2,340 research outputs found
PCV157 ACCOUNTING FOR TRIAL-EXCLUDED MEDICAL CONDITIONS WHEN SIMULATING MORTALTIY IN CLINICAL TRIAL POPULATIONS
Cyclic AMP Inhibits Secretion From Electroporated Human Neutrophils
It has long been known that Intracellular cAMP inhibits and cGMP enhances intact neutrophil function. However, these effects are modest and require relatively high concentrations of the cyclic nucleotides. We decided to reâexamine the effects of cyclic nucleotides on Ca2+âinduced secretion by electroporated cells. This system allowed us to bypass normal cell surface receptorâligand interactions as well as to directly expose the intracellular space to native cyclic nucleotides. We found that concentrations of cAMP as low as 3 ÎŒM inhibited Ca2+âinduced secretion; 30â300 ÎŒM cAMP was maximally inhibitory. cAMP was actually slightly more potent than dibutyryl cAMP, a membraneâpermeant derivative. In contrast, cGMP was only slightly stimulatory at 3 ÎŒM and modestly inhibitory at 300 ÎŒM; dibutyryl cGMP was ineffective. A more detailed investigation of the effects of cAMP showed that inhibition was only obtained in the presence of Mg2+. Halfâmaximal inhibition by cAMP occurred at 10â30 ÎŒM. Inhibition by cAMP was achieved by shifting the Ca2+ doseâresponse curve for secretion to the right; this was observed for the release of both specific granules (vitamin B12 binding protein) and azurophil granules (Bâglucuronidase). We previously showed that ATP could enhance Ca2+âinduced secretion in the presence of Mg2+, apparently by interacting with a cell surface purine receptor. However, increasing concentrations of ATP could not overcome inhibition by cAMP; this suggested that cAMP acted at some site other than the purine receptor. Inhibition by cAMP was also less apparent in the presence of the protein kinase C agonist phorbol myristate acetate (PMA), suggesting that the cyclic nucleotide did not produce systemic desensitization of the neutrophils. In summary, these results demonstrate that low, physiologically relevant concentrations of cAMP can modulate neutrophil responsiveness.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141578/1/jlb0172.pd
Combined depletion of interleukin-1 and interleukin-6 does not exceed single depletion of interleukin -1 in TNF-mediated arthritis
Human neutrophil phosphodiesterase
Extracts of human neutrophils were examined for phosphodiesterase activity using a radiochemical assay. As reported by other investigators, both high- and low- K m forms of the enzyme were found. Although calmodulin could be measured in these extracts, human neutrophil phosphodiesterase proved not to be calmodulin dependent. Activity of the neutrophil phosphodiesterase was also not altered by physiologic concentrations of indomethacin, p -bromophenacyl bromide, eicosatetraenoic acid, or eicosatetraynoic acid, all inhibitors of arachidonic acid metabolism. These results are relevant to stimulus-secretion coupling in neutrophils, wherein calmodulin-dependent reactions play a vital role.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44535/1/10753_2004_Article_BF00916094.pd
Glucose metabolism and oscillatory behavior of pancreatic islets
A variety of oscillations are observed in pancreatic islets.We establish a
model, incorporating two oscillatory systems of different time scales: One is
the well-known bursting model in pancreatic beta-cells and the other is the
glucose-insulin feedback model which considers direct and indirect feedback of
secreted insulin. These two are coupled to interact with each other in the
combined model, and two basic assumptions are made on the basis of biological
observations: The conductance g_{K(ATP)} for the ATP-dependent potassium
current is a decreasing function of the glucose concentration whereas the
insulin secretion rate is given by a function of the intracellular calcium
concentration. Obtained via extensive numerical simulations are complex
oscillations including clusters of bursts, slow and fast calcium oscillations,
and so on. We also consider how the intracellular glucose concentration depends
upon the extracellular glucose concentration, and examine the inhibitory
effects of insulin.Comment: 11 pages, 16 figure
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