparent rate of turnover of noradrenaline in rat cortex/striatum, without affecting the rate of turnover of dopamine. This was in contrast to yohimbine (5–20 mg/kg, po) which increased the turnover rates of both catecholamines. In the absence of α-methyl- p-tyrosine, idazoxan (5–40 mg/kg, po) produced a dose related increase in the MHPG concentration and a small (20–30%) reduction in the steady state concentration of NA; the duration of the reduction was dose-related. DA steady state concentrations were unaffected. Idazoxan is a new selective α 2-adrenoceptor antagonist which should prove a valuable investigative tool in neurochemical studies and which may be a useful clinical agent in the management of the affective disorders.