Effect of anaesthesia on ovarian follicular development and ovulation in the sheep subsequent to prostaglandin-induced luteolysis

Prostaglandin analogues were used to induce luteal regression simultaneously in a number of ewes, thereby synchronizing the final stages of follicular maturation in these animals. Some of the ewes were anaesthetized for 24 h immediately after the injection of prostaglandin (experiment 1), and others for 15 h, starting 24 h after the injection of prostaglandin (experiment 2). In both experiments administration of anaesthetic significantly delayed the onset of oestrus and the time of ovulation relative to prostaglandin-treated control animals. The results from assays of blood samples collected at regular intervals in experiment 1 indicated that the preovulatory peak in the concentration of LH and the periovulatory changes in the concentration of FSH were similarly delayed and that during anaesthesia the level of LH was significantly reduced. It is suggested that the reduced level of LH, which probably resulted from a reduction in the secretion of releasing factor due to anaesthesia, failed to support oestrogen production by the Graafian follicle(s), thereby delaying the occurrence of oestrus and ovulation.     

Effect of carprofen and indomethacin on gastric function, mucosal integrity and generation of prostaglandins in men

The effects of indomethacin and carprofen on gastric secretion, serum gastrin level, electropotential difference, gastric microbleeding, DNA loss, mucosal blood flow and the production of mucosal prostaglandins (PGs) were investigated in a double-blind cross-over study in 18 healthy volunteers after one week of treatment. We did not observe any significant changes in basal and pentagastrin-stimulated gastric secretory parameters, serum gastrin level and electro-potential difference before and after treatment with these drugs. Mucosal blood flow was significantly reduced following indomethacin treatment. The most pronounced differences were found in endoscopic score studies of gastric mucosa. After indomethacin all subjects developed multiple erosions, submucosal haemorrhages, and half of them showed diffuse antral erythema. These effects were accompanied by a significant increase in both gastric microbleeding and DNA loss, and significant decrease in the production of PGE2. We concluded that carprofen, in contrast to indomethacin, did not alter gastric mucosal integrity and production of PGE2. This study indicates that the gastric mucosal damage by non-steroid anti-inflammatory compounds (NOSAC) depends upon the suppression of PGE2 biosynthesis, and that endogenous PGE2 is involved in the control of mucosal blood flow and mucosal integrity.     

Effect of prostaglandins on collagen synthesis in rabbit ovarian follicles during the ovulatory process

Collagen fibers in the ovarian follicle undergo drastic changes at ovulation due to the preovulatory increase of collagenolytic activities. The collagen synthesis in ovaries, however, has not been elucidated yet. To clarify the regulatory role of prostaglandins (PGs) