British journal of pharmacology
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1. The location of the B1 bradykinin receptors involved in inflammatory hyperalgesia was investigated. 2. No specific binding of the B1 bradykinin receptor ligand [3H]-des-Arg10-kallidin was detected in primary cultures of rat dorsal root ganglion neurones, even after treatment with interleukin-1 beta (100 iu ml-1). 3. ⋯ Bradykinin (25 nM to 300 nM) evoked ventral root responses when applied to peripheral receptive fields or central terminals of primary afferents in the neonatal rat spinal cord and tail preparation. In contrast, des-Arg9-bradykinin (50 nM to 500 nM) failed to evoke ventral root depolarizations in either control rats or in animals that developed inflammation following ultraviolet irradiation of the tail skin. 6. The results of the present study imply that the B1 bradykinin receptors that contribute to hypersensitivity in models of persistent inflammatory hyperalgesia are located on cells other than sensory neurones where they may be responsible for releasing mediators that sensitize or activate the nociceptors.
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1. Chronic benzodiazepine treatment of rat cerebellar granule cells induced a transient down-regulation of the gamma-aminobutyric acidA (GABAA) receptor alpha 1 subunit protein, that was dose-dependent (1 nM-1 microM) and prevented by the benzodiazepine antagonist flumazenil (1 microM). After 2 days of treatment with 1 microM flunitrazepam the alpha 1 subunit protein was reduced by 41% compared to untreated cells, which returned to, and remained at, control cell levels from 4-12 days of treatment. ⋯ This study has shown that both flunitrazepam and GABA treatment, via their respective binding sites, caused a reduction in the expression of the GABAA receptor alpha 1 subunit protein; an effect mediated through the same neurochemical mechanism. The results also imply that the benzodiazepine effect is independent of GABA, and that the benzodiazepine and GABA sites may not be equally coupled to the down-regulation process, with the benzodiazepine site being the more dominant. The biochemical mechanism underlying the benzodiazepine-mediated down-regulation of the alpha 1 subunit protein seems to involve the activity of staurosporine-sensitive protein kinases.
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1. To evaluate the possible contribution of endothelin-1 (ET-1) to the pathophysiology of porcine septic shock, the non-peptide, mixed ET-receptor antagonist, bosentan (RO 47-0203) was administered (5 mg kg-1, i.v.) 30 min before infusion of lipopolysaccharide (LPS) (E. coli., serotype 0111:B4) (15 micrograms kg-1 h-1) and at 3.5 h of endotoxaemia in six anaesthetized and mechanically ventilated pigs. Six other pigs served as controls and received only LPS infusion. ⋯ This elevation was not influenced by bosentan. 4. From these studies using bosentan, a non-peptide, selective and mixed ET-receptor antagonist, we conclude that during LPS-induced shock bosentan can abolish the late phase pulmonary hypertension and improve cardiac output as well as increase blood flow to the splenic and intestinal vascular beds without causing a further decrease in mean arterial blood pressure. Further investigations in the clinical setting are needed to evaluate the use of ET-receptor antagonists, such as bosentan, in treatment of septic shock.
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1. The relative roles of ETA and ETB receptor activation on cholinergic nerve-mediated contraction and acetylcholine (ACh) release were examined in sheep isolated tracheal smooth muscle. 2. Electrical field stimulation (EFS; 90 V, 0.5 ms duration, 1 Hz, 10 s train) applied to sheep isolated tracheal smooth muscle strips induced monophasic contractile responses that were abolished by either 1 microM tetrodotoxin or 0.1 microM atropine, but were insensitive to 10 microM hexamethonium and 100 microM L-NAME. ⋯ In summary, sheep isolated tracheal smooth muscle contains two anatomically and functionally distinct endothelin receptor populations. ETA receptors located on airway smooth muscle mediate contraction, whereas ETB receptors appear to exist on cholinergic nerves that innervate tracheal smooth muscle cells and mediate inhibition of ACh release. The inhibitory effect of ETB receptor stimulation on cholinergic neurotransmission is in stark contrast to the enhancing effects hitherto described in the airways.
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1. A comparative study of the actions of structurally diverse allosteric modulators on mammalian (human alpha 3 beta 2 gamma 2L) or invertebrate (Drosophila melanogaster Rdl or a splice variant of Rdl) recombinant GABA receptors has been made using the Xenopus laevis oocyte expression system and the two electrode voltage-clamp technique. 2. Oocytes preinjected with the appropriate cRNAs responded to bath applied GABA with a concentration-dependent inward current. ⋯ By contrast, the Rdl, or Rdl splice variant forms of the invertebrate GABA receptor were insensitive to the positive allosteric modulating actions of etomidate. Neither the mammalian nor the invertebrate receptors, were directly activated by etomidate. 10. delta-Hexachlorocyclohexane enhanced GABA-evoked currents with EC50 values of 3.4 +/- 0.1 microM and 3.0 +/- 0.1 microM for the human alpha 3 beta 1 gamma 2L receptor and the Rdl splice variant receptor respectively. The maximal enhancement was 4.5