Modulation of NSAID-induced antinociceptive and anti-inflammatory effects by alpha2-adrenoceptor agonists with gastroprotective effects

Tizanidine, an alpha2-adrenergic receptor agonist with myospasmolytic action, is indicated for the treatment of back pain either as monotherapy or in combination with nonsteridal anti-inflammatory drugs (NSAIDs). Tizanidine (0.25-1.0 mg/kg) significantly produced analgesic and anti-inflammatory effect in acetic acid induced writhing in mice and carrageenan-induced paw edema in rats, respectively. The effects were comparable with clonidine (0.25 and 0.50 mg/kg), another alpha2-agonist. Yohimbine (1 mg/kg), alpha2-adrenergic antagonist reversed the effect of tizanidine. Tizanidine (0.25 mg/kg) and clonidine (0.25 mg/kg) significantly potentiated the antinociceptive and anti-inflammatory effect of NSAIDs (nimesulide, meloxicam and naproxen). Tizanidine (1 mg/kg) did not alter basal pH, acidity (free and total) of gastric content and did not produce any mucosal injury in fasted rats. Tizanidine (1 mg/kg) significantly reduced meloxicam (UD50 3.21 mg/kg), nimesulide (UD50 24.52 mg/kg) and naproxen (UD50 14.10 mg/kg)-induced ulcerogenic effect (ulcer index, pH and free/total acidity). It is expected that tizanidine exerted gastrotprotection through stimulation of gastric and central alpha2-adrenergic receptors. Present investigation suggested that tizanidine not only enhance the analgesic and anti-inflammatory effect of NSAIDs but also improved gatstrointestinal tolerability of NSAIDs through modulation of central alpha-2-receptors. From this study, it can be speculated that tizanidine and NSAID combination therapy would prove to be a novel approach to treat nociceptive/inflammatory conditions with improved gastric tolerability of NSAIDs.     

"Pertussis toxin induces tachycardia and impairs the increase in blood pressure produced by alpha 2-adrenergic agonists"

Administration of purified pertussis toxin to rats induced persistent tachycardia, (observed in conscious rats but not after pithing); as little as 0.05 microgram/100 g produced a significant effect. Pertussis toxin-treatment did not affected the pressor response produced in the pithed rats by the alpha 2-adrenergic agonist methoxamine but markedly diminished the pressor effect of the alpha 2-adrenergic agonists clonidine and azepexole. A role of adenylate cyclase inhibition in the action of postsynaptic vascular alpha 2-adrenergic receptors is suggested.     

Mediation of isoproterenol-induced thirst in rats by beta2-adrenergic receptors.

Isoproterenol-induced thirst in rats has been attributed to the activation of beta-adrenergic receptors. Since these receptors can be further differentiated pharmacologically into beta1 and beta2 types, experiments were performed using several beta-adrenergic agonists and antagonists to determine the receptor type initiating the isoproterenol-induced thirst. The beta1- and beta2-adrenergic antagonist, d,l-propranolol (1 mg/kg, ip), blocked the increase in water intake usually accompanying acute subcutaneous administration of isoproterenol (25 microgram/kg) to female rats. Since l-propranolol is known to stabilize membranes and to possess anesthetic-like properties, d-propranolol was also used. This isomer has little beta-adrenergic-blocking activity but possesses anesthetic-like activity. Administration of d-propranolol (1 mg/kg, ip) failed to affect the drinking response to acute administration of isoproterenol (25 microgram/kg). Practolol (125 mg/kg), a beta1-adrenergic antagonist with little anesthetic properties, also had no effect on water intake of isoproterenol-treated rats. Butoxamine, a selective beta2-adrenergic antagonist, attenuated the drinking response to isoproterenol. Salbutamol (150 microgram/kg), a beta2-adrenergic agonist, mimicked the effect of isoproterenol on water intake. These results are consistent with the suggestion that beta2-adrenergic receptors mediate the isoproterenol-induced thirst in rats.     

alpha(2)-adrenergic receptor-mediated increase in NO production buffers renal medullary vasoconstriction

