Enhanced cortical dopamine output and antipsychotic-like effects of raclopride by alpha2 adrenoceptor blockade.
(65/2042)
Clozapine exerts superior clinical efficacy and markedly enhances cortical dopamine output compared with classical antipsychotic drugs. Here the alpha2 adrenoceptor antagonist idazoxan was administered to rats alone or in combination with the D2/3 dopamine receptor antagonist raclopride. Dopamine efflux in the medial prefrontal cortex and conditioned avoidance responding were analyzed. Idazoxan selectively potentiated the cortical output of dopamine and augmented the suppression of conditioned avoidance responding induced by raclopride. These results challenge basic assumptions underlying the dopamine hypothesis of schizophrenia and provide insight into clozapine's mode of action. (+info)
Alpha-adrenergic vasoreactivity of canine intrapulmonary bronchial arteries in pacing-induced heart failure.
(66/2042)
We hypothesized that pacing-induced congestive heart failure alters alpha-adrenergic constriction in intrapulmonary bronchial arteries. Cumulative dose responses to norepinephrine (NE), phenylephrine (PE), acetylcholine (ACh) and sodium nitroprusside (SNP) were determined in pressurized vessel segments. ED(50) values for NE and PE were higher for control (-5.34 +/- 0.09 and -4.27 +/- 0.08 M, respectively) vs. paced (-5.73 +/- 0.10 and -5.06 +/- 0.28 M, respectively) groups. Prazosin increased the ED(50) values for NE and PE in both control and paced groups. Yohimbine decreased NE ED(50) in the control group only. Endothelium removal or nitric oxide synthase (NOS) inhibition decreased control but not paced NE ED(50). Maximum vasodilation and sensitivity (i.e., -ED(50) values) were decreased for ACh but were similar for SNP in paced vs. control groups. Secondary segments were more reactive than paired primary segments in both groups, although pacing effects on ED(50) were unrelated to branching order. In conclusion, adrenergic constriction of canine intrapulmonary bronchial arteries is predominantly mediated via alpha(1)-adrenoreceptors and is enhanced after pacing. Endothelium-derived relaxing factor(s) normally opposes alpha-adrenergic vasoconstriction but not after pacing in this vasculature. (+info)
alpha-adrenergic blockade restores normal fluid transport capacity of alveolar epithelium after hemorrhagic shock.
(67/2042)
Activation of beta-adrenergic receptors in the lung is an important mechanism that can prevent alveolar flooding after brief but severe hemorrhagic shock. However, a neutrophil-dependent oxidant injury to the alveolar epithelium prevents the normal upregulation of alveolar fluid clearance by catecholamines after prolonged hemorrhagic shock. Because hemorrhage increases proinflammatory cytokine expression in the lung partly through the activation of alpha-adrenergic receptors, the objective of this study was to determine whether alpha-adrenergic blockade would restore the normal fluid transport capacity of the alveolar epithelium after hemorrhagic shock. Hemorrhagic shock was associated with a significant increase of interleukin-1beta (IL-1beta) concentration in the lung and a failure of the alveolar epithelium to respond to beta-adrenergic agonists, with the upregulation of vectorial fluid transport despite intra-alveolar administration of exogenous catecholamines. In contrast, catecholamine-mediated upregulation of alveolar liquid clearance was restored by pretreatment with phentolamine, an alpha-adrenergic-receptor antagonist. Phentolamine pretreatment also significantly attenuated the shock-mediated increase of IL-1beta concentration in the lung. Additional experiments demonstrated that the inhibition of IL-1beta binding to its receptor by the administration of IL-1-receptor antagonist restored the normal fluid transport capacity of the alveolar epithelium after hemorrhagic shock. In summary, the results of these studies indicate that the activation of alpha-adrenergic receptors after hemorrhagic shock prevents the beta-adrenergic-dependent upregulation of alveolar fluid clearance by modulating the severity of the pulmonary inflammatory response. (+info)
Activation of antilipolytic alpha(2)-adrenergic receptors by epinephrine during exercise in human adipose tissue.
