European journal of pharmacology
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N-tosyl-L-phenylalanyl-chloromethylketone (TPCK) in vitro blocks apoptotic pathways leading to cell death. We wished to see if TPCK would reduce brain injury in vivo. Seven-day-old rat pups had the right carotid artery ligated and then received either vehicle or TPCK (5 to 100 mg/kg i.p.). ⋯ TPCK decreased the reduction in right hemisphere weight from 15+/-3% (vehicle, n=20), to 4+/-2% (10 mg/kg, n = 19, P<0.01). TPCK reduced the number of cells staining for DNA breaks 3 days after injury from 1729+/-275 mm(-2) (vehicle, n = 8) to 550+/-236 mm(-2) (10 mg/kg TPCK, n = 9, P<0.01), decreased the amount of DNA fragmentation 3 days after injury by gel electrophoreses (20 mg/kg, n = 16, P<0.01) and eliminated the increase in nitric oxide metabolites 6 h after injury (vehicle 1.5+/-0.4, n = 10; and 20 mg/kg TPCK 0.0+/-0.1 nM/mg protein, n = 10, P<0.001). TPCK pretreatment in the newborn rat model of hypoxic-ischemic brain injury reduces DNA fragmentation, nitric oxide production and brain injury.
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Tactile allodynia, the enhanced perception of pain in response to normally non-painful stimulation, represents a common complication of diabetic neuropathy. The activation of endothelin ET(A) receptors has been implicated in diabetes-induced reductions in peripheral neurovascularization and concomitant endoneurial hypoxia. Endothelin receptor activation has also been shown to alter the peripheral and central processing of nociceptive information. ⋯ The endothelin ET(B) receptor-selective antagonist, 2R-(4-propoxyphenyl)-4S-(1, 3-benzodioxol-5-yl)-1-(N-(2, 6-diethylphenyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxy lic acid (A-192621; 20 mg/kg, i.p.), did not significantly alter tactile allodynia thresholds in streptozotocin-treated rats. Although combined i.p. administration of ABT-627 and A-192621 produced a significant, acute increase in tactile allodynia thresholds, this effect was significantly less than that produced by ABT-627 alone. These results indicate that the selective blockade of endothelin ET(A) receptors results in an attenuation of tactile allodynia in the streptozotocin-treated rat.
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Comparative Study
Dose-dependent effects of propofol on renal sympathetic nerve activity, blood pressure and heart rate in urethane-anesthetized rabbits.
To evaluate the role of the autonomic nervous system in hemodynamic changes after propofol bolus injection, we used direct recordings of renal sympathetic nerve activity to examine the dose-dependent effects of propofol (2.5, 5, 10, and 20 mg/kg) on heart rate, mean blood pressure and renal sympathetic nerve activity in urethane-anesthetized rabbits. The animals were divided into four groups: animals with an intact neuraxis (intact group), cervical vagal nerve-sectioned animals (vagotomy group), carotid sinus and aortic-nerve sectioned animals (SAD group), and animals with SAD plus vagotomy (SADV group). Heart rate did not change significantly even after administration of 2.5 and 5 mg/kg but decreased markedly on 20 mg/kg injection in all groups. ⋯ These results suggest the following: (1) propofol-induced hypotensive effects are probably produced by the central-mediated sympathetic depression. (2) The baroreceptor reflex may be preserved at the lower dose of the agent. (3) Heart rate does not change significantly unless a large dose of propofol is used. The difference in effects on heart rate and on mean blood pressure may denote a greater inhibition of sympathetic vascular outflow than of the cardiac sympathetic outflow regulating cardiac rate and contractility. This hypothesis needs further clarification.
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Comparative Study
Activation of rat locus coeruleus neuron GABA(A) receptors by propofol and its potentiation by pentobarbital or alphaxalone.
The action of propofol on the rat locus coeruleus was examined using intracellular recording from in vitro brain slice preparations. Concentrations of propofol between 3 and 300 microM were tested. At 100 microM, propofol completely inhibited the firing of all neurons tested (n=34); this was associated with a 5.7-mV hyperpolarization (range 0-16 mV, n=33) and a 35.6% reduction in input resistance (range 7.3-66.1%, n=33). ⋯ In contrast, diazepam caused no potentiation of either propofol- or GABA-induced responses. Our data also indicate that locus coeruleus neuron GABA(A) receptors possess distinctive pharmacologic characteristics, such as blocking of the propofol effects by zinc and insensitivity to diazepam and the direct action of pentobarbital. On the basis of these pharmacologic properties, we suggest that locus coeruleus neuron GABA(A) receptors do not contain the gamma subunit.
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Comparative Study
Up-regulation of cortical AMPA receptor binding in the fawn-hooded rat following ethanol withdrawal.
The present study has employed quantitative receptor autoradiography to compare the binding of (S)-[3H]5-fluorowillardiine to (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors in the brains of alcohol-preferring Fawn-Hooded (FH) rats, alcohol non-preferring Wistar-Kyoto (WKY) rats, and FH rats following a 28-day period of 5% ethanol consumption with or without ethanol withdrawal. Significantly higher binding of [3H]5-fluorowillardiine was found in the cingulate cortex (+12%) and claustrum (+13%) in alcohol naïve FH rats compared to WKY rats. ⋯ In contrast, ethanol withdrawal induced a significant "rebound" increase in binding by +22% in frontal and parietal cortex, by +17% in cingulate cortex and +13% in claustrum, and by +14% in the septohippocampal nucleus compared to chronic ethanol-exposed FH rats. The findings suggest that AMPA receptors in frontal cortical regions are sensitive to ethanol and therefore may be implicated in the predisposition of alcohol preference in FH rats.