The present study was designed to investigate the role of nitric oxide (NO) in modulating the adrenergic vasoconstrictor response of the renal medullary circulation. In anesthetized rats, intravenous infusion of norepinephrine (NE) at a subpressor dose of 0.1 microgram. kg(-1). min(-1) did not alter renal cortical (CBF) and medullary (MBF) blood flows measured by laser-Doppler flowmetry nor medullary tissue PO(2) (P(m)O(2)) as measured by a polarographic microelectrode. In the presence of the NO synthase inhibitor nitro-L-arginine methyl ester (L-NAME) in the renal medulla, intravenous infusion of NE significantly reduced MBF by 30% and P(m)O(2) by 37%. With the use of an in vivo microdialysis-oxyhemoglobin NO-trapping technique, we found that intravenous infusion of NE increased interstitial NO concentrations by 43% in the renal medulla. NE-stimulated elevations of tissue NO were completely blocked either by renal medullary interstitial infusion of L-NAME or the alpha(2)-antagonist rauwolscine (30 microgram. kg(-1). min(-1)). Concurrently, intavenous infusion of NE resulted in a significant reduction of MBF in the presence of rauwolscine. The alpha(1)-antagonist prazosin (10 microgram. kg(-1). min(-1) renal medullary interstitial infusion) did not reduce the NE-induced increase in NO production, and NE increased MBF in the presence of prazosin. Microdissection and RT-PCR analyses demonstrated that the vasa recta expressed the mRNA of alpha(2B)-adrenergic receptors and that medullary thick ascending limb and collecting duct expressed the mRNA of both alpha(2A)- and alpha(2B)-adrenergic receptors. These subtypes of alpha(2)-adrenergic receptors may mediate NE-induced NO production in the renal medulla. We conclude that the increase in medullary NO production associated with the activation of alpha(2)-adrenergic receptors counteracts the vasoconstrictor effects of NE in the renal medulla and may play an important role in maintaining a constancy of MBF and medullary oxygenation.     

Effects of alpha 1 and alpha 2 activation of adrenergic receptors on aqueous humor dynamics

Effects of phenylephrine (alpha 1-adrenergic agonist), prazosin (alpha 1-adrenergic antagonist), clonidine (alpha 2-adrenergic agonist), and yohimbine (alpha 2-adrenergic antagonist) on aqueous humor (AH) dynamics were studied with a cat eye model. Phenylephrine (130 microgram/ml) inhibited AH outflow (67% at 90 min. period) more than AH formation (26% at the same period) indicating the intraocular pressure (IOP) might be raised by the administration of phenylephrine. Prazosin (0.1 microgram/ml) produced effects opposite to those of phenylephrine (55% reduction of AH formation and 25% reduction of AH outflow at 3 hr. period) suggesting the alpha 1-adrenergic receptor is responsible for increases rather than decreases of IOP. Both clonidine (10 microgram/ml) and yohimbine (0.1-1.0 microgram/ml) inhibited AH formation (60% inhibition) more than AH outflow (no inhibition for clonidine and 40% inhibition for yohimbine) to lower IOP. The conventional theory of receptor antagonism does not seem to function at alpha 2-receptor sites.     

Cross-regulation between G-protein-coupled receptors. Activation of beta 2-adrenergic receptors increases alpha 1-adrenergic receptor mRNA levels.

Stimulation of DDT1 MF-2 vas deferens cells with epinephrine resulted in a time- and dose-dependent loss of alpha 1-adrenergic receptor-specific ligand binding. Regulation of alpha 1-adrenergic receptor mRNA was characterized. In monolayer culture, cells displayed 0.7 +/- 0.05 amol of alpha 1-adrenergic receptor mRNA/microgram of total cellular RNA. Epinephrine, which acts at both alpha 1- and beta 2-adrenergic receptors of DDT1 MF-2 cells, induced a short term (2-8 h) increase (50-70%) in the abundance of alpha 1-adrenergic receptor mRNA. Propranolol, a beta 2-adrenergic receptor antagonist, attenuated the epinephrine-mediated increase in alpha 1-adrenergic receptor mRNA but did not affect the decrease in alpha 1-adrenergic receptor-specific ligand binding. Phentolamine, an alpha 1-adrenergic receptor antagonist, did not attenuate the epinephrine-mediated increase in alpha 1-adrenergic receptor mRNA at 4 h but did block the decrease in alpha 1-adrenergic receptor-specific ligand binding. The half-life of the alpha 1-adrenergic receptor mRNA was approximately 7 h in untreated cells as well as in cells challenged with epinephrine. The epinephrine-promoted increase in alpha 1-adrenergic receptor mRNA was found to result from cross-regulation via beta 2-adrenergic receptors. Cholera toxin, forskolin, as well as the cyclic AMP analog CPT cAMP (8-(4-chlorophenylthio)adenosine 3':5'-cyclic monophosphate) increased the alpha 1-adrenergic receptor mRNA at 4 h, as did epinephrine in the presence of alpha 1-antagonists but not in the presence of a beta-adrenergic antagonist. This is the first report of heterologous up-regulation of mRNA levels of adrenergic receptors. Cross-regulation between alpha 1- and beta 2-adrenergic receptor-mediated pathways at 4 h occurs at the level of mRNA whereas later down-regulation of alpha 1-receptor mRNA and binding proceed via agonist activation of alpha 1-adrenergic receptors.     