(68/2042)
The involvement of the antilipolytic alpha(2)-adrenergic pathway and the specific role of epinephrine in the control of lipolysis during exercise in adipose tissue (AT) were investigated in healthy male subjects (age: 24.1 +/- 2.2 yr; body mass index: 23.0 +/- 1.6). An in vitro study carried out on isolated adipocytes showed that the weak lipolytic effect of epinephrine was potentiated after blockade of alpha(2)-adrenergic receptor (AR) by an alpha(2)-AR antagonist and reached that of isoproterenol, a beta-AR agonist. The effect of the nonselective alpha(2)-AR antagonist phentolamine on the response of the extracellular glycerol concentration (EGC) in AT during two successive bouts of aerobic exercise (50% maximum O(2) uptake, 60 min duration) was evaluated using the microdialysis method. The metabolic responses measured in perfused probes with Ringer solution were compared with those obtained in perfused probes with Ringer plus 0.1 mmol/l phentolamine. Plasma norepinephrine level was not different during the two exercise bouts, whereas that of epinephrine was 2.5-fold higher during the second exercise. EGC in AT was twofold higher in the second compared with the first exercise, and the same response pattern was found for plasma glycerol. The exercise-induced increase in EGC was higher in the probe perfused with phentolamine compared with the control probe in both bouts of exercise. However, the potentiating effect of phentolamine on EGC was significant during the second exercise bout but did not reach a significant level during the first. These results suggest that epinephrine is involved in the control of lipid mobilization through activation of antilipolytic alpha(2)-AR in human subcutaneous AT during exercise. (+info)
Analysis of vasoconstrictor responses to histamine in the hindlimb vascular bed of the rabbit.
(69/2042)
Hemodynamic responses to histamine were investigated in the anesthetized rabbit. Intravenous injections of histamine induced dose-dependent decreases in systemic arterial pressure that were blocked by the H(1)-receptor antagonist pyrilamine but not the H(2) antagonist cimetidine. Injections of histamine and the H(1) agonist 6-[2-(4-imidazolyl)ethylamine]-N-(4-trifuormethylphenyl)-heptan ecardo xamide dimaleate (HTMT) into the hindlimb perfusion circuit increased hindlimb perfusion pressure, whereas the H(2) agonist dimaprit decreased perfusion pressure and the H(3)-receptor agonist R-(-)-alpha-methylhistamine did not alter perfusion pressure. Pyrilamine reduced hindlimb vasoconstrictor responses to histamine and HTMT but did not alter vasodilator responses to dimaprit. Cimetidine reduced the response to dimaprit but did not alter vasoconstrictor responses to histamine or HTMT. The H(3)-receptor antagonist thioperamide was without effect on responses to the histamine agonists. These data suggest the presence of H(1) and H(2) receptors and that histamine for the most part acts by stimulating H(1) receptors to produce vasoconstriction in the hindlimb vascular bed of the rabbit. Responses to histamine, HTMT, and norepinephrine were significantly enhanced by a nitric oxide synthase inhibitor at a time when vasodilator responses to dimaprit were unaltered and responses to acetylcholine were significantly reduced. Responses to histamine and the H(1) and H(2) agonists were not affected by the cyclooxygenase inhibitor meclofenamate or by ATP-sensitive K(+) channel, alpha-adrenergic, or angiotensin AT(1) receptor antagonists. The present data suggest that H(1) receptors mediate both systemic vasodepressor and hindlimb vasoconstrictor responses to histamine. (+info)
Modulation of sibutramine-induced increases in extracellular noradrenaline concentration in rat frontal cortex and hypothalamus by alpha2-adrenoceptors.
