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Biomedical subjects

S Moncada

Publications and source records attributed to S Moncada.

At least 325 records · Page 18Linked to original sources
PubMed1988

Leucocyte infiltration and cartilage proteoglycan loss in immune arthritis in the rabbit.

1. The relationship between phagocytic leucocyte infiltration and cartilage degradation in immune arthritis has been investigated in groups of normal and neutropenic rabbits. 2. Injection of antigen into the knee joints of sensitized control animals induced joint swelling, prostaglandin E2 (PGE2) synthesis, leucocyte accumulation and proteoglycan loss from articular cartilage. 3. Intravenous injection of nitrogen mustard caused a selective depletion of circulating neutrophils and monocytes with little or no effect on platelets or lymphocytes. In neutropenic animals challenged with antigen, there was virtually no joint swelling, PGE2 synthesis or leucocyte infiltration but cartilage proteoglycan loss was unchanged after 1 day and increased by day 4 compared to control animals. 4. The numbers of circulating leucocytes returned to normal 3-4 days after nitrogen mustard treatment and leucocyte infiltration occurred in antigen-challenged joints but this was not accompanied by joint swelling. Subsequent intra-articular injection of PGE2 did, however, cause swelling. 5. Lysosomal enzyme levels in arthritic joint fluids were measured. The levels of beta-glucuronidase, which is released by activated phagocytes, were decreased in neutropenic animals but the levels of N-acetyl-beta-glucosaminidase, which is a marker of tissue damage, were not changed by neutrophil depletion. 6. Intra-articular injections of the cytokine interleukin-1 (IL-1) induced a pattern of leucocyte infiltration and cartilage proteoglycan loss similar to that seen in immune arthritis. In neutropenic animals, IL-1 did not cause significant accumulation of leucocytes in the joint but the loss of proteoglycan from cartilage was unimpaired. 7. These results indicate that both leucocyte infiltration and prostaglandin synthesis are required for joint swelling but that tissue degradation is mediated by resident cells. It is likely that release of IL-1 by synovial cells stimulates the synthesis and activation of metalloproteinases which initiate the process of tissue degradation.

Animals↗
PubMed1988

The effects of a novel series of selective inhibitors of arachidonate 5-lipoxygenase on anaphylactic and inflammatory responses.

In conclusion, we have described a novel series of acetohydroxamic acids that are potent and selective inhibitors of arachidonate 5-lipoxygenase in vitro and in vivo. In addition, we have shown that these compounds attenuate "leukotriene-dependent" anaphylactic bronchospasm, the accumulation of inflammatory leukocytes, and the development of fever in experimental models. It now remains to be determined if these compounds have any therapeutic value in man.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1988

The discovery of nitric oxide as the endogenous nitrovasodilator.

Endothelium-derived relaxing factor (EDRF) is a labile humoral agent released by vascular endothelium that mediates the relaxation induced by some vasodilators, including acetylcholine and bradykinin. EDRF also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to vascular endothelium. These actions of EDRF are mediated through stimulation of the soluble guanylate cyclase and the consequent elevation of cyclic guanosine 3',5'-monophosphate. EDRF has been identified as nitric oxide (NO). The pharmacology of NO and EDRF is indistinguishable; furthermore, sufficient NO is released from endothelial cells to account for the biological activities of EDRF. Organic nitrates exert their vasodilator activity following conversion to NO in vascular smooth muscle cells. Thus, NO may be considered the endogenous nitrovasodilator. NO is synthesized by vascular endothelium from the terminal guanido nitrogen atom(s) of the amino acid L-arginine. This indicates the existence of an enzymic pathway in which L-arginine is the endogenous precursor for the synthesis of NO. The discovery of the release of NO by vascular endothelial cells, the biosynthetic pathway leading to its generation, and its interaction with other vasoactive substances opens up new avenues for research into the physiology and pathophysiology of the vessel wall.

Animals↗
PubMed1987

The role of nitric oxide and cGMP in platelet adhesion to vascular endothelium.