The effect of alpha2-adrenergic receptors on cutaneous water evaporation in the rock pigeon (Columba livia)

The role of beta-adrenergic receptors in regulating cutaneous water evaporation (CWE) in the rock pigeon (Columba livia) is well documented. Here, we studied the involvement of the alpha2-adrenergic receptors in this cooling mechanism of the heat-acclimated (HAc) pigeon. Systemic alpha2-adrenergic activation [clonidine, 50 microg kg(-1), intramuscular (i.m.)] was found to increase CWE in heat-acclimated pigeons at an ambient temperature (T(a)) of 25 degrees C. Subcutaneous administration of the drug had no significant effect. Preinjection of an alpha2-adrenergic antagonist (yohimbine, 10 mg kg(-1), i.m.) completely prevented clonidine-induced CWE and attenuated propranolol-induced CWE by 53%. Pretreatment with a beta-adrenergic agonist (isoproterenol, 4 mg kg(-1), i.m.) abolished the effect of clonidine. None of the above treatments was found to elicit significant CWE in nonacclimated (NAc) pigeons. These findings, in addition to previously reported data, indicate a complex regulatory pathway of CWE in the heat-acclimated pigeon consisting of alpha2- and beta2-adrenergic receptors. The possible hierarchical pattern of these receptors is discussed.     

Noradrenergic stimulation of BDNF synthesis in astrocytes: mediation via alpha1- and beta1/beta2-adrenergic receptors

Brain-derived neurotrophic factor (BDNF) synthesis in astrocytes induced by noradrenaline (NA) is a receptor-mediated process utilizing two parallel adrenergic pathways: beta1/beta2-adrenergic/cAMP and the novel alpha1-adrenergic/PKC pathway. BDNF is produced by astrocytes, in addition to neurons, and the noradrenergic system plays a role in controlling BDNF synthesis. Since astrocytes express various subtypes of alpha- and beta-adrenergic receptors that have the potential to be activated by synaptically released NA, we focused our present study on the mediatory role of adrenergic receptors in the noradrenergic up-regulation of BDNF synthesis in cultured neonatal rat cortical astrocytes. NA (1 microM) elevates BDNF levels by four-fold after 6 h of incubation. Its stimulation was partly inhibited by either the beta1-adrenergic antagonist atenolol, the beta2-adrenergic antagonist ICI 118,551, or by the alpha1-adrenergic antagonist prazosin, while the alpha2-adrenergic antagonist yohimbine showed no effect. BDNF levels in astrocytes were increased by the specific beta1-adrenergic agonist dobutamine and the beta2-adrenergic agonist salbutamol, as well as by adenylate cyclase activation (by forskolin) and PKA activation (by dBcAMP). However, none of the tested agonists or mediators of the intracellular beta-adrenergic pathways were able to reach the level of NA's stimulatory effect. BDNF cellular levels were also elevated by the alpha1-adrenergic agonist methoxamine, but not by the alpha2-adrenergic agonist clonidine. The increase in intracellular Ca2+ by ionophore A23187 showed no effect, whereas PKC activation by phorbol 12-myristate 13-acetate (TPA) potently stimulated BDNF levels in the cells. The methoxamine-stimulated BDNF synthesis was inhibited by desensitizing pretreatment with TPA, indicating that the alpha1-stimulation was mediated via PKC activation. In conclusion, the synthesis of astrocytic BDNF stimulated by noradrenergic neuronal activity is an adaptable process using multiple types (alpha1 and beta1/beta2) of adrenergic receptor activation.     

