Prostaglandins, leukotrienes, and medicine最新文献

Inhibition of canine mucus secretion in vivo induced by arachidonic acid administration was correlated with a reduction of 15 Hete levels in canine mucus. Antioxidants and inhibitors of lipid peroxidation were effective inhibitors of both mucus secretion and 15 Hete production. This same series of inhibitors also dose dependently inhibited Fe²⁺ dependent oxidation of arachidonic acid in vitro as assessed by an inhibition of thiobarbituric acid reactive material and conjugated diene formation. These data argue for an involvement of reactive oxygen species and lipid peroxidation in the generation and elaboration of mucus secretion.

This study was undertaken to evaluate the efficacy of iloprost and UK 38485 in the prevention of gastric lesions due to restraint-cold stress, ethanol or indomethacin. Prior injection of iloprost to the rats significantly prevented the increase in ulcer index by restraint- cold stress or indomethacin but nonsignificantly reduced the ulcer index induced by ethanol. UK 38 485 at lower doses caused a highly significant decrease in the ulcer index induced by all noxious stimuli used in this study. UK 38 485 also reduced the increased ³H back diffusion due to restraint-cold stress. Higher doses of the compound, however, failed to decrease the mucosal damage due to restraint-cold stress. Combination of iloprost and UK 38 485 produced a further significant decrease in the ulcer index induced by all noxious stimuli and increased ³H back diffusion induced by restraint-cold stress. In relation to these results the importance of PGI₂/TXA2 ratio in the production of gastric mucosal lesions is discussed.

Monoclonal antibodies to thromboxane B₂ (TXB₂) have been produced and characterized. Both liquid and solid phase radio immunoassays have been developed using one of these monoclonal antibodies. The two assays gave similar results when used to quantitate TXB₂ in 11 serum samples; however the solid phase assay was more sensitive than the liquid phase assay (i.e., 63 pg/ml vs 19 pg/ml) at a B/B₀ = 90%). Despite a difference in the sensitivity of the two assay systems, the cross-reactivity of the monoclonal antibody for PGD₂, PGE₂, PGF_2α and 6 keto-PGF_1α was the same.

The effect of OKY-046, a newly synthetized thromboxane A₂ (TxA₂) synthetase inhibitor, on IgE mediated experimental asthma in guinea pigs was investigated. Indomethacin, a cyclooxygenase inhibitor, and tranilast (N-5′), a potent anti-allergic agent, were used as comparative drugs. OKY-046 clearly improved asthmatic respiratory disorders in guinea pigs. Whereas indomethacin had no effect on the changes of asthmatic respiration, tranilast significantly inhibited the changes. OKY-046 inhibited the in vitro antigen-induced contraction of sensitized guinea pig lung parenchyma. This antigen-induced contraction was also inhibited by tranilast, but not by indomethacin. OKY-046 inhibited the contractions of lung parenchyma caused by leukotriene C₄, D₄ and E₄ (LTC₄, LTD₄ and LTE₄), but not by histamine. Indomethacin showed a biphasic action on the contractile responses caused by histamine and LTD₄ Consequently, contractions due to either agonist at low concentrations were inhibited by indomethacin, but those at high concentrations were enhanced. Tranilast inhibited the contraction of lung parenchyma induced by a low concentration of LTD₄ but not that produced by histamine. Moreover, OKY-046 inhibited an elevation of concentration of thromboxane B₂ (TxB₂) in guinea pig lung perfusate after infusion of LTC₄ but did not affect the elevation of 6-keto-PGF_1α. OKY-046 had no effect on the antigen-induced release of histamine but it inhibited the release of the slow reacting substance of anaphylaxis (SRS-A) from sensitized chopped lung tissues. Indomethacin at a high concentration inhibited the release of histamine but did not affect the release of SRS-A. Tranilast clearly inhibited the release of both mediators. These results suggest that OKY-046 inhibits IgE mediated experimental asthma in guinea pigs and that its main mechanism is related to the inhibition of LT induced contraction of airway smooth muscle and the release of SRS-A from lung tissues.

Trapidil and four selected 5,7-disubstituted s-triazolo (1,5-a)pyrimidine derivatives (AR 12456, AR 12463, AR 12464, AR 12465) which have already been shown to possess inhibitory effects on arachidonic acid(AA)-induced aggregation and thromboxane A₂(TXA₂) formation in human and rabbit platelets in vitro diminished the AA-stimulated TXAZ production in murine blood in vivo. The inhibitory effects of the derivatives were generally stronger than those of trapidil. The strongest inhibitor of TXA₂ formation was the derivative AR 12456. These in vivo results correspond well with our previous in vitro findings.

