Prostaglandins, leukotrienes, and medicine最新文献

Growth of BN175, a malignant fibrosarcoma, was correlated with high plasma TXB₂ and PGE₂ levels. This statistically significant increase was first detected 17 days after inoculation of the tumor, at which time the tumors were 20 mms in diameter. A further increase in tumor size was associated with still higher PGE₂ and TXB₂ values. At the same time, progressive alterations in platelet function, as measured by ADP-induced platelet aggregation, were observed.6-keto-PGF_1α levels remained normal throughout the whole experiment.

It was concluded that tumor growth was associated with changes in PG synthesis and platelet function, although it remains unclear whether these changes were caused by some host immunological response towards the tumor or were predominantly the result of tumor PG-synthesis.

The effect of diphenylamine derivatives such as diclofenac sodium, mefenamic acid and lobenzarit disodium on arachidonic acid metabolism in rat peritoneal macrophages was examined. Lobenzarit disodium has no effect on prostaglandin E₂ production as measured by radioimmunoassay although two other diphenylamine derivatives have a potent inhibito activity. Three diphenylamine derivatives have no effect on Ca²⁺ ionophore-stimulated release of radioactivity from (³H)arachidonic acid-labeled macrophages. HPLC analysis revealed that lobenzarit disodium had no effect on the synthesis of lipoxygenase products as observed in diclofenac sodium and mefenamic acid. It is concluded that lobenzarit disodium, although its fundamental chemical structure resembles diclofenac sodium and mefenamic acid, has no inhibitory activity on arachidonic acid metabolism, suggesting that immunomodulatory activities of lobenzarit disodium are manifested without interfering with arachidonic acid metabolism.

The possible antiatherogenic action of eicosapentaenoic acid (EPA) was pharmacologically investigated using purified and ethylesterified fish oil containing 75% EPA (EPA-E) in multiple oral doses in rats and rabbits.

EPA-E showed dose-dependent prevention of thrombus formation in a vascular shunt or sudden death caused by arachidonic acid injection in rats. EPA-E in daily doses ranging from 3 to 30 mg/kg slightly altered platelet aggregability and prostacyclin-like activity generated from arterial ring preparations of rats, but these alterations were not statistically significant. Further, EPA-E showed no effect on blood viscosity of rats. In cholesterol-fed rabbits, EPA-E in daily doses of 10 and 30 mg/kg moderately lowered the levels of plasma cholesterol, β-lipoprotein, triglyceride and phospholipid, but these changes showed neither dose-dependency nor time-dependency. In this experiment, EPA-E moderately altered atherogenic plaque formation and platelet aggregability, but these alterations were not statistically significant. EPA-E showed no effect on prostacyclin-like activity generated from arterial ring preparations and blood viscosity of cholesterol-fed rabbits. It is, therefore, proposed that the antithrombotic action of EPA-E may be partially related to its effects on platelet aggregability and prostacyclin generation, but the major mechanism remains unclear.

A reliable system for evaluating 5-lipoxygenase (5-LO) pathway inhibitors employing human whole blood stimulated by the calcium ionophore, A-23187, and yeast cell walls (YCW) is described.

In developing this system, we have shown that leukotriene B₄ (LTB₄) and 5-hydroxyeicosatetraenoic acid (5-HETE) can be recovered quantitatively from whole blood, and can be measured with accuracy and a precision (standard deviation) of ± 129% Apparent differences in LTB₄/5-HETE levels between donors can be minimized by normalizing the LTB₄/5-HETE production to neutrophil number. Variability in LTB₄/5-HETE production among different donors was reduced by increasing the ionophore concentration. The kinetics of ionophore stimulated product production display a 1–4 min lag which is dependent on ionophore concentration. The lag is removed by pretreatment of blood with 5 μg/ml cytochalasin B. Likewise, the kinetics of product formation after stimulation with yeast cell walls demonstrated a lag period, which could be shortened by prior opsonization of the YCW. The amount of LTB₄ metabolism to 20-OH-LTB₄ and 20-COOH-LTB₄ in this system is approximately 20%. Phenidone, nordihydroguaiaref acid, and nafazatrom, known inhibitors of the 5-LO pathway, display half-maximal inhibition points of 0.4, 1.5, and 9 μg/ml, respectively. In summary, we believe that this assay offers a guide for predicting systemic levels of drug needed to be achieved for effective inhibition of cellular LTB₄/5-HETE synthesis/release in humans.