Attenuating effects of intrathecal clonidine on the exercise pressor reflex

We tested the hypothesis that intrathecal injection of clonidine, an alpha 2-adrenergic agonist, attenuated the reflex cardiovascular and ventilatory responses to static muscular contraction in cats. Before clonidine (1 microgram in 0.2 ml), contraction-induced reflex increases (n = 10) in mean arterial pressure and ventilation averaged 25 +/- 3 mmHg and 359 +/- 105 ml/min, respectively, whereas after clonidine these increases averaged 8 +/- 4 mmHg and 200 +/- 114 ml/min, respectively (P less than 0.05). Clonidine had no effect on the heart rate response to contraction. Intrathecal injection of yohimbine (10 micrograms; n = 5), an alpha 2-adrenergic antagonist, but not prazosin (10 micrograms; n = 3), an alpha 1-adrenergic antagonist, prevented the attenuating effects of clonidine on the reflex pressor and ventilatory responses to contraction. Our findings were not due to the spread of clonidine to the medulla, because the reflex pressor and ventilatory responses to contraction were not attenuated by injection of clonidine (1 microgram) onto the medulla (n = 3). In addition, our findings were not due to a clonidine-induced withdrawal of sympathetic outflow, because intrathecal injection of clonidine (1 microgram) did not attenuate increases in arterial pressure and ventilation evoked by high-intensity electrical stimulation of the cut central end of the sciatic nerve (n = 5). Furthermore, our findings were not due to a local anesthetic action of clonidine, because application of this agent to the dorsal roots had no effect on the discharge of group IV muscle afferents. We conclude that stimulation of alpha 2-adrenergic receptors in the spinal cord attenuates the reflex pressor and ventilatory responses to static contraction.     

Presynaptic alpha 2 -adrenergic stimulation leads to growth hormone release in the dog

In previous studies we have shown that the alpha 2 -adrenergic receptor agonist clonidine (CLON) releases growth hormone (GH) in conscious dogs, an effect abolished by the selective alpha 2-receptor antagonist yohimbine (YOH) and by reserpine, but not by the alpha 1-receptor antagonist prazosin (1). In the present work intravenous (iv) administration of CLON in conscious dogs evoked a dose-related rise in plasma GH at doses of 2-8 /micrograms/Kg, but not at 16 and 32 /micrograms/Kg. Acute pretreatment with the selective inhibitor of norepinephrine (NE) synthesis, DU-18288, or with a potent antagonist of presynaptic alpha 2-receptors, mianserin abolished the GH rise induced by CLON (4 /micrograms/Kg iv). In contrast, a 10-day-pretreatment with YOH greatly enhanced the GH-releasing effect of CLON (2 /micrograms/Kg iv). In all these data indicate that in the dog: 1) CLON induces GH release via activation of alpha 2-adrenergic receptors; 2) these receptors are likely located on presynaptic sites [experiments with reserpine (1), DU-18288, mianserin, dose-response curve with CLON 2-32/micrograms/kg iv]; 3) the adrenergic receptors involved in GH release exhibit supersensitivity upon (YOH-induced) chronic pharmacologic denervation. In view of the inhibitory action of presynaptic alpha 2-adrenergic receptors (autoreceptors) on NE function, it may be envisioned that in the dog noradrenergic activation is inhibitory and not stimulatory to GH release.     

Role of KATP channels in reduced antinociceptive effect of morphine in streptozotocin-induced diabetic mice

The nociceptive effect was measured using withdrawal latency in tail flick test in mice rendered diabetic by administering streptozotocin (200 mg/kg, i.p.). The antinociceptive effect of morphine (4 and 8 mg/kg, s.c.) and cromakalim, a KATP channel opener, (0.3, 1 and 2 micrograms, i.c.v.) was significantly reduced in diabetic mice. Moreover, co-administration of cromakalim(0.3 microgram) did not alter the reduced antinociceptive effect of morphine(4 mg/kg) in diabetic mice. Spleenectomy in diabetic mice restored the decrease in antinociceptive effect of morphine and cromakalim. Multiple dose treatment with insulin to maintain euglycaemia for 3 days in diabetic mice prevented the decrease in antinociceptive effect of morphine and cromakalim. However, hyperglycaemic tyrode's buffer did not alter the pD2 value of morphine in isolated guinea pig ileum suggesting that hyperglycaemia does not interfere with mu receptor mediated responses in vitro. The results suggest that hyperglycaemia induced decrease in antinociceptive effect of morphine and cromakalim may be due to alteration in KATP channels. Some unknown factor from spleen in diabetic mice may be responsible for this alteration in KATP channels in diabetic mice.     

