Prostaglandins and medicine最新文献

The aggregability of platelets to arachidonic acid (AA) was investigated in 26 control subjects, 40 patients with essential hypertension, 20 patients with ischemic cerebrovascular diseases (CVD) not taking aspirin and 11 patients with CVD taking aspirin. The aggregability of platelets was evaluated on the basis of threshold concentrations of AA to induce irreversible platelet aggregation. The enhanced sensitivity of platelets to AA was observed more frequently in hypertensives and/or CVD patients not taking aspirin than in the controls. The relationship between platelet aggregation induced by AA and thromboxane B₂ (TXB₂) formation from AA or prostaglandin H2 (PGH₂) in platelets was also studied in the subjects taking or not taking aspirin. It was proposed that the assessment of platelet aggregability with AA could provide a tool for identifying a subgroup of patients who might substantially benefit from the secondary preventive treatment with aspirin or other anti-platelet drugs. The clinical usefulness of this aggregation test for the management of the patients taking aspirin was also discussed.

The effects of PGE₁ on vascular resistance, vasoconstrictor responses to sympathetic nerve stimulation and pressor hormones and vasodilator responses to bradykinin and nitroglycerin were investigated in the feline mesenteric vascular bed. Infusions of PGE₁, 1.0 and 0.1 μg/min, into the superior mesenteric artery dilated the mesenteric vascular bed and markedly inhibited vasoconstrictor responses to sympathetic nerve stimulation, norepinephrine and angiotensin and to vasodilator responses to bradykinin and nitroglycerin. The response to the highest dose of bradykinin was reversed to a pressor response during infusion of PGE₁. In contrast, mesenteric perfusion pressure and vasoconstrictor responses to nerve stimulation and pressor hormones and vasodilator responses to bradykinin and nitroglycerin were unchanged during the lowest rate of infusion of PGE₁, 0.01 μg/min. When the decrease in (initial value) vascular resistance was taken into account by expressing vasodilator responses on a percent decrease basis, infusion of PGE₁ reduced or reversed the vasodilator responses to bradykinin whereas the vasodilator responses to nitroglycerin were not altered. Results of these studies suggest that PGE₁ may influence vasomotor tone and responses to pressor hormones and bradykinin in the mesenteric vascular bed of the cat.

In order to study production of prostaglandins (PGs) by human pre-ovulatory ovarian tissue, bioconversion of ¹⁴Carachidonic acid to PGs was examined using homogenates of human Graafian follicles and stromal tissues fully stimulated by endogenous follicle-stimulating hormone in the regular menstrual cycle. Among the radioactive metabolites extracted, PGE₂ and 6-keto PGF_1α were purified and identified by silicic acid column-, thin layer-, reversed phase partition chromatographies and radiogaschromatography. The follicular tissue was shown to convert¹⁴ C-arachidonic acid to PGE₂ at a conversion rate of 0.34% but not to 6-keto PGF_1α. On the other hand, the stromal tissue was demonstrated to produce not only ¹⁴C-labelled PGE₂ at a conversion of 0.09% but mainly ¹⁴C-labelled 6-keto PGF_1α at 0.26%.

¹⁴C-Arachidonic acid (AA, 66 nmol) was injected into the pulmonary circulation of isolated perfused hamster lungs. The metabolites were analysed from the nonrecirculating perfusion effluent, which was extracted with ethyl acetate first at pH 7.4 (to extract unmetabolized AA, metabolites of lipoxygenase and HHT) and then at pH 3.5 for prostaglandins and thromboxanes. When indomethacin was infused into the pulmonary circulation, the metabolism of AA was decreased dose dependently. The amounts of all metabolites were decreased rather similarly by indomethacin. The present study indicates that indomethacin inhibits arachidonate metabolism via cyclo-oxygenase and lipoxygenase in hamster isolated lungs.

Intravenous injection of deaggregated human gamma globulin and deaggregated keyhole limpet hemocyanin into C57B1/6 mice does not result in an increase in splenic prostaglandin F_2α. However, when aggregated human gamma globulin or aggregated keyhole limpet hemoeyapin were injected, significant increases in splenic PGF_2α were observed. Mice which had been rendered immunologically tolerant to human gamma globulin (HGG) also demonstrated increases in splenic PGF_2α and PGE₂ 5 min after boosting with aggregated HGG with no increases in antibody titer against HGG. These results imply that the property of protein aggregation will engender increases in splenic prostaglandin levels and that these increases don't appear to affect the tolerant state.

Rats with unilateral intrauterine silastic devices (made.from 60 or 100 mg indomethacin/3 g silastic mixture) were found to have regular estrous cycles. No interference with body weight gain occurred in animals with the 100 mg/mix devices.The patterns of indomethacin release were dependent on the initial loading of the drug in the device, with the 60 and 100 mg/mix devices having delivery periods of approximately 50 days and 120 days respectively.Nevertheless, the absolute quantities of indomethacin delivered at any chosen time was remarkably similar for the two different loadings, suggesting that the properties of the external environment govern the total amount of drug released at specific times from these systems in utero.

The m-6 and w-9 hydroperoxides of arachidonic acid (AA) caused dose-dependent contraction of rabbit aortic strip (RAS) and guinea pig ileum (GPI) at concentrations between 5 and 200pM. At these concentrations, arachidonic acid had no effect in these preparations. The contractions could not be blocked by indomethacin, methysergide, phenoxybenzamine, propranolol, diphenhydramine, scopolamine, or the SRS-A antagonist FPL-55712, but were abolished by the calcium channel blocker nimodipine. In both tissues, the hydroperoxides initiated a sustained contraction. The onset of GPI contraction however, was much faster than the response of RAS to these hydroperoxides. 15-HPETE produced a more sustained contraction than 12-HPETE in both RAS and GPI.These results suggest that hydroperoxides generated from AA by the action of lipoxygenase can directly induce smooth muscle contraction and this effect is probably mediated through altering calcium fluxes in these smooth muscle preparations.

Ethanol preincubated with human platelet rich plasma (PRP) inhibited the formation of endoperoxide metabolites in a dose dependent fashion. The lowest inhibitory concentration was within the reported range of blood levels reached by tolerable amounts of alcohol ingestion.

Recent evidence suggests that glucose stimulation of insulin release may trigger a classic negative feedback loop involving local release of an inhibitor of beta cell function. one or more metabolite of arachidonic acid could comprise such a putative system. Several metabolic events triggered by glucose-induced stimulus-secretion coupling (such as calcium influx, membrane turnover, augmented reduced pyridine nucleotide or glutathione levels, and alterations in toxic oxygen radical availability) would be expected to alter arachiclonic acid release and subsequent metabolism via the lipoxygenase or cyclo-oxygenase pathways. At least one arachichidonate derivative (prostaglandin E) inhibits insulin secretion, and several inhibitors of prostaglandin synthesis augment glucose-induced insulin release in normal subjects and type II diabetics. Development of more selective inhibitors of arachidonate metabolism could represent a new approach to therapeutic manipulation of beta cell function.