The inhibition of platelet adhesion by nitric oxide (NO) and prostacyclin and their mechanism of action was studied. Platelet adhesion to collagen fibrils and endothelial cell matrix was inhibited completely by NO but only partially by prostacyclin. Adhesion of platelets to endothelial cell monolayers was inhibited by bradykinin. This effect of bradykinin was unaffected by aspirin, and was accounted for by the amounts of NO released by the endothelial cells. Inhibition of platelet adhesion by NO and prostacyclin was potentiated by selective inhibitors of cGMP phosphodiesterase, but not of cAMP phosphodiesterase, indicating that elevation of cGMP regulates platelet adhesion.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1987

Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium.

The adhesion of human platelets to monolayers of bovine endothelial cells in culture was studied to determine the role of endothelium-derived nitric oxide in the regulation of platelet adhesion. The adhesion of unstimulated and thrombin-stimulated platelets, washed and labelled with indium-111, was lower in the presence than in the absence of bradykinin or exogenous nitric oxide. The inhibitory action of both bradykinin and nitric oxide was abolished by haemoglobin, but not by aspirin, and was potentiated by superoxide dismutase to a similar degree. It is suggested that the effect of bradykinin is mediated by the release of nitric oxide from the endothelial cells, and that nitric oxide release contributes to the non-adhesive properties of vascular endothelium.

Animals↗
PubMed1987

Comparative pharmacology of EDRF and nitric oxide on vascular strips.

The comparative pharmacology of endothelium-derived relaxing factor (EDRF) and nitric oxide (NO) was studied on isolated strips of rabbit aorta. Both compounds were equally unstable. The relaxations of the bioassay tissues induced by EDRF released by bradykinin (3-100 nM) and by NO (4-134 nM) were indistinguishable. The stability of both compounds was increased to a similar extent by infusions of superoxide dismutase (SOD; 15 U.ml-1) or of cytochrome c (40 microM). The relaxations induced by EDRF and NO were inhibited to similar extents by infusions of Fe2+, hydroquinone and pyrogallol, an effect attenuated by a concomitant infusion of SOD or cytochrome c. The relaxations induced by both compounds were also inhibited by haemoglobin, however, this effect was unaltered by concomitant infusion of SOD. These data indicate that EDRF and NO have identical biological activity, stability and susceptibility to inactivation by superoxide anions and haemoglobin, providing further confirmation that EDRF is NO.

Animals↗
PubMed1987

Effects of calcium and parathyroid hormone on prostacyclin synthesis by vascular tissue.

Prostacyclin generation by rat aortic rings was studied at different calcium concentrations. Extracellular calcium influenced prostacyclin synthesis, as reflected by the release of 6-keto-PGF1 alpha into the medium, in a concentration-dependent fashion. Calcium levels beyond the physiological range (1.12-1.25 mM unbound calcium) markedly stimulated 6-keto-PGF1 alpha production when compared with calcium-free solutions. On the other hand, addition of purified parathyroid hormone did not change 6-keto-PGF1 alpha production at any calcium concentration tested. These data suggest that parathyroid hormone has no direct effect on prostacyclin synthesis by vascular tissue, although it might influence prostacyclin generation through changes in extracellular calcium levels.

Animals↗
PubMed1987

Prostaglandins in the pathogenesis and prevention of vascular disease.

Metabolism of arachidonic acid gives rise to a number of products with potent, and sometimes opposing, biological actions. Prostacyclin, the main product of arachidonic acid in vascular tissue, is a vasodilator and inhibitor of platelet aggregation whereas thromboxane A2, produced by the platelet, is a vasoconstrictor and inducer of platelet aggregation. Generation of these products may be modified in certain diseases, such as atherosclerosis and diabetes, so that prostacyclin production is reduced and thromboxane A2 production increased, resulting in a pro-thrombotic condition. Synthesis of arachidonic acid metabolites may be manipulated using drugs such as aspirin or imidazole analogues which selectively inhibit different enzymes in the metabolic pathway. Such drugs have proved beneficial in the treatment of some vascular disorders. Clinical use of prostacyclin has shown it to be effective in the treatment of peripheral vascular disease, Raynaud's Syndrome and pulmonary hypertension. Stable analogues of prostacyclin are being developed which may lead to a separation of the vasodilator and anti-platelet actions of prostacyclin.