Significance of the adrenergic system in the regulation of vasopressin secretion in rat neurohypophyseal tissue cultures

The effects of adrenaline (A) and noradrenaline (NA) on vasopressin (VP) secretion were studied in 13-14-day cultures of isolated rat neurohypophyseal (NH) tissue. The VP contents of the supernatant media were determined by radioimmunoassay after a 1 or 2-h incubation. Significantly increased VP levels were detected in the tissue culture media following the administration of A (an alpha+beta(2)-receptor agonist), depending on the dose of A. The VP secretion elevation was totally blocked by the previous administration of phentolamine (an alpha(1)+alpha(2)-receptor antagonist) or corynanthine (an alpha(1)-receptor antagonist). Yohimbine (an alpha(2)-receptor antagonist) did not influence the VP secretion increase induced by A. After the administration of NA (a beta+alpha(1)-receptor agonist), a VP secretion elevation was again detected, but the degree of enhancement proved smaller than that of the VP secretion increase induced by A. Propranolol (a beta(1)+beta(2)-receptor antagonist) before NA administration prevented the VP secretion increase. Atenolol (a beta(1)-receptor antagonist) did not block the VP secretion elevation induced by NA. Corynanthine (an alpha(1)-receptor antagonist) treatment before NA administration reduced the NA-induced VP enhancement, because NA has an alpha(1)-receptor agonist character in addition to its main character (a beta-receptor agonist). Surprisingly, the administration of pindolol (a beta(1)+beta(2)-receptor antagonist) enhanced VP secretion. This contradictory effect can be explained in that pindolol not only acts as a blocker, but also exerts "intrinsic sympathomimetic action" and a strong adrenergic agonist effect. Pindolol before NA administration significantly increased the NA-induced VP elevation. CONCLUSIONS: Mainly the alpha(1)- and beta(2)-adrenergic receptors are involved in the A- or NA-induced increase of VP secretion in isolated NH tissue cultures. The results indicate that VP release is influenced directly by the adrenergic system, and the adrenergic control of VP secretion from the NH tissue in rats can occur at the level of the posterior pituitary.     

Regulation of DNA polymerase alpha activity by the alpha 1-adrenergic receptors in proliferatively activated rat liver cells.

The administration of the alpha 1-adrenergic antagonist prazosin to hepatectomized rats inhibited DNA synthesis induced in the remaining hepatocytes. This inhibitory effect could be reversed by the simultaneous injection of the agonist phenylephrine. In order to establish how the alpha 1-adrenergic receptors can regulate DNA replication, the effect of prazosin administration on DNA polymerase alpha was examined. At 24 h after partial hepatectomy, the activity of DNA polymerase alpha increased 5, 7 and 9 fold in the homogenates, nuclei and nuclear matrix, respectively. This increase was inhibited by 70%-80% when prazosin was injected at 1, 8 or 11 h after surgery. Kinetic studies revealed that the Km for DNA was 2 fold lower in hepatectomized than in control animals. The administration of prazosin to hepatectomized rats increased the Km to the control values. These results indicate that the alpha 1-adrenergic receptors are involved in the regulation of DNA synthesis through the activation of DNA polymerase alpha and that this activation could be produced by increasing its affinity for DNA.     

Interaction between diazepam and oral antidiabetic agents on serum glucose,insulin and chromium levels in rats

This study was undertaken to investigate the effect of diazepam in the presence and absence of glibenclamide, metformin or their combination on serum levels of glucose, insulin and chromium in rats. Results indicated that diazepam (10 mg/kg i.p.) induced marked hyperglycaemic effects in hyperglycaemic rats. This effect was associated with significant reductions in serum chromium levels and insignificant reduction in serum insulin levels. Diazepam-induced hyperglycaemia was counter-acted by concurrent administration of glibenclamide (5 mg/kg orally), metformin (500 mg/kg orally) or their combination. The effect of diazepam on serum chromium level was counteracted partially by administration of glibenclamide and augmented in the presence of metformin or its combination with glibenclamide. It is concluded that the diazepam-induced hyperglycaemia, as well as the hypoglycaemic effect of glibenclamide, might be related to changes in serum chromium levels.     

