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Biomedical subjects

M M Dale

Publications and source records attributed to M M Dale.

At least 19 recordsLinked to original sources
PubMed1994

The effect of non-steroidal anti-inflammatory drugs on the accumulation and release of interleukin-1-like activity by peritoneal macrophages from the mouse.

1. The non-steroidal anti-inflammatory drugs (NSAIDs) indomethacin, 10 and 100 microM, piroxicam, 100 microM, and sodium meclofenamate, 1 and 100 microM, potentiated the lipopolysaccharide (LPS)-stimulated release of interleukin-1 (IL-1)-like activity from mouse peritoneal macrophages. Aspirin up to 100 microM was without effect. The drugs did not themselves stimulate the release of IL-1-like activity at the concentrations used. 2. LPS, 1 microgram ml-1, stimulated prostaglandin E2 production by mouse peritoneal macrophages and this was totally inhibited by aspirin, 100 microM, indomethacin, 1 microM, piroxicam, 10 microM and sodium meclofenamate, 0.1 microM. 3. The potentiation of LPS-stimulated release of IL-1-like activity produced by indomethacin, 100 microM, piroxicam, 100 microM, or sodium meclofenamate, 10 microM, was inhibited by prostaglandin E2, (PGE2) 10 ng ml-1. 4. Aspirin, 100 microM, indomethacin, 100 nM to 10 microM, piroxicam, 1 to 100 microM, and sodium meclofenamate, 10 nM, all potentiated cell-associated IL-1-like activity in LPS- stimulated macrophages. The drugs had no effect on cell-associated IL-1-like activity by themselves. 5. Exogenous PGE2, 2 to 30 ng ml-1, inhibited the cell-accumulation of IL-1-like activity stimulated by LPS in the presence of indomethacin, 1 microM, or sodium meclofenamate, 0.1 microM. 6. The 5-lipoxygenase inhibitors BWA4C, 0.01 to 10 microM, and L-651,392, 0.01 to 10 microM, had no effect on LPS-stimulated released or cell-associated IL-1-like activity. Over the same concentration-ranges,neither of the 5-lipoxygenase inhibitors affected released or cell-associated IL-1-like activity in LPS stimulated mouse macrophages in the presence of indomethacin, 1 JM.7. The synthetic diacylglycerol, DiC8, 10 to 200 JAM, did not itself increase released or cell-associated IL-I-like activity but in the presence of the diacylglycerol kinase inhibitor, R59022, 10 JM, DiC8increased released and cell-associated IL-i-like activity. The activity of DiC8 on released and cell associated IL-l-like activity was not increased by indomethacin, 100 micro M.8. NSAIDs increase LPS-induced cell-associated IL-i-like activity in mouse macrophages by inhibiting the formation of cyclo-oxygenase products such as PGE2 but at higher concentrations the NSAIDs potentiate LPS-induced release of IL-I-like activity by a mechanism independent of cyclo-oxygenase inhibition. The potentiation of the release of IL-i-like activity appears not to be related to an effect of NSAIDs on either 5-lipoxygenase or diacylglycerol metabolism.

Animals↗
PubMed1992

Cyclooxygenase-independent effects of non-steroidal anti-inflammatory drugs on the neutrophil respiratory burst.

A range of 12 non-steroidal anti-inflammatory drugs (NSAIDs), including members from each of the main chemical groups, were examined for their effects on the oxidative burst induced by the receptor stimulus, platelet-activating factor, and the two post-receptor stimuli, fluoride and dioctanoylglycerol. It was found that the NSAIDs fell into three categories: (1) those that increased the stimulated superoxide (O2-) response, (2) those that had no effect and (3) those that decreased O2- production. All the drugs were without effect in unstimulated cells. The mode of action of those drugs that caused enhancement of the O2- response is unlikely to be due to an inhibition of the cyclooxygenase pathway of arachidonate metabolism as not all NSAIDs caused the enhancement. This data could have clinical implications for the therapy of inflammatory disorders such as rheumatoid arthritis, in that those NSAIDs which cause an increased O2- response, while providing temporary relief of symptoms, could be exacerbating the underlying inflammatory condition and associated tissue damage.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1991

A novel conformationally restricted protein kinase C inhibitor, Ro 31-8425, inhibits human neutrophil superoxide generation by soluble, particulate and post-receptor stimuli.