Humans↗
PubMed1987

Comparative pharmacology of endothelium-derived relaxing factor, nitric oxide and prostacyclin in platelets.

1 The pharmacological effects of endothelium-derived relaxing factor (EDRF), nitric oxide (NO) and prostacyclin on human and rabbit platelets were examined. 2 EDRF is released from porcine aortic endothelial cells, cultured on microcarriers and treated with indomethacin, in sufficient quantities to inhibit platelet aggregation induced by 9,11-dideoxy-9 alpha, 11 alpha-methano epoxy-prostaglandin F2 alpha (U46619) and collagen. 3 The anti-aggregating activity of EDRF was potentiated by M&B 22948, a selective inhibitor of cyclic GMP phosphodiesterase, and by superoxide dismutase (SOD) and was inhibited by haemoglobin and Fe2+. 4 Both NO and prostacyclin inhibited platelet aggregation. 5 The anti-aggregatory activity of NO, but not that of prostacyclin, was potentiated by M&B 22948 and by SOD and was inhibited by haemoglobin and Fe2+. Thus NO is a potent inhibitor of platelet aggregation whose activity on platelets mimics that of EDRF. 6 It is likely that the inhibitory effect of NO on platelets represents the action of endogenous EDRF and therefore this substance, together with prostacyclin, is a regulator of platelet-vessel wall interactions.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1987

The anti-aggregating properties of vascular endothelium: interactions between prostacyclin and nitric oxide.

1. The interactions between endothelium-derived nitric oxide (NO) and prostacyclin as inhibitors of platelet aggregation were examined. 2. Porcine aortic endothelial cells treated with indomethacin and stimulated with bradykinin (10-100 nM) released NO in quantities sufficient to account for the inhibition of platelet aggregation attributed to endothelium-derived relaxing factor (EDRF). 3. In the absence of indomethacin, stimulation of the cells with bradykinin (1-3 nM) released small amounts of prostacyclin and EDRF which synergistically inhibited platelet aggregation. 4. EDRF and authentic NO also caused disaggregation of platelets aggregated either with collagen or with U46619. 5. A reciprocal potentiation of both the anti- and the dis-aggregating activity was also observed between low concentrations of prostacyclin and authentic NO or EDRF released from endothelial cells. 6. It is likely that interactions between prostacyclin and NO released by the endothelium play a role in the homeostatic regulation of platelet-vessel wall interactions.

Animals↗
PubMed1987

Release of vasoactive substances from guinea pig isolated lungs perfused via the trachea.

These findings suggest that a given stimulus, when delivered via the pulmonary circulation of a guinea pig isolated lung, does not reach a population of cells that participate in the anaphylactic response. It is likely that the endothelium in the guinea pig isolated lung acts as a barrier to stimuli coming from the circulation. This may have important therapeutic implications, particularly in regards to the respective efficacy of pharmacologic agents administered systemically or by inhalation in patients with lung injury.

Animals↗
PubMed1987

Leukotriene B4 production in normal rat glomeruli.

The production of the lipoxygenase metabolite of arachidonic acid, leukotriene B4 (LTB4) by normal rat glomeruli has been studied. Isolated glomeruli from saline-perfused rat kidneys were incubated in Kreb's buffer for 15 min at 37 degrees C. The concentrations of LTB4 and other eicosanoids in cell-free supernatants were determined by direct radioimmunoassays (RIA). Mean basal syntheses of eicosanoids were: thromboxane B2 (TXB2) 0.77 +/- 0.13, prostaglandin (PG) E2 0.40 +/- 0.05, 6-keto-PGF1 alpha 0.38 +/- 0.06 ng/mg glomerular protein (mean +/- SEM n = 8). In these assays immunoreactive LTB4 synthesis was 0.12 +/- 0.02 ng/mg. In samples incubated with BW755C, 50 micrograms/ml, an inhibitor of arachidonate metabolism via both the cyclo-oxygenase and lipoxygenase pathways, there was more than 80% inhibition of the synthesis of TXB2, PGE2 and 6-keto-PGF1 alpha. However, immunoreactive LTB4 was only reduced by 44%, suggesting the presence of other materials which cross-react in the RIA. The presence of authentic LTB4 in the supernatants was confirmed after extraction and high-pressure liquid chromatography (HPLC). This material represented 25% of the original material detected by RIA. Although the physiological role of LTB4 in the normal state is unknown, its chemotactic activity may be of great significance during glomerular inflammation.