Toxicity of soluble protein extracts from epidermal gel secretions of the catfish, $\text{Arius thalassinus}$, was examined in rabbits. Intravenous injections containing doses as low as 2 mg protein/kg body weight caused mortality in all animals tested. An increase in plasma levels of thromboxane B₂ (TXB₂) and of 6-keto prostaglandin F_1α (6-keto PGF_1α) were observed following injections. Both the mortality and prostaglandin release were prevented by pretreatment of rabbits with either indomethacin or hydrocortisone. A similar indomethacin sensitive induction of prostaglandin release was noted following the $\text{in vitro}$ treatment of arterial tissue sections with gel. Lethality appears to result from gel substances stimulating phospholipase activity to yield arachidonic acid, which is then metabolized to give toxic levels of prostaglandins.

The ability of aortic rings to produce PGI₂ markedly decreased in streptozotocin-induced diabetic rats when compared with age-matched controls. Arachidonic acid dose-dependently stimulated the production of PGI₂ both in normal and diabetic rat aorta during 5 min incubation. The deficiency in PGI₂ production in diabetic rat aorta was temporarily corrected by the addition of 5–20 μM of arachidonic acid. However, when aortic rings were incubated over a period of 10 min in the presence of arachidonic acid, the ability of PGI production in diabetic rats markedly decreased. Repeated exposures A aortic rings to arachidonic acid also markedly reduced PGI₂ production in diabetic rats. PGI₂ production in diabetic rat aorta was inactivated more readily than in normal rat aorta by pre-incubation with t-butyl hydroperoxide. Phenol had a protective effect on incubation-induced inactivation of PGI₂ generating activity in diabetic rat aorta. Serum markedly stimulate PGI₂ synthesis in normal and diabetic rat aorta. The serum activity in diabetic rats was less potent than in normal rats. Melittin and dipyridamole were effective in stimulating PGI₂ release from diabetic rat aorta.

These results suggest that enzymes in the aorta involved in PGI₂ synthesis from released arachidonic acid are susceptible to self inactivation in diabetic rats during the metabolism of arachidonic acid. This may contribute to the defect of PGI₂ synthesis in diabetic rat aorta in addition to the decreased availability of the substrate.

An assay for $\text{in vitro}$ measurement of hormone or agonist-stimulated lipase activity, using exogenous prostaglandin synthetase as a trap for liberated arachidonic acid is described. Fifteen of twenty-six hormones and agonists previously tested $\text{in vivo}$, were tested $\text{in vitro}$ and either stimulated or inhibited release of arachidonic acid parallel to their activity $\text{in vivo}$. Vasopressin stimulated the release of arachidonic acid in ⁻⁵ linear, log-dose manner, from 10⁻¹¹ M to 10⁻⁵ M.

Platelet-activating factor (PAF), 10–11 mol decreased the threshold of ouabain induced arrhythmia in guinea-pigs. The thresholds inducing premature ventricular beats and ventricular flutter were statistically significantly decreased by 27.4 % and 15.6 %, respectively. BM 13.177 (30 mg/kg), a thromboxane receptor antagonizing substance, and esculetin (1.2 mg/kg), a lipoxygenase inhibitor, abolished this arrhythmogenic effect of PAF. Acetylsalicylic acid (10 mg/kg) showed only a tendency to inhibit the PAF effect. These results suggest that PAF could play a role in cardiac arrhythmias under special conditions and it supports the hypothesis that PAF action is mediated by the release of leukotrienes and thromboxane.

The effect of phenobarbital administration on serum lipoproteins and thromboxane A₂ synthesis in platelets was studied in rats. Phenobarbital decreased the serum LDL level by 33% and increased the HDL level by more than 15%. The synthesis of thromboxane A₂ in the platelets of the phenobarbital treated animals was found to be reduced by 43%. Thromboxane A₂ synthesis in the platelets of the control animals was inhibited by HDL and stimulated by LDL. Hence it appears that the decreased thromboxane A₂ synthesis in the platelets of Phenobarbital treated rats was at least partly due to the increased HDL and decreased LDL in the serum. Phenobarbital treatment also caused a 15% increase in the serum HDL-cholesterol although it did not have any significant effect on the total. serum cholesterol.