A novel, bis-indolylmaleimide, Ro 31-8425, bearing a conformationally restricted side chain, inhibits protein kinase C isolated from rat brain and human neutrophils with a high degree of selectivity over cAMP-dependent kinase and Ca2+/calmodulin-dependent kinase. It also inhibits phorbol ester-induced intracellular events known to be mediated by protein kinase C (p47 phosphorylation in intact platelets, CD3 and CD4 down-regulation in T-cells). Ro 31-8425 inhibited superoxide generation in human neutrophils activated by both receptor stimuli (formyl-methionyl-leucylphenylalanine, opsonized zymosan, IgG and heat aggregated IgG) and post-receptor stimuli (1,2-dioctanoylglycerol and fluoride). The compound also blocked antigen driven, but not IL-2 induced, T-cell proliferation. These results support a central role for protein kinase C in the activation of the respiratory burst and antigen-driven T-cell proliferation.

Animals↗
PubMed1991

The protein kinase C inhibitor, K252a, inhibits superoxide production in human neutrophils activated by both PIP2-dependent and -independent mechanisms.

We report that the putative protein kinase C inhibitor, K252a, at concentrations of 0.2 and 1 microM, inhibited the respiratory burst induced by fluoride and formyl-methionyl-leucyl-phenyl-alanine respectively, both in human neutrophils primed with a subthreshold dose of phorbol myristate acetate and in non-primed neutrophils. In addition, K252a effectively inhibited ConA-zymosan-mediated superoxide generation in Ca2(+)-depleted neutrophils, with virtually maximal inhibition seen at 1 microM. These results suggest that protein kinase C is involved in the putative phosphatidylinositol bisphosphate-independent signal transduction mechanism of the respiratory burst as well as the pathway dependent on phosphatidylinositol bisphosphate hydrolysis.

Calcium↗
PubMed1990

The effect of new potent selective inhibitors of protein kinase C on the neutrophil respiratory burst.

New potent inhibitors of protein kinase C were found to inhibit protein kinase C isolated from rat brain and human neutrophils, with a large degree of selectivity over cAMP-dependent kinase and Ca2+/calmodulin-dependent kinase. These novel compounds were potent inhibitors of the fluoride, diC8- and formyl-methionyl-leucyl-phenylalanine-mediated respiratory bursts in intact neutrophils. The opsonized zymosan-stimulated burst was only marginally affected by the compounds. These results differ from those obtained in studies with H7 and CI, (which are less potent and less specific protein kinase C inhibitors) and are consistent with the hypothesis that protein kinase C has a role in the transduction mechanism for the neutrophil oxidative burst stimulated with fluoride, formyl-methionyl-leucyl-phenylalanine and diC8.

Alkaloids↗
PubMed1990

The activation of gold complexes by cyanide produced by polymorphonuclear leukocytes--II. Evidence for the formation and biological activity of aurocyanide.

Experiments have been conducted to investigate a possible mechanism which might explain why aurothiomalate (Autm), a gold complex used in the treatment of rheumatoid arthritis, is active in vivo but not in vitro, by testing the hypothesis that Autm is converted to aurocyanide by activated polymorphonuclear leukocytes (PMN) which generate cyanide from thiocyanate, an anion which is present in plasma at concentrations ranging from 20 to 200 microM. Two-stage experiments were conducted in which PMN, in the first stage, were activated by opsonized zymosan in the presence of Autm both with and without thiocyanate. Then, in the second stage, the effect of the drugs on superoxide (O2-) production stimulated by a further addition of zymosan was measured. Autm at concentrations of 10 and 100 microM decreased O2- production if thiocyanate was present, but not if it was absent. By contrast, preformed aurocyanide at 10 and 100 microM decreases O2- production by PMN stimulated by opsonized zymosan both in the presence and absence of thiocyanate. Changes in the ultraviolet spectra of the supernatants of PMN indicated that aurocyanide was formed by activated PMN in the presence of thiocyanate but not in its absence.

Cyanates↗
PubMed1990

Enhancement of A23187-induced release of enteric vasoactive intestinal polypeptide by phorbol 12,13-dibutyrate.

The effect of phorbol 12,13-dibutyrate on calcium ionophore (A23187)-induced release of vasoactive intestinal polypeptide from enteric nerves was examined. A23187 caused release of vasoactive intestinal polypeptide dose dependently and phorbol 12,13-dibutyrate (100 nM) markedly shifted the dose-response curve of A23187 to the left. The significance of these findings will be discussed in relation to the mechanism of release of vasoactive intestinal polypeptide from enteric nerves.

Animals↗
PubMed1990

The effect of putative protein kinase C inhibitors, K252a and staurosporine, on the human neutrophil respiratory burst activated by both receptor stimulation and post-receptor mechanisms.

