Halothane inhibits increases in Ca2+ sensitivity of canine tracheal smooth muscle primarily by interfering with the activation of heterotrimeric G-proteins, probably by inhibiting their dissociation.
We tested the hypothesis that increases in force at a given cytosolic Ca(2+) concentration (i.e., Ca(2+) sensitization) produced by muscarinic stimulation of canine tracheal smooth muscle (CTSM) are produced in part by mechanisms independent of changes in regulatory myosin light chain (rMLC) phosphorylation. This was accomplished by comparing the relationship between rMLC phosphorylation and force in alpha-toxin-permeabilized CTSM in the absence and presence of acetylcholine (ACh). Forces were normalized to the contraction induced by 10 microM Ca(2+) in each strip, and rMLC phosphorylation is expressed as a percentage of total rMLC. ACh (100 microM) plus GTP (1 microM) significantly shifted the Ca(2+)-force relationship curve to the left (EC(50): 0.39 +/- 0.06 to 0.078 +/- 0.006 microM Ca(2+)) and significantly increased the maximum force (104.4 +/- 4.8 to 120.2 +/- 2.8%; n = 6 observations). The Ca(2+)-rMLC phosphorylation relationship curve was also shifted to the left (EC(50): 1.26 +/- 0.57 to 0.13 +/- 0.04 microM Ca(2+)) and upward (maximum rMLC phosphorylation: 70.9 +/- 7.9 to 88.5 +/- 5. 1%; n = 6 observations). The relationships between rMLC phosphorylation and force constructed from mean values at corresponding Ca(2+) concentrations were not different in the presence and absence of ACh. We find no evidence that muscarinic stimulation increases Ca(2+) sensitivity in CTSM by mechanisms other than increases in rMLC phosphorylation.
Although current rates of intervention provided by anaesthesiologists and surgeons are low, there is considerable interest among these physicians in learning more about interventions. Given the relatively high prevalence of smoking in Japan and the potential for surgery to serve as a 'teachable moment' to promote abstinence from smoking, leadership by these specialists in the area of tobacco control could have a major impact on public health in Japan.
Midazolam directly relaxes airway smooth muscles by decreasing [Ca2+]i; this can be attributed to the inhibition of the influx of extracellular Ca2+. Midazolam has no effect on the release of stored Ca2+. In addition, midazolam has no effect on Ca2+ sensitivity of the contractile apparatus. Finally, benzodiazepine antagonists, flumazenil and PK11195, have no effect on this mechanism of direct action of midazolam on airway smooth muscles.
We studied 168 children with acute lymphoblastic leukemia (ALL) and 57 with acute nonlymphoblastic leukemia (ANLL) by retrospectively analyzing clinical symptoms, bone or joint involvement, and hematological findings to verify the clinical features and prognosis of children with acute leukemia who showed radiographic bone changes at the time of diagnosis. Of these, 36 with ALL (21.4%) and 6 with ANLL (10.5%) had symptoms referable to the bones or joints. Thirteen patients (7.7%) with ALL showed bone lesions radiographically. Phenotypically, 12 of the 13 had common ALL, 8 were incorrectly diagnosed and had received treatment for osteomyelitis or juvenile rheumatoid arthritis for 1 to 7 months prior to diagnosis of ALL. Leukocyte count was nearly normal with few or no blasts, and anemia and thrombocytopenia were mild or absent in all patients. Twelve of them remained in a complete remission for 26 to 148 months. Our data suggest that children with bone lesions related to acute leukemia exhibit clinical features that mimic infectious or collagen disease at diagnosis, and may belong to a subgroup of ALL with a better prognosis.
We studied in β-escin-permeabilized canine tracheal smooth muscle (CTSM) the effect of the protein kinase C (PKC) agonist phorbol 12,13-dibutyrate (PDBu) on isometric force at a constant submaximal Ca2+ concentration (i.e., the effect on Ca2+ sensitivity) and regulatory myosin light-chain (rMLC) phosphorylation. PDBu increased Ca2+sensitivity, an increase associated with a concentration-dependent, sustained increase in rMLC phosphorylation. PDBu altered the relationship between rMLC phosphorylation and isometric force such that the increase in isometric force was less than that expected for the increase in rMLC phosphorylation observed. The effect of four PKC inhibitors [calphostin C, chelerythrine chloride, a pseudosubstrate inhibitor for PKC, PKC peptide-(19—31) (PSSI), and staurosporine] on PDBu-induced Ca2+ sensitization as well as the effect of calphostin C and PSSI on rMLC phosphorylation were determined. Whereas none of these compounds prevented or reversed the PDBu-induced increase in Ca2+sensitivity, the PDBu-induced increase in rMLC phosphorylation was inhibited. We conclude that PDBu increases rMLC phosphorylation by activation of PKC but that the associated PDBu-induced increases in Ca2+ sensitivity are mediated by mechanisms other than activation of PKC in permeabilized airway smooth muscle.
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