Different effects of intracerebral and systemic administration of buspirone in the forced swimming test: involvement of a metabolite

Buspirone, a drug with high affinity for serotonin1A receptors, was studied for its ability to reduce rats' immobility in the forced swimming test when injected systemically or into the nucleus raphe dorsalis (DR). Between 0.1 and 10 mg/kg buspirone had no effect on rats' immobility when injected systemically as a single dose or as a 3-injection course during 24 hours. Direct injection of 1 and 5 mu/0.5 microliter buspirone in the DR significantly reduced the duration of immobility without changing rats' activity in an open field. The anti-immobility effect of 1 microgram/0.5 microliter buspirone in the DR was completely prevented by injecting 2.5 micrograms (-)-propranolol in the same area. Oral administration of 0.3-1.0 mg/kg 1-(2-pyrimidinyl)piperazine (1-PP), one of the main metabolites of buspirone, and 0.3-3.0 mg/kg s.c. idazoxan, two substances with alpha 2 adrenergic blocking properties, completely antagonized the effect of 0.25 mg/kg s.c. 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), an agent with selective affinity for serotonin1A receptors. The anti-immobility effect of an infusion of 1 microgram/0.5 microliter buspirone or 8-OH-DPAT in the DR was also antagonized by 1 mg/kg p.o. 1-PP. The results suggest that buspirone possesses potential antidepressant properties but its effects may be masked in certain tests by its metabolite, 1PP, through its alpha 2 adrenergic blocking activity.     

Noradrenergic Inhibition and α2-Adrenergic Stimulation of Melatonin Secretion in the Pigeon

Adrenergic regulatory mechanisms of melatonin synthesis and secretion were studied in the pigeon in vivo. Late-afternoon intraperitoneal injection of noradrenaline (NA; 1 mg/kg) resulted in a significant decrease in plasma melatonin levels in 3 h. The same effect was seen after phenylephrine treatment (1 mg/kg i.p.), indicating that an alpha 1-adrenergic mechanism may mediate the inhibition. Propranolol treatment had no effect on plasma melatonin levels, supporting this concept. Detomidine (1 mg/kg i.p.), an alpha 2-adrenergic agonist, increased melatonin levels. This stimulatory effect was blocked by yohimbine, an alpha 2-adrenergic antagonist. However, yohimbine alone had no effect on the plasma melatonin levels, suggesting that alpha 2-adrenergic transmission is not primarily responsible for the nocturnal stimulation of melatonin synthesis and secretion in the pigeon.     

Central injection of nicotine increases hepatic and splenic interleukin 6 (IL-6) mRNA expression and plasma IL-6 levels in mice: involvement of the peripheral sympathetic nervous system.

Accumulating evidence suggests that plasma levels of interleukin 6 (IL-6), a major cytokine stimulating the synthesis of acute-phase proteins, are intimately regulated by the central nervous system. Nicotine, one of the major drugs abused by humans, has been shown to affect immunological functions. In the present study, effects of intracerebroventricular (i.c.v.) injection of nicotine on plasma IL-6 levels were investigated in mice. Nicotine administered i.c.v. dose-dependently increased plasma IL-6 levels; the lowest effective dose was 0.3 ng/mouse and the maximal effect was attained with the dose of 105 ng/mouse. The nicotine (105 ng/mouse, i.c.v.)-induced plasma IL-6 levels peaked at 3 h and approached basal levels 6 h after injection. Mecamylamine, a nicotinic receptor antagonist, blocked nicotine-induced plasma IL-6 levels. Depletion of peripheral norepinephrine with 6-hydroxydopamine [100 mg/kg, intraperitoneal (i. p.)] inhibited the nicotine-induced plasma IL-6 levels by 57%, whereas central norepinephrine depletion with 6-hydroxydopamine (50 microgram/mouse, i.c.v.) had no effect. Pretreatment with prazosin (alpha1-adrenergic antagonist; 1 mg/kg, i.p.), yohimbine (alpha2-adrenergic antagonist; 1 mg/kg, i.p.), and ICI-118,551 (beta2-adrenergic antagonist; 2 mg/kg, i.p.), but not with betaxolol (beta1-adrenergic antagonist; 2 mg/kg, i.p.), inhibited nicotine-induced plasma IL-6 levels. Among the peripheral organs, including the pituitary, adrenals, heart, lung, liver, spleen, and lymph nodes, nicotine (105 ng/mouse, i.c.v.) increased IL-6 mRNA expression only in the liver and spleen, which was inhibited by peripheral norepinephrine depletion. These results suggest that stimulation of central nicotinic receptors induces plasma IL-6 levels and IL-6 mRNA expression in the liver and spleen via the peripheral sympathetic nervous system, alpha1-, alpha2-, and beta2-adrenoreceptors being involved.     