(70/2042)
1. The effects of sibutramine (0.25 - 10 mg kg-1 i.p.) on extracellular noradrenaline concentration in the frontal cortex and hypothalamus of freely-moving rats were investigated using microdialysis. The role of presynaptic alpha2-adrenoceptors in modulating the effects of sibutramine in these brain areas was also determined. 2. Sibutramine induced an increase in extracellular noradrenaline concentration, the magnitude of which paralleled dose, in both brain areas. In the cortex, this increase was gradual and sustained, whereas in the hypothalamus it was more rapid and of shorter duration. 3. In both the cortex and hypothalamus, pretreatment of rats with the alpha2-adrenoceptor antagonist RX821002 (3 mg kg-1 i.p.) potentiated increases in the accumulation of extracellular noradrenaline induced by sibutramine (10 mg kg-1 i. p.), by 7 and 10 fold respectively. RX821002 also reduced the latency of sibutramine to reach its maximum effect in the cortex, but not in the hypothalamus. 4. Infusion of RX821002 (1 microM) via the probe increased the accumulation of extracellular noradrenaline induced by sibutramine (10 mg kg-1 i.p.) in both brain areas. In the hypothalamus, the effects of RX821002 on the accumulation of noradrenaline induced by sibutramine were 2 fold greater than those in the cortex. 5. These findings support evidence that sibutramine inhibits the reuptake of noradrenaline in vivo, but that the accumulation of extracellular noradrenaline is limited by noradrenergic activation of presynaptic alpha2-adrenoceptors. Furthermore, the data suggest that terminal alpha2-adrenoceptors in the hypothalamus exert a greater inhibitory effect over the control of extracellular noradrenaline accumulation than do those in the cortex. (+info)
Alpha-2 adrenergic modulation of prefrontal cortical neuronal activity related to spatial working memory in monkeys.
(71/2042)
The effects of systemically administered or iontophoretically applied clonidine (alpha-2 adrenergic agonist) and iontophoretically applied yohimbine (alpha-2 adrenergic antagonist) were examined on prefrontal cortical (PFC) neurons related to spatial working memory (SWM). Systemically administered clonidine (0.04 mg/kg) enhanced SWM-related PFC neuronal activity by 32.5 +/- 14.5%, (mean +/- SD; n = 25 neurons). The facilitatory effect of clonidine was antagonized by iontophoretically applied yohimbine. Iontophoretically applied clonidine enhanced SWM-related PFC neuronal activity by 38.2 +/- 18.6%, (n = 13 neurons), whereas similarly applied yohimbine suppressed it by 34.4 +/- 17.8% (n = 28 neurons). These results indicate that: a) systemically administered clonidine can facilitate SWM-related PFC neuronal activity through actions at alpha-2 adrenoceptors in the PFC; and b) conversely, blockade by yohimbine of alpha-2 adrenoceptors in the PFC suppresses SWM-related neuronal activity. The present study provides neurophysiological evidence that alpha-2 adrenoceptors in the PFC are involved in the cellular mechanisms underlying working memory. (+info)
Treatment with the noradrenergic alpha-2 agonist clonidine, but not diazepam, improves spatial working memory in normal young rhesus monkeys.
(72/2042)
Noradrenergic alpha-2 agonists such as clonidine and guanfacine improve working memory performance in aged monkeys. Guanfacine also improves cognition in young monkeys, but there are conflicting reports of the effects of clonidine in young adult human and nonhuman primates. In the present study, high doses of clonidine (0.02-0.1 mg/kg) significantly improved performance of the delayed response task, a test of spatial working memory, in young adult monkeys. Lower doses (0.0001-0.01 mg/kg), similar to those used in human studies (0.001-0.003 mg/kg), had no effect on task performance. In contrast, monkeys experimentally depleted of catecholamines by chronic reserpine treatment have been improved by both dose ranges. These results provide further support for the hypothesis that alpha-2 agonists improve cognition via actions at post-synaptic alpha-2 receptors, and suggest that conflicting results with clonidine in previous studies of prefrontal cortical function may result from insufficient dosage. (+info)