1. Two compounds, reported to be potent inhibitors of protein kinase C (PKC), K252a and staurosporine, have been examined in order to gain further information as to the possible role played by PKC in the signal transduction sequence of the neutrophil respiratory burst as determined by superoxide (O2-) production. 2. A number of stimuli were used in the study, some acting at receptors i.e. fMet-Leu-Phe (fMLP), opsonized zymosan and heat-aggregated IgG (HAGG), one acting on a G-protein, fluoride, and two direct PKC activators, dioctanoylglycerol (diC8) and phorbol myristate acetate (PMA). 3. K252a and staurosporine inhibited the respiratory burst with all the stimuli but the order of agonist sensitivity was very different with the two inhibitors. 4. For K252a-induced inhibition of O2- release, the order of potency was fluoride greater than fMLP, HAGG greater than opsonized zymosan greater than PMA, DiC8. For staurosporine-induced inhibition of O2- release, the order of potency changed to fluoride greater than DiC8, PMA greater than HAGG, fMLP greater than opsonized zymosan. The significance of this unexpected difference in relative rank order of potency is discussed with reference to the reported mechanism of action of the two inhibitors and the events involved in the oxidative burst. 5. Staurosporine at low concentrations increased the fMLP-stimulated O2- response by 100%, the maximum effect occurring at 35 nM. 6. To the extent that the compounds used are specific inhibitors of PKC, these findings support a role for the enzyme PKC in stimulus-activation coupling in O2- generation with all the stimuli used in this study.

Alkaloids↗
PubMed1989

The effect of smooth muscle relaxants working through different transduction mechanisms on the phorbol dibutyrate-induced contraction of the guinea-pig lung parenchymal strip: possible relevance for asthma.

It has been suggested that protein kinase C activation may have a role in the maintained, 'latch-bridge' phase of smooth muscle contraction. We have examined the effects of a range of smooth muscle relaxants on the maintained contraction produced in the guinea-pig parenchymal lung strip by the protein kinase C activator, 4 beta-phorbol dibutyrate (4 beta-PDBu). The maximum histamine contraction (produced by 10 microM) was used as a standard and the effects of the smooth muscle relaxants were also studied on this histamine-induced contraction. After 4 beta-PDBu, 1 microM, had produced contraction, enprofylline, forskolin and papaverine caused concentration-dependent relaxation, producing total reversal of the contraction, while prostaglandin E2 and prostacyclin caused a concentration-dependent relaxation but less than total reversal. The concentrations required for the effects on the phorbol ester contraction were 10 to 100-fold higher than were necessary for relaxation of the maximum contraction produced by histamine. Isoprenaline, 1 microM, a concentration which caused total reversal of the histamine-induced contraction, caused only 22% decrease of the phorbol dibutyrate-induced contraction and no further relaxation occurred with higher concentrations. Cromakalim--a potassium channel activator proposed as a therapy for nocturnal asthma--had virtually no effect on preparations pre-contracted with 4 beta-PDBu, 1 microM, or histamine, 10 microM, but caused about 70% and 20% reversal of the contraction produced by 3 microM histamine and 100 nM 4 beta-PDBu respectively. When single doses of the relaxants were administered before a series of doses of 4 beta-PDBu given cumulatively, enprofylline, 1 microM, and aminophylline, 100 microM and 1 microM, caused a moderate right-shift of the phorbol dibutyrate concentration-response curve, but isoprenaline, 1 microM, was less effective, while cromakalim had no discernible effect. These results are discussed in the light of suggestions that inappropriate activation of protein kinase C in smooth muscle cells, may contribute to the pathogenesis of the late phase of asthma.

Animals↗
PubMed1989

The effect of relaxants working through different transduction mechanisms on the tonic contraction produced in rat aorta by 4 beta-phorbol dibutyrate.

