Pre-operative dilatation of the cervix was attempted in 223 cases prior to vacuum aspiration in patients seeking late first trimester termination beyond ten weeks. 15 Me PGF2a was used in the form of vaginal suppositories, intramuscular and intracervical injections. Dilatation of cervix of 10 mm or more was achieved within 4 hours in 86% cases with intra-cervical injections. Gastro-intestinal disturbances caused by intra-muscular injections could be avoided by intra-cervical injections, as the amount of prostaglandin required was only 100 ugm, but the success rate was significantly lower. The success with multiple dose suppositories was 80%. There was no significant difference in the success with 1.5 mgm or 1.0 mgm dosage, but the side effects were significantly higher with 1.5 mgm suppositories. Intra-cervical Hylase did not dilate the cervix but successfully softened it within 5 minutes to make metallic dilatation simple. The hygroscopic Isogel tents achieved dilatation of 10 mm or more in 73% of the patients in 12 hours. The tents as well as intracervical prostaglandin injection had the disadvantage of requiring an additional theatre procedure prior to suction curettage.
A suspension of mixed peripheral blood leukocytes was incubated with arachidonic acid. After ether extraction and silicic acid fractionation of the products, the fraction containing the mono- and dihydroxy derivatives of arachidonic acid was further analyzed by high pressure liquid chromatography on silica gel and octadecyl silica (reversed-phase) columns. A previously undescribed metabolite was detected and isolated in pure form. The compound co-chromatographed with leukotriene B4 on octadecyl silica but was eluted earlier than leukotriene B4 from silica gel columns. Ultraviolet spectrophotometry, gas chromatography-mass spectrometry, ozonolysis and steric analysis indicated that the new metabolite was the 5S,12S-dihydroxy-6,8,10,14-icosatetraenoic acid. The yield of the novel dihydroxy acid was 1 to 4% of the added substrate. The new metabolite showed less than 1% of the myotropic activity of leukotriene B4 on the guinea pig lung parenchymal strip.
The present study investigated the effect of PGI2 on ouabain induced arrhythmias in cats. PGI2 was infused at a dose of 1.0, 2.0 and 5.0 μg/kg·min. PGI2 in a dose of 1.0 μg/kg·min was without any antiarrhythmic effect. Infusions of 2.0 and 5.0 μg/kg·min PGI2 in 3 of 10 and 7 of 10 animals, respectively, converted the ouabain induced arrhythmias into a sinus rhythm. The duration of the antiarrhythmic effect after infusion of 2.0 μg/kg·min lasted about 21 min, whereas the higher dose (5.0 μg/kg·min) had a shorter effect (about 2 min). Under these conditions and doses the systolic blood pressure decreased between 35% and 39% and the diastolic blood pressure was reduced by about 50%. Thus PGI2 showed, when used in the given dose range, an antiarrhythmic effect on ouabain induced arrhythmias in cats. The importance of dosage, methods and species is here discussed.
To examine the possibility that prostaglandin metabolism is pathophysiologically important in Raynaud's phenomenon, peripheral venous 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha) and thromboxane B2 (TXB2) concentrations were measured in 45 patients with severe Raynaud's phenomenon. Patients with Raynaud's phenomenon had a significantly higher plasma concentration of 6-keto PGF1 alpha compared to controls (p less than .001), although their plasma TXB2 concentration was not statistically different from control patients. Subgroup analysis revealed that only patients with progressive systemic sclerosis (PSS) had an elevated plasma 6-keto PGF1 alpha concentration. To gauge the functional significance of the 6-keto PGF1 alpha elevations, seven patients with Raynaud's phenomenon were chronically administered indomethacin (50 mg P.O. b.i.d.); six of the seven patients noted no improvement in their Raynaud's phenomenon. Three of the patients developed pedal edema shortly after starting indomethacin. This study suggests that the increased plasma 6-keto PGF1 alpha concentration in Raynaud's phenomenon may be due to a compensatory release of prostacyclin and that the pathophysiologic defect does not involve the thromboxane mechanism.
Addition of prostaglandin E2 or inhibitors of prostaglandin biosynthesis to Mishell-Dutton cultures results in changes of immunoglobulin levels, particularly IgM, secreted into the culture supernatant. These changes in the quantity of immunoglobulin found in the supernatant are minimal in cultures containing naive cells. When BSA educated cells from C57B1/6 immunized mice were cultured, PGE2 was very effective in amplifying the biosynthesis of immunoglobulin when placed in culture in the presence of BSA. Whole spleen cell cultures from C57B1/6 mice immunized with sRBC also had increased immunoglobulin concentrations in culture supernatants upon exposure to PGE2 at culture initiation. However, the addition of sRBC to these cultures did not further increase immunoglobulin production. In all cases indomethacin inhibited the appearance of immunoglobulin into the supernatant by antigen educated cells. This inhibition which may be a result of inhibited immunoglobulin synthesis and not an impairment of transport, could be overcome by the inclusion of PGE2 in the cultures. PGE2 added to cultures containing cells educated against human gamma globulin caused an increase in the quantity of human gamma globulin-specific antibody in the culture supernatant while it had no effect on naive cells. These results indicate that prostaglandin metabolism may exert a greater influence on educated lymphocytes than naive lymphocytes in terms of immunoglobulin secretion and specific antibody production.
