Biochemical pharmacology
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Biochemical pharmacology · Feb 2005
Histamine H1 receptor antagonist blocks histamine-induced proinflammatory cytokine production through inhibition of Ca2+-dependent protein kinase C, Raf/MEK/ERK and IKK/I kappa B/NF-kappa B signal cascades.
Histamine H1 receptor (H1R), a therapeutic target for alleviation of acute allergic reaction, may be also involved in mediating inflammatory responses via effects on cytokine production. However, the mechanisms whereby histamine induces cytokine production are poorly defined. In this study, we comprehensively investigated the signaling pathway involved in cytokine expression caused by histamine, using native human epidermal keratinocytes. ⋯ Furthermore, in addition to the above cytokines, histamine stimulated the biosynthesis and/or release of numerous keratinocyte-derived mediators, which are probably regulated by the ERK or NF-kappa B cascades. Our study suggests that histamine activates Ca(2+)-dependent PKC isoforms that play crucial roles in the activation of Raf/MEK/ERK and IKK/I kappa B/NF-kappa B cascades, leading to up-regulation of cytokine expression. Thus, the anti-inflammatory benefit of H1 antagonists may be in part due to prevention of cytokine production.
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Biochemical pharmacology · Feb 2005
3,5-di-t-butylcatechol (DTCAT) as an activator of rat skeletal muscle ryanodine receptor Ca2+ channel (RyRC).
In the present study, the effects of 3,5-di-t-butylcatechol (DTCAT) on ryanodine receptor Ca(2+) channel (RyRC) of skeletal muscle sarcoplasmic reticulum (SR) vesicles were investigated, both by monitoring extravesicular Ca(2+) concentration directly with the Ca(2+) indicator dye arsenazo III and by studying the high-affinity [(3)H]ryanodine binding. DTCAT stimulated Ca(2+) release from junctional (terminal cisternae) vesicles in a concentration-dependent manner, with a threshold activating concentration of 30 microM and a pEC(50) value of 3.43+/-0.03 M. ⋯ DTCAT inhibited [(3)H]ryanodine binding to SR vesicles with a K(i) of 232.5 microM, thus indicating that it acted directly at the skeletal muscle ryanodine receptor binding site to stimulate Ca(2+) release. In conclusion, the ability of DTCAT to release Ca(2+) from TC vesicles of skeletal muscle is noteworthy in view of its possible use as an alternative compound to either caffeine or halothane for performing the "In vitro contracture test" to diagnose the susceptibility of some patients to develop malignant hyperthermia under particular pharmacological treatments.