1. We have examined the effects of a range of smooth muscle relaxants on the maintained contractions produced in rat aortic rings by the protein kinase C activator, 4 beta-phorbol dibutyrate; these effects were compared with those on the contraction induced by the selective alpha 1-adrenoceptor agonist, methoxamine. The phorbol ester, at 0.3 microM, gave a sustained contraction which was, on average, of approximately the same magnitude as the maximum contraction produced by methoxamine, 10 microM. 2. The beta-adrenoceptor agonist, isoprenaline (0.01-1 microM) caused a dose-related relaxation of the methoxamine-induced contraction but had no effect on the contraction induced by the phorbol ester. 3. An activator of adenylate cyclase, forskolin (0.01-1 microM) produced a dose-related relaxation of the methoxamine-induced contraction and at 0.01-10 microM caused relaxation of the contraction induced by the phorbol ester. Similar results were obtained with the potassium channel activator, cromakalim (0.001-10 microM). 4. An activator of guanylate cyclase, sodium nitroprusside (0.001-100 microM) caused a dose-related relaxation of both the methoxamine-induced and the phorbol ester-induced contraction, being more effective on the former than on the latter. Similar results were obtained with enprofylline (1-1000 microM). 5. Methoxamine (10 nM-100 microM), given cumulatively, caused a dose-related contractile response. Pretreatment with isoprenaline (1 microM), enprofylline (10 microM) and nicorandil (1 microM) resulted in partial decrease of the subsequent response to methoxamine, while nicorandil (10 microM), forskolin (1 microM), sodium nitroprusside (10 microM) and cromakalim (1 microM) totally abolished it. 6. The phorbol ester, given cumulatively, caused increasing contraction in the concentration range 30 nM-10 microM. Pretreatment with forskolin (1 microM), sodium nitroprusside (10 microM), isoprenaline (1 microM), enprofylline (10 microM), nicorandil (1 microM or 10 microM), or cromakalin (1 microM or 10 microM), resulted in partial decrease of the subsequent response to 4 beta-phorbol dibutyrate. 7. These results are discussed in the light of the suggestion that protein kinase C may have a role in the 'latch-bridge' phase of smooth muscle contraction, and that inappropriate activation of protein kinase C may contribute to the pathogenesis of hypertension and other conditions involving vasospasm.

Animals↗
PubMed1988

The effect of inhibition of both diacylglycerol metabolism and phospholipase A2 activity on superoxide generation by human neutrophils.

A 'cocktail' consisting of an inhibitor of diacylglycerol kinase (R59022, 10 microM), an inhibitor of diacylglycerol lipase (RHC80267, 10 microM), and an inhibitor of phospholipase A2 (either 100 microM indomethacin, or 100 microM sodium meclofenamate) markedly enhanced superoxide production by human neutrophils stimulated with post-receptor stimuli, fluoride and gamma-hexachlorocyclohexane. On the other hand, the response to the C3b/Fc receptor stimulus, opsonized zymosan, was marginally decreased whilst that to the Fc receptor stimulus, aggregated IgG, was virtually unaffected. Since the inhibitors used are deemed to inhibit the main routes of arachidonate production, these results call into question the role of arachidonate in the transduction of O2- generation by post-receptor stimuli, but support a role for arachidonate in receptor-mediated transduction.

Cyclohexanones↗
PubMed1988

The leucocytosis of exercise. A review and model.

Exercise is known to induce an immediate leucocytosis, the magnitude of which is related, in most instances, to the intensity and duration of the work. On finishing exercise, however, the leucocyte count may change in any one of several different ways. The pattern of postexercise changes in the leucocyte count is determined mainly by the time which has elapsed since beginning exercise, rather than the work intensity or the total work done, if, for example, exercise has been intermittent. Consideration of, firstly, the circumstances under which the plasma concentrations of catecholamines and cortisol have been found separately to correlate with the leucocyte count at the finish of exercise, and, secondly, the effects on the leucocyte count of exogenous administration of these substances has led us to develop a model which can satisfactorily account for all of the principal changes in the leucocyte count that have been noted during and after exercise. It is proposed that catecholamines produced during exercise act to increase the ratio of circulating to non-circulating leucocytes, while cortisol acts, by a mechanism which involves a time lag, to increase the total number of leucocytes in the vascular compartment. Examination of previously published reports shows that many contain results which support this model. Using the model as a basis, some predictions are made that can be tested experimentally, and some experiments are suggested which should help elucidate the mode of action of catecholamines and cortisol.

Adolescent↗
PubMed1988

Interactions between phorbol esters and agents which increase cytosolic calcium in the guinea pig parenchymal strip: direct and indirect effects on the contractile response.

In the guinea pig parenchymal strip the cumulative concentration-response curve to 4 beta-phorbol dibutyrate (4 beta-PDBu) occurred over the range 10 nM to 10 microM, the response to 10 microM being 246 +/- 22% of the mean maximum histamine response. A "cocktail" of agents which inhibit synthesis and/or release of mediators (mepyramine, 1 microM; indomethacin, 1 microM; mepacrine, 300 microM; atropine, 10 microM; cimetidine, 10 microM; phentolamine, 10 microM; and quercetin, 50 microM) had no effect on the cumulative 4 beta-PDBu concentration-response curve, indicating that the response was not due to the release of noradrenaline, acetylcholine, histamine, platelet activating factor or eicosanoids. When the cumulative curves to vanadate and A23187 were measured in the presence of the cocktail of inhibitors, the vanadate response was unaffected, but the response to A23187 was reduced marginally. Threshold concentrations of four agents which increase cytosolic calcium (Bay K 8644, 1 and 10 nM; ionomycin, 100 nM; A23187, 100 nM; and vanadate, 3 microM) shifted the cumulative 4 beta-PDBu curve to the left. A threshold concentration of 4 beta-PDBu (30 nM) shifted the cumulative-response curve of vanadate to the left, had no effect on the Bay K 8644 response and left-shifted the A23187 curve whether the tissue was immersed in cocktail-containing Krebs' solution or not. Threshold concentrations of A23187 and 4 beta-PDBu added together in the inhibitory cocktail caused only a transient contraction as compared to a sustained contraction with 1 microM 4 beta-PDBu.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1987