In 30 patients after kidney transplantation, 6-oxo-PGF1 alpha was examined in unextracted plasma by a specific radioimmunoassay. The material was divided into three groups. Patients with acute transplant rejection showing the highest 6-oxo-PGF1 alpha levels, patients with delayed transplant rejection having significantly lower plasma values and a third group of patients with stable transplant function. In these patients the plasma 6-oxo-PGF1 alpha-values were below the lower limit of detection (70 pg/ml). The enhanced 6-oxo-PGF1 alpha during rejection crisis could be interpreted as a self protection mechanism of vascular tissue which is, however, not sufficient in many cases, to prevent the irreversible rejection of the transplant.
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.
Platelets from patients with the Hermansky-Pudlak (HPS) syndrome are deficient in the storage pool of adenine nucleotides and serotonin. As a result, the storage pool deficient (SPD) platelets develop only single waves of clumping when stimulated by threshold concentrations of aggregating agents which cause irreversible, biphasic aggregation of normal platelets. Yet, patients with HPS either have no bleeding problems or only mild symptoms.In the present study we have evaluated the importance of prostaglandin synthesis and secretion to the irreversible aggregation of HPS platelets. Results of the study demonstrate that aspirin-treated SPD platelets, which cannot form thromboxane or undergo the release reaction on stimulation by arachidonate, can still undergo irreversible aggregation in response to thrombin and ADP if treated first with epinephrine. A mechanism of membrane modulation mediated by a-adrenergic receptors cooperatively linked to the endoperoxide and thromboxane receptor can secure irreversible aggregation of normal or abnormal platelets despite absence of secretion and prostaglandin synthesis.
The effects of 6-keto-PGE1 on aggregatory responses to arachidonic acid (AA), adenosine diphosphate (ADP) and collagen were studied in human platelet-rich plasma (PRP). In addition, experiments were carried out to determine if these effects correlate with changes in platelet cyclic AMP and cyclic GMP levels. 6-Keto-PGE1 incubated in PRP produced dose-related increases in platelet cyclic AMP levels whereas platelet cyclic GMP levels were unchanged. Control aggregations induced by AA and ADP did not alter cyclic AMP and cyclic GMP levels whereas control aggregations induced by collagen elevated cyclic GMP levels with cyclic AMP were unchanged. 6-Keto-PGE1 produced a dose-dependent inhibition of platelet aggregation induced by AA, ADP and collagen and this inhibition correlated with a dose-related increase in cyclic AMP levels. Since 6-keto-PGE1 does not consistently alter cyclic GMP levels in human PRP, the present data support previous studies suggesting that 6-keto-PGE1 produces inhibition of platelet aggregation through the stimulation of cyclic AMP accumulation.
17(s) methyl-omega-homo-trans-delta2-PGE1 (ONO 1206) produced qualitatively similar effects to PGE1 in several systems. It was 18.4 and 25.6 times respectively more potent than PGE1 in inhibiting ADP-induced baboon and human platelet aggregation in vitro. Intravenous infusion of ONO 1206 in baboon also produced ex-vivo inhibition of ADP-induced platelet aggregation. However, this was accompanied by a significant fall in blood pressure and an increase in heart rate. The potent relaxant effect of ONO 1206 on human respiratory tract smooth muscle in vitro suggests that this compound may be a bronchodilator in man.
Trapidil inhibited the aggregation of rat platelets and the contraction of the isolated aortic strip of rabbit mainly caused by thromboxane A2, and the thromboxane A2 biosynthesis in rabbit platelets. The drug also reduced ischemic changes in ECG, the incidence of myocardial infarction, histopathological changes and a decrease in serum high density lipoprotein cholesterol, and inhibited an increase in plasma thromboxane B2 and a decrease in plasma 6-keto-prostaglandin F1α content in the animals with an experimental ischemic heart injury caused by the injection of thromboxane A2 into the coronary artery. These findings suggest that trapidil is a new type of a therapeutic agent for ischemic heart disease which not only dilates the coronary artery but also inhibits the actions and biosynthesis of thromboxane A2 and may promote the biosynthesis of prostaglandin I2.
The compound 2(3-ethoxyphenyl)-5, 6-dihydro-s-triazole- [5, 1-2] isoquinoline (DL-204-IT or L-11204) inhibited PMS-induced superovulation and reduced the number of recoverable ova in the oviducts of hamsters. PGE2 non-significantly reduced the number of ova shed but significantly decreased the number of oviductal ova. DL-204-IT was more potent than PGE2 for these effects. Administration of both compounds resulted in a complete block of ovulation. Inhibition of prostaglandin metabolism by DL-204-IT may be the cause for these effects, but no direct evidence is presently available.