Ethanol exhibits alpha receptor blocking-like properties in anesthetized rats

The ability of ethanol to reduce alpha-adrenergic receptor-mediated pressor responsiveness in vivo was investigated in chloralose-anesthetized male Sprague-Dawley rats. Catheters were inserted in the jugular vein and the femoral artery of rats for the injection of drugs and the measurement of blood pressure, respectively. Dose-response curves for phenylephrine and norepinephrine were constructed by plotting the change in mean arterial pressure following a bolus dose of the agent against the dose of the pressor agent used. Following construction of an initial dose-response curve, animals were challenged with either a 1 g/kg dose of ethanol or an equivalent volume of saline (iv) and the dose-response curves were repeated. Using a similar protocol, pressor responsiveness was evaluated in animals pretreated with either yohimbine (1 mg/kg) or prazosin (3.9 micrograms/kg), a dose sufficient to produce partial blockade of alpha receptor-mediated pressor responsiveness, and then treated with ethanol. Ethanol produced a partial blockade of alpha receptors when the animals were challenged with either phenylephrine or norepinephrine. This blockade produced by ethanol was shown to be similar to that produced by the receptor blocking agents used in this study. To rule out any nonspecific effects of ethanol in reducing vascular reactivity, some animals were challenged with angiotensin II both before and after treatment with ethanol, yohimbine, or prazosin and after both drugs were administered together. Ethanol, as well as the alpha 1- and alpha 2-adrenergic blocking agents tested failed to have any significant effect on angiotensin II-pressor responsiveness, ruling out any nonspecific effect of ethanol on the vasculature. It is concluded, therefore, that ethanol has alpha receptor blocking-like activity in vivo.     

Effect of repeated treatment with mirtazapine on the central alpha1-adrenergic receptors.

Mirtazapine (MIR) is an antidepressant which enhances noradrenergic and serotonergic 5-HT1A neurotransmission via antagomism of central alpha2-adrenergic autoreceptors and heteroreceptors. The drugs does not inhibit noradrenaline and serotonin reuptake but blocks the 5-HT, and 5-HT3 receptors and has high affinity only for central and peripheral histamine H1 receptors. The present study was aimed at determining whether repeated MIR treatment induced adaptive changes in the alpha1-adrenergic receptors, similar to those reported by us early for tricyclic antidepressants, The experiments were carried out on male mice and rats. MIR was administered at a dose of 10 mg/kg once or repeatedly (twice daily for 14 days). The obtained results showed that MIR administrated repeatedly potentiated the methoxamine- induced exploratory hyperactivity in rats and clonidine-induced aggressiveness in mice, those effects being mediated by alpha1-adrenergic receptors. MIR given repeatedly (but not acutely) increased the binding (Bmax ) of [3H]prazosin to alpha1-adrenergic receptors in cerebral cortex, however, the ability of the alpha1-adrenoceptor agonist phenylephrine to compete for the these sites was not significantly changed. The above results indicate that repeated MIR administration increases the responsiveness of alpha1-adrenergic system (behavioural and biochemical changes), as tricyclics do. However, the question whether the increased functional responsiveness found in the present study is important for the clinical antidepressant efficacy, remains open.     

Effect of alpha-adrenergic blockers on calmodulin association with the nuclear matrix of rat liver cells during proliferative activation

A transient peak of cytosolic calmodulin (CaM) was produced during the prereplicative phase of rat liver cell proliferation following partial hepatectomy. After accumulating in the cytosol, CaM apparently translocated into the nuclei, associating with the nuclear matrix. The administration of alpha 1-adrenergic blockers to hepatectomized rats prevented the association of CaM with the nuclear matrix without affecting the increase in the total nuclear CaM. The inhibitory effect of the alpha 1-antagonists was reversed by the simultaneous injection of the alpha-agonist noradrenaline. Since the activation of alpha 1-adrenergic receptors results in the release of Ca2+ from endoplasmic reticulum stores, the results suggest that the association of CaM with the nuclear matrix during proliferative activation is mediated by Ca2+ released from endoplasmic reticulum and show that the association with the matrix is independent of its intranuclear accumulation.