Animals↗
PubMed1986

The synthesis of eicosanoids induced by anaphylaxis in guinea-pig isolated lungs perfused via the trachea.

We have monitored the release of prostanoids and leukotrienes from isolated lungs taken from previously sensitized guinea-pigs perfused either via the pulmonary artery or via the trachea. The eicosanoids were monitored by direct radioimmunoassay and further identified by bioassay and radioimmunoassay following separation by RP-HPLC. When ovalbumin is delivered via the trachea it releases more cyclo-oxygenase products (3-fold) and lipoxygenase products (10-fold) than when delivered via the pulmonary circulation. Indomethacin enhanced leukotriene release whereas BW755C did not affect the release of leukotrienes induced by ovalbumin. These results suggest that perfusing the lungs via the trachea might be relevant for the study of anaphylaxis and other conditions in which the pathophysiological development is determined by cells closer to the alveolar surface in the lung.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1986

Release of eicosanoids from isolated lungs of guinea-pigs exposed to pure oxygen: effect of dexamtethasone.

The effect of dexamethasone on bradykinin-induced release of eicosanoids from isolated lungs of guinea-pigs exposed to pure oxygen (O2) is described. Pathological changes were induced in the lungs of guinea-pigs exposed to pure O2 for 72 and 96 h. Bradykinin-induced release of 6-oxo-PGF1 alpha and thromboxane B2 (TXB2) was increased in lungs from guinea-pigs exposed to 72 and 96 h of O2. Removal of PGI2 and PGE2 was not affected by the exposure to O2, but the removal of bradykinin was significantly reduced after 96 h of O2 exposure. Dexamethasone did not reduce bradykinin-induced release of eicosanoids from lungs of control animals, but it did inhibit the release from lungs of guinea-pigs exposed to O2. Dexamethasone had no effect on the metabolism of Bk by the inflamed lungs.

Animals↗
PubMed1986

Eicosapentaenoic acid as a modulator of inflammation. Effect on prostaglandin and leukotriene synthesis.

Products derived from arachidonic acid (AA) via both the cyclo-oxygenase and lipoxygenase pathways play a role in inflammation: prostaglandins (PGs), particularly PGE2, contribute to the formation of oedema, erythema and hyperalgesia whereas leukotriene B4 (LTB4), a product of the 5' lipoxygenase, may modulate the recruitment of leukocytes. We have previously reported that supplementation of a standard rat diet with eicosapentaenoic acid (EPA) caused a significant increase in the formation of LTB5, which is less active biologically than LTB4, and a decrease in the synthesis of LTB4 by stimulated leukocytes. Now we have assessed the effects of administration of highly purified EPA ethyl ester (79% pure), in two models of acute inflammation. Supplementation of a standard rat diet with 240 mg/kg/day EPA for 4 weeks significantly decreased the concentration of PGE2 and TXB2 in inflammatory exudate derived from implantation of carrageenin impregnated sponges: neither the concentration of LTB4 nor the cell number were reduced significantly. Triene prostaglandins were not detected in the exudate, however, significant levels of LTB5 were present. In the second model, oedema induced by injection of carrageenin into rat paws was significantly reduced in animals fed an EPA-rich diet. Supplementation of the diet with EPA could, by mainly reducing the synthesis of prostaglandins, offer a novel and non-toxic approach to the modulation of an inflammatory response.

Animals↗