To probe the interaction of zinc with polyunsaturated fatty acids we have studied the effect of zinc on the cooxygenation of ferrous iron and arachidonic acid. Zinc inhibited the process of cooxygenation in a concentration dependent fashion. Further evaluation of the interaction of zinc and arachidonic acid gave spectroscopic evidence that zinc, oxygen and arachidonic acid can form an unstable hydroperoxide-like complex similar to that postulated earlier for iron, oxygen and arachidonic acid. However, in the case of zinc the complex will not proceed further to form stable peroxides and the unstable complex falls apart to give zinc and arachidonic acid intact. The findings have implications for the role of zinc in enzyme reactions and for antioxidant reactions of zinc within the cell. The influence of zinc on platelet aggregation was also evaluated. Zinc was found to inhibit cell-cell aggregation. However, in contrast to the known ability of zinc to inhibit prostaglandin synthesis in a broken cell preparation, zinc did not inhibit prostaglandin or thromboxane synthesis in the intact platelet. Inhibition of platelet aggregation by zinc must result from some other action of this cation.
Inhibition of collagen-induced platelet aggregation by either endothelial extracts, prostacyclin, prostaglandin E1 or prostaglandin D2 was investigated. The inhibition was less efficient with diabetic platelets than with platelets from normal donors. The refractoriness of diabetic platelets to inhibitory prostaglandins was observed both with platelet-rich plasma and platelets isolated from their plasma. Moreover levels of cyclic AMP in resting platelets and after stimulation by either PGE1 or PGD2 were lower in diabetic platelets than in normal platelets. It is concluded that the weaker response of diabetic platelets to inhibitory prostaglandins could be related to their content in cyclic AMP.
Plasma levels of 6-oxo-PGF1 alpha, the hydrolysis product of prostacyclin, were significantly reduced in men with proliferative diabetic retinopathy, compared with normal controls. Male diabetics with background or no retinopathy formed an intermediate group with plasma levels of 6-oxo-PGF1 alpha lower than controls and higher than patients with proliferative retinopathy. Forearm ischaemia increased plasma levels of 6-oxo-PGF1 alpha by 30% in normal subjects. The increase occurred during arterial occlusion and was diminished by pretreatment with aspirin. The increase after ischaemia may reflect increased prostacyclin production. In diabetic patients forearm ischaemia produced an increase in plasma 6-oxo-PGF1 alpha similar to that seen in control subjects.
Age and sex related platelet biosynthesis of prostaglandins, thromboxane B2, prostaglandin endoperoxides, HHT and HETE was studied in normal human subjects and in acute myocardial infarction (AMI) patients (all males over 50 yr). The following results were obtained. 1. No significant difference was observed in the platelet biosynthesis of prostaglandins (F2α, E2, D2 ), TxB2 and HHT in normal subjects when values of these arachidonic acid metabolites were compared for different age groups and sex. 2. HETE formation in females was significantly more (p < 0.001) than that in males. 3. No significant difference was observed in the prostaglandin endoperoxide level (PGG2, PGH2 + PGF2α) amongst different age groups and sex in the normal subjects and this was so when compared with AMI patients. 4. Significantly less TxB2 was produced by platelets from the AMI patients compared to normal males over 50 years. 5. In AMI patients, platelets produced significantly more HHT (p < 0.005) and PGF2α (p < 0.02) compared to normal males over 50 years. 6. A significantly reduced (p < 0.005) formation of HETE in the AMI patients compared to normal males (over 50 yr) was observed. A comparison of ratios between HHT, HETE and TxB2 for normal males (over 50 yr) and AMI patients was made for their possible use in diagnostic purposes.
We have found a correlation between the activity of the PGI2 synthetase in the microsomal fraction of pig aorta and the amount of high density lipoprotein (HDL) cholesterol in the incubation fluid. The reverse was true for low density lipoprotein (LDL) cholesterol. These correlations exist independently of whether the lipoproteins were isolated from men than from women as it is for HDL isolated from women than from men. This result may give an explanation for the differential risk against the incidence of cardiovascular disease between women and men at the same concentration of the individual lipoproteins in their blood.
In order to study production of prostaglandins (PGs) by human pre-ovulatory ovarian tissue, bioconversion of 14C-arachidonic 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 PGF1 alpha were purified and identified by silicic acid column-, thin layer-, reversed phase partition chromatographies and radio-gas chromatography. The follicular tissue was shown to convert 14C-arachidonic acid to PGE2 at a conversion rate of 0.34% but not to 6-keto PGF1 alpha. On the other hand, the stromal tissue was demonstrated to produce not only 14C-labeled PGE2 at a conversion of 0.09% but mainly 14C-labelled 6-keto PGF1 alpha at 0.26%.
Chick embryos were treated with prostaglandin El (10, 20, 30, and 50 μg) at 48 and 72 hours incubation. Live embryos were recovered on day 9, staged, and examined for external malformations after weighing. There was no significant increase in embryonic mortality and malformation rates compared to the controls. Embryonic growth was also not affected.