Polymorphonuclear leukocytes (PMNs) were isolated on a Ficoll-Hypaque gradient, suspended in modified Hank's buffer, and aggregated alone or in the presence of washed platelets (4 or 8/PMN). Platelets had no effect on formyl-methionyl-leucyl-phenylalanine (FMLP)-induced aggregation of PMNs that had been allowed to equilibrate at 37°C for 5 min after storage at room temperature. Pretreatment of platelets with an inhibitor of cyclooxygenase (ASA) or lipoxygenase (nordihydroguaiaretic acid, NDGA) produced no significant effect whereas pretreatment with an inhibitor of both enzymes (eicosatetraynoic acid) or of phospholipase (methylprednisolone sodium succinate) caused a modest but statistically-significant inhibition of PMN aggregation which appeared to be a direct effect on PMNs rather than through platelets.

The warming of PMNs from 0°C or 22°C to 37°C produced a spontaneous, reversible aggregation within 2 or 3 min, the extent of which was dependent on the degree of temperature change. This aggregation was enhanced by the presence of platelets in a ‘dose’ (count) dependent fashion. This enhancement was not decreased by any of the aforementioned drugs, in fact, the aggregation was augmented by all drugs, the difference being statistically significant for NDGA. Thus different mechanisms appear to be involved in spontaneous vs FMLP-induced aggregation. The role of platelets in PMN aggregation remains to be elucidated but the importance of controlling for the effects of temperature changes in such studies is self-evident.

The influence of in vitro treatment of platelets with antiplatelet drugs on the interaction of these cells with the subendothelium was studied using citrated human blood obtained from normal control donors. Reconstituted blood following drug treatment was circulated thwaigh a special chamber which housed averted segments of de-ardothelialized rabbit aorta. The wall shear rate used in these studies was 800 sec^−l. Surface coverage of platelets on the subsndothelium were morptrically evaluated. Aspirin, Ibuprofen, Prostaglandin E_l and 13 Azaprostanoic acid significantly reduced platelet thrombi an exposed sabendothelium. The calcium antagonists, Quin 2 and Diltiazem, exerted similar inhibitory effects, whereas Verapamil was a poor inhibitor. Aspirin treatment significantly enhanced platelet adhesion to the exposed vascular surface. Salicylate and Salicylamide did not enhance platelet. Only Aspirin enhanced the formation of lipcaygonase metabolites of radiolabeled arachidonate.Results suggest that drugs which inhibit platelet aggregation and seerertion of granule cot*Ants reduce formation of platelet thrombi. However, these drugs may or may not have a similar influence on platelet interaction with the subendathelium leading to spreading, adherence or formation of aggregates.

The quantity of leukotrienes produced in an inflammation model, the stimulated mouse peritoneum, was affected by dietary manipulation of tissue arachidonic acid, the immediate leukotriene (LT) precursor. Fifty ng of LTE4 was synthesized (after injection of zymosan) by the peritoneal cavity of mice maintained on olive oil as a dietary source of unsaturated fatty acids . Animals maintained on corn oil, exhibited significantly enhanced leukotriene biosynthesis upon stimulation by zymosan. Mice fed menhaden oil, a fat source rich in n-3 fatty acids produced 50% less leukotriene E4 than animals fed olive oil. The results indicated that production of leukotrienes, potent mediators of inflammatory reactions,are affected by the type of polyunsaturated fatty acids in the diet.

Trapidil and some other 5,7-disubstituted s-triazolo(l,5-a)pyrimidine derivatives (TPDs) which were shown to have potent actions against platelet aggregation also inhibited in vitro platelet thromboxane A₂ (TXA₂) biosynthesis in clotting human and rabbit whole blood as well as in arachidonic acid-activated platelet-rich human plasma. The inhibitory potency of TPDs on TXB2 formation paralleled the antiaggregatory effectiveness to a certain extent and decreased in the following order: AR 12456 > AR 12463 ≈ AR 12464 ≈AR 12465 > trapidil. When TPDs were administered orally to rabbits and blood was taken 2 hours later, no changes of serum TXB₂ level were observed. After i.v. injection of TPDs in rabbits, the most active TPDs AR 12456 and AR 12463 led to a short-lasting reduction of serum TXB₂ by 61.4 and 49.4 %, resp.. The TXB₂ levels returned nearly to pre-treatment level after 80 min. The possibility is discussed that TPDs mainly prevent platelet TXA₂ formation by inhibiting phosphodiesterase activity.