4 beta-PDBu contracts parenchymal strip and synergizes with raised cytosolic calcium.

The effect of various concentrations of 4 beta-phorbol dibutyrate, (4-beta PDBu) phorbol myristate acetate (PMA), and 4 beta-phorbol didecanoate (4 beta-PDD) were studied on the guinea-pig parenchymal strip. The order of potency, 4 beta-PDBu greater than PMA greater than 4 beta-PDD, was the inverse of their lipid solubility. 4 beta-PDBu, 10(-9)-10(-4) M, caused a powerful, slow, sustained contraction starting within 2-3 min and reaching maximum in approximately 45 min, the maximum being 170% of the maximum histamine contraction. The responses to PMA and 4 beta-PDD were slower and less marked. 4 alpha-Phorbol dibutyrate had no effect. These results differ from those reported for guinea-pig trachea. In calcium-free Krebs solution + EGTA (1 mM) the cumulative concentration-response curve to 4 beta-PDBu was still obtained but was slower and was diminished. A23187, ionomycin and vanadate also caused contraction, the respective concentration ranges being 10(-7)-10(-5), 10(-8)-10(-6) and 10(-6)-10(-3) M. When a low concentration of 4 beta-PDBu, which on its own produced no effect, was given with a low concentration of A23187, ionomycin or vanadate, marked synergism was seen. These results are consistent with the model of smooth muscle contraction in which it was proposed that the initial response to stimulation is mediated by both the trisphosphate/calcium and diacylglycerol/protein kinase C pathways, while the sustained response is mediated by the diacylglycerol/protein kinase C pathway, only.

Animals↗
PubMed1987

The diacylglycerol kinase inhibitor, R59022, enhances the superoxide generation from human neutrophils induced by stimulation of fMet-Leu-Phe, IgG and C3b receptors.

A specific diacylglycerol kinase inhibitor, at a concentration of 10(-5) M, consistently enhanced superoxide generation from human neutrophils stimulated with fMet-Leu-Phe, IgG, heat-aggregated IgG and opsonized zymosan. The concentration-response curve for fMet-Leu-Phe was displaced to the left and the maximum superoxide release was also consistently increased by R59022 whereas the diacylglycerol lipase inhibitor, RHC80267, 10(-5) M, had no significant effect. These results suggest that the diacylglycerol formed after fMet-Leu-Phe stimulation in human neutrophils is metabolized largely by the kinase and not the lipase, which implies that diacylglycerol is not the major source of arachidonate during signal-transduction.

Cyclohexanones↗
PubMed1987

Comparison of the effects of indomethacin, RHC80267 and R59022 on superoxide production by 1,oleoyl-2,acetyl glycerol and A23187 in human neutrophils.

1 Indomethacin (10(-4)M) causes marked augmentation of O-2 release from human neutrophils when these are stimulated by either 1,oleoyl-2,acetylglycerol or the divalent cation ionophore, A23187, the concentration-response curve for each agent being shifted to the left and the maximum response to each increased. 2 The diacylglycerol kinase inhibitor, R59022 (10(-5)M) has effects very similar to those of indomethacin on both the 1,oleoyl-2,acetylglycerol-induced and the A23187-induced concentration-response curves for O-2 generation. 3 The diacylglycerol lipase inhibitor, RHC80267 (10(-5 M) on the other hand, has a similar effect to indomethacin on 1,oleoyl-2,acetylglycerol-induced O2- generation but, unlike indomethacin, has no effect on A23187-induced O2- generation. Comparison of the effects of these three agents provides a clue to the locus of the action of indomethacin in increasing superoxide release, suggesting that it may act as a diacylglycerol kinase inhibitor. A component of diacylglycerol lipase inhibition may also be present. It is suggested that these results could have relevance for the use of indomethacin as an anti-inflammatory agent in chronic rheumatoid diseases.

Angiotensin-Converting Enzyme Inhibitors↗