The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Feb 1998
Hypoxia inhibits cyclic nucleotide-stimulated epithelial ion transport: role for nucleotide cyclases as oxygen sensors.
Decreased oxygen delivery to cells (hypoxia) is prevalent in a number of important diseases. Little is known about mechanisms of oxygen sensing at the cellular level or about whether functional correlates of oxygen sensing exist. In this study, we examined the impact of hypoxia on stimulated epithelial ion transport function. ⋯ Because guanylate cyclase is a heme protein, we measured the influence of cobalt on activity of guanylate cyclase in purified plasma membrane preparations and found cobalt to inhibit stimulated cGMP levels in this cell-free system. Finally, pharmacological lowering of intracellular cGMP (using LY83583) resulted in decreased cAMP-stimulated Cl- secretion, and direct elevation of cGMP (using 8-bromo-cGMP or dibutyryl-cGMP) restored this hypoxia-induced activity. We conclude that a potential oxygen-sensing mechanism of epithelial cells involves the cooperation of heme-containing proteins such as guanylate cyclase and that biochemical cross-talk between cAMP- and cGMP-stimulated pathways may be important in such responses.
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J. Pharmacol. Exp. Ther. · Feb 1998
Pharmacological effects of SB 220025, a selective inhibitor of P38 mitogen-activated protein kinase, in angiogenesis and chronic inflammatory disease models.
Chronic inflammatory diseases often are accompanied by intense angiogenesis, supporting the destructive proliferation of inflammatory tissues. A model of inflammatory angiogenesis is the murine air pouch granuloma, which has a hyperangiogenic component. In this model, we explored the regulation of inflammatory angiogenesis using SB 220025, a specific inhibitor of human p38 mitogen-activated protein (MAP) kinase, with an IC50 value of 60 nM and 50- to 1000-fold selectivity vs. other kinases tested. ⋯ To further study the effects of p38/CSBP MAP kinase inhibition in angiogenesis-dependent chronic inflammatory disease, SB 220025 was tested in murine collagen-induced arthritis. In this model, SB 220025 was able to prevent the progression of established arthritis. Thus, this p38/CSBP MAP kinase inhibitor, which can reduce inflammatory cytokine production and inhibit angiogenesis, is an effective treatment for chronic proliferative inflammatory disease.
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J. Pharmacol. Exp. Ther. · Feb 1998
Repetitive opioid abstinence causes progressive hyperalgesia sensitive to N-methyl-D-aspartate receptor blockade in the rat.
The opioid abstinence syndrome is associated with spinal excitatory amino acid (EAA) release, hyperalgesia and long-term changes in dorsal horn cellular excitability. N-Methyl-D-aspartate (NMDA) receptor antagonism attenuates opioid tolerance but also blocks EAA release during abstinence. This study examines the effect of repetitive abstinence, and NMDA receptor antagonism during abstinence, on thermal nociceptive thresholds and spinal tolerance. ⋯ Hyperalgesia was most pronounced in groups subjected to repetitive abstinence, and least evident in groups in which continuous infusion was maintained or in which MK was administered during abstinence. MK administered during abstinence did not prevent tolerance. These results show that repetitive opioid abstinence is associated with progressive hyperalgesia mediated via NMDA receptor activation, but that NMDA receptor antagonism during such periods of abstinence does not prevent progressive opioid tolerance.