The role of I(1)-imidazoline and alpha(2)-adrenergic receptors in the modulation of glucose metabolism in the spontaneously hypertensive obese rat model of metabolic syndrome X.
(41/222)
We examined glucose metabolism after I1-imidazoline (I1R) and alpha2-adrenergic receptor (alpha2AR) activation in an animal model of metabolic syndrome X. Fasted spontaneously hypertensive obese rats (SHROB) were given the I1R/alpha2AR agonists moxonidine and rilmenidine or the alpha2AR agonist guanabenz. Because of the dual specificity of moxonidine, its actions were split into adrenergic and nonadrenergic components by using selective antagonists: rauwolscine (alpha2AR) efaroxan (I1R/alpha2AR), or 2-endo-amino-3-exo-isopropylbicyclo[2.2.1.]heptane (AGN 192403) (I1R). Hyperglycemia induced by moxonidine, rilmenidine, and guanabenz resulted from inhibition of insulin secretion. Similar responses were observed after oral dosing and in lean littermates. Glucagon was reduced by the I1R agonists (moxonidine, 32 +/- 5%; rilmenidine, 24 +/- 7%) but elevated by guanabenz (71 +/- 32%). The hyperglycemic and hypoinsulinemic responses to moxonidine were blocked by rauwolscine. In contrast, rauwolscine potentiated the reduction in glucagon (39 +/- 6%). AGN 193402 blocked the glucagon response without affecting hyperglycemia and hypoinsulinemia. Efaroxan blocked all responses to moxonidine. When SHROB rats were treated with moxonidine 15 min before an oral glucose tolerance test, the glucose area under the curve (AUC) was increased. Antagonizing the alpha2AR component of moxonidine's action with rauwolscine improved glucose AUC 3-fold and facilitated the insulin secretory response and reduced glucagon secretion. Testing fasting glucose and insulin during 3 weeks of oral moxonidine revealed early hyperglycemia that later faded, and a progressive drop in fasting insulin. The acute hyperglycemia and hypoinsulinemia elicited by moxonidine and rilmenidine was mediated by alpha2AR, whereas I1R may reduce glucagon and increase insulin, particularly after a glucose load. (+info)
Altered prejunctional modulation of intestinal cholinergic and noradrenergic pathways by alpha2-adrenoceptors in the presence of experimental colitis.
(42/222)
1 This study investigates the influence of intestinal inflammation on: (1) the control of intestinal neurotransmission and motility by prejunctional alpha(2)-adrenoceptors and (2) the expression of intestinal alpha(2)-adrenoceptors. Experimental colitis was induced by intrarectal administration of 2,4-dinitrobenzenesulphonic acid (DNBS) to rats. 2 UK-14,304 inhibited atropine-sensitive electrically evoked contractions of ileal and colonic longitudinal muscle preparations. UK-14,304 acted with similar potency, but higher efficacy, on tissues from DNBS-treated animals; its effects were antagonized with greater potency by phentolamine than rauwolscine. 3 Electrically induced [(3)H]noradrenaline release from ileal preparations was reduced in the presence of colitis. Tritium outflow was decreased by UK-14,304 and stimulated by rauwolscine or phentolamine: these effects were enhanced in preparations from animals with colitis. 4 Reverse transcription-polymerase chain reaction and Western blot assay demonstrated the protein expression of alpha(2A)-adrenoceptors in mucosal and muscular tissues isolated from ileum and colon. The induction of colitis increased alpha(2A)-adrenoceptor expression in both ileal and colonic muscular layers, without concomitant changes in mucosal tissues. 5 Induction of colitis reduced gastrointestinal propulsion of a charcoal suspension in vivo. In this setting, the gastrointestinal transit was inhibited by intraperitoneal (i.p.) UK-14,304 and stimulated by i.p. rauwolscine. After pretreatment with guanethidine, the stimulant action of rauwolscine no longer occurred, and UK-14,304 exerted a more prominent inhibitory effect that was antagonized by rauwolscine. 6 The present results indicate that, in the presence of intestinal inflammation, prejunctional alpha(2)-adrenoceptors contribute to an enhanced inhibitory control of cholinergic and noradrenergic transmission both at inflamed and noninflamed distant sites. Evidence was obtained that such modulatory actions depend on an increased expression of alpha(2A)-adrenoceptors within the enteric nervous system. (+info)
Differences in the mechanisms that increase noradrenaline efflux after administration of d-amphetamine: a dual-probe microdialysis study in rat frontal cortex and hypothalamus.
(43/222)
1. The extent to which impulse-independent release of noradrenaline and/or inhibition of its reuptake contribute to the response to d-amphetamine in vivo is unclear. Here, dual-probe microdialysis was used to investigate this question in the rat frontal cortex and hypothalamus. 2. After systemic administration of d-amphetamine (10 mg kg(-1)), or its local infusion (10 micro M), the increase in noradrenaline efflux in the hypothalamus was greater than in the frontal cortex. 3. In contrast, during local infusion of the noradrenaline reuptake inhibitor, BTS 54 354 (50 micro M), the noradrenaline response was similar in the frontal cortex and hypothalamus, even after systemic administration of the alpha(2)-antagonist, atipamezole, to block presynaptic inhibition of transmitter release and neuronal firing. 4. In the frontal cortex, but not the hypothalamus, the noradrenaline response to 10 micro M d-amphetamine was constrained by activation of alpha(2)-adrenoceptors. This suggests that, at this concentration, inhibition of reuptake of noradrenaline, following its impulse-dependent release, is evident in the frontal cortex, but that the noradrenaline response in the hypothalamus derives mostly from impulse-independent release (retrotransport). 5. Atipamezole did not affect the noradrenaline response to 100 micro M d-amphetamine in either brain region possibly because, at this higher concentration, retrotransport of noradrenaline masks any compensatory reduction in impulse-evoked release. 6. It is concluded that inhibition of reuptake and retrotransport make different contributions to the noradrenaline response to d-amphetamine in the frontal cortex and hypothalamus and that retrotransport increases with the concentration of d-amphetamine. (+info)
Activation of alpha2 adrenergic receptors suppresses fear conditioning: expression of c-Fos and phosphorylated CREB in mouse amygdala.
(44/222)
alpha(2) adrenergic agonists such as dexmedetomidine generally suppress noradrenergic transmission and have sedative, analgesic, and antihypertensive properties. Considering the importance of the neurotransmitter norepinephrine in forming memories for fearful events, we have investigated the acute and chronic effects of dexmedetomidine on discrete cue and contextual fear conditioning in mice. When administered before training, dexmedetomidine (10-20 microg/kg, i.p.) selectively suppressed discrete cue fear conditioning without affecting contextual memory. This behavioral change was associated with a decrease in memory retrieval-induced expression of c-Fos and P-CREB in the lateral, basolateral, and central nuclei of the amygdala. Dexmedetomidine's action on discrete cue memory did not occur in alpha(2A) adrenoceptor knockout (KO) mice. When dexmedetomidine was administered after training, it suppressed contextual memory, an effect that did not occur in alpha(2A) adrenoceptor KO mice. We conclude that dexmedetomidine, acting at alpha(2A) adrenoceptors, must be present during the encoding process to decrease discrete cue fear memory; however, its ability to suppress contextual memory is likely the result of blocking the consolidation process. The ability of alpha(2) agonists to suppress fear memory may be a valuable property clinically in order to suppress the formation of memories during stressful situations. (+info)
Impaired function of alpha2-adrenergic autoreceptors on sympathetic nerves associated with mesenteric arteries and veins in DOCA-salt hypertension.
(45/222)
The present study tested the hypothesis that there is impaired function of alpha(2)-adrenergic autoreceptors and increased transmitter release from sympathetic nerves associated with mesenteric arteries and veins from DOCA-salt rats. High-performance liquid chromatography was used to measure the overflow of ATP and norepinephrine (NE) from electrically stimulated mesenteric artery and vein preparations in vitro. In sham arteries, nerve stimulation evoked a 1.5-fold increase in NE release, whereas in DOCA-salt arteries there was a 3.9-fold increase in NE release over basal levels (P < 0.05). In contrast, stimulated ATP release was not different in DOCA-salt arteries compared with sham arteries. In sham veins, nerve stimulation evoked a 2.9-fold increase in NE release, whereas in DOCA-salt veins there was a 8.4-fold increase in NE release over basal levels (P < 0.05). In sham rats NE release, normalized to basal levels, was greater in veins than in arteries (P < 0.05). The alpha(2)-adrenergic receptor antagonist yohimbine (1 microM) increased ATP and NE release in sham but not DOCA-salt arteries. The alpha(2)-adrenergic receptor agonist UK-14304 (10 microM) decreased ATP release in sham but not DOCA-salt arteries. In sham veins, UK-14304 decreased, but yohimbine increased, NE release; effects that were not observed in DOCA-salt veins. These data show that nerve stimulation causes a greater increase in NE release from nerves associated with veins compared with arteries. In addition, impairment of alpha(2)-adrenergic autoreceptor function in sympathetic nerves associated with arteries and veins from DOCA-salt rats results in increased NE release. (+info)
Effect of cyclooxygenase and NO synthase inhibitors administered centrally on antinociceptive action of acetaminophen (Part II).
(46/222)
As it has been demonstrated in a previous study, both cyclooxygenases (COXs) and nitric oxide synthases (NOSs) participate in the mechanism of acetaminophen (ACETA) action. Results obtained in this study indicate that intrathecal (it) or intracerebroventricular (icv) pretreatment with LG-nitro-L-arginine (L-NO-Arg), a non-selective inhibitor of NOS activity, as well as with 7-nitroindazole (7-NI), a selective nNOS inhibitor, potentiated the antinociceptive activity of subceiling doses of ACETA, but were without effect on the action of supramaximal doses in Randall-Selitto test. Similar effect of L-NO-Arg and 7-NI it was observed in writhing test, whereas L-NO-Arg icv or L-NIL it did not influence the action of ACETA in this model. Indomethacin (IND), an inhibitor preferentially acting on COX-1, as well as nimesulide (NIM) and celecoxib (CECOX), i.e. preferential and selective inhibitor of COX-2, respectively, administered icv almost completely blocked the antinociceptive effect of ACETA in Randall-Selitto method. On the other hand, pretreatment with NSAIDs it initially increased and then attenuated the ACETA antinociception. Yohimbine (YOH), an alpha2-adrenergic receptor antagonist, did not modify the antinociceptive action of ACETA administered alone. However, YOH decreased the nociceptive threshold increased by simultaneously administered IND and ACETA, NIM and ACETA, as well as CECOX and ACETA in Randall-Selitto model. In contrast to the peripheral (sc) application, IND administered centrally (icv or it) did not modify the ACETA antinociception in writhing test. Neither NIM nor CECOX administered sc, it or icv changed the ACETA antinociception in this model. Possible mechanisms and sites of antinociceptive effects of ACETA are discussed. (+info)
Differential modulation by estrogen of alpha2-adrenergic and I1-imidazoline receptor-mediated hypotension in female rats.
(47/222)
We have recently shown that estrogen negatively modulates the hypotensive effect of clonidine (mixed alpha2-/I1-receptor agonist) in female rats and implicates the cardiovascular autonomic control in this interaction. The present study investigated whether this effect of estrogen involves interaction with alpha2- and/or I1-receptors. Changes evoked by a single intraperitoneal injection of rilmenidine (600 microg/kg) or alpha-methyldopa (100 mg/kg), selective I1- and alpha2-receptor agonists, respectively, in blood pressure, hemodynamic variability, and locomotor activity were assessed in radiotelemetered sham-operated and ovariectomized (Ovx) Sprague-Dawley female rats with or without 12-wk estrogen replacement. Three time domain indexes of hemodynamic variability were employed: the standard deviation of mean arterial pressure as a measure of blood pressure variability and the standard deviation of beat-to-beat intervals (SDRR) and the root mean square of successive differences in R-wave-to-R-wave intervals as measures of heart rate variability. In sham-operated rats, rilmenidine or alpha-methyldopa elicited similar hypotension that lasted at least 5 h and was associated with reductions in standard deviation of mean arterial pressure. SDRR was reduced only by alpha-methyldopa. Ovx significantly enhanced the hypotensive response to alpha-methyldopa, in contrast to no effect on rilmenidine hypotension. The enhanced alpha-methyldopa hypotension in Ovx rats was paralleled with further reduction in SDRR and a reduced locomotor activity. Estrogen replacement (17beta-estradiol subcutaneous pellet, 14.2 microg/day, 12 wk) of Ovx rats restored the hemodynamic and locomotor effects of alpha-methyldopa to sham-operated levels. These findings suggest that estrogen downregulates alpha2- but not I1-receptor-mediated hypotension and highlight a role for the cardiac autonomic control in alpha-methyldopa-estrogen interaction. (+info)
Selective modulation of noradrenaline release by alpha 2-adrenoceptor blockade in the rat-tail artery in vitro.
(48/222)
The effects of blocking alpha(2)-adrenoceptors on noradrenaline (NA) and adenosine 5'-triphosphate (ATP) release from postganglionic sympathetic nerves have been investigated in rat-tail artery in vitro. Continuous amperometry was used to measure NA release and intracellularly recorded excitatory junction potentials (e.j.p.'s) were used to measure ATP release. Application of the alpha(2)-adrenoceptor antagonist, idazoxan (1 microm), increased the amplitude of NA-induced oxidation currents evoked by trains of 10 stimuli at 1 and 10 Hz. In cells deep in the media, idazoxan (1 microm) had no effect on the amplitude of e.j.p.'s evoked by trains of 10 stimuli at 1 and 10 Hz. In cells close to the adventitial - medial border, idazoxan produced a small increase in the amplitude of e.j.p.'s evoked at the end of trains of 10 stimuli at 1 Hz. In tissues pretreated with the neuronal NA uptake inhibitor, desmethylimpramine (0.3 microm), idazoxan (1 microm) markedly increased the amplitude of e.j.p.'s in cells deep in the media. The alpha(2)-adrenoceptor agonist, clonidine (0.5 microm), produced similar reductions in the amplitudes of both NA-induced oxidation currents and e.j.p.'s evoked by 10 stimuli at 1 Hz. These effects of clonidine were reversed by the subsequent addition of idazoxan (1 microm). The release of both NA and ATP is inhibited to a similar extent by activation of prejunctional alpha(2)-adrenoceptors by clonidine. In contrast, endogenously released NA more markedly inhibits NA release. These findings provide further support for the differential modulation of NA and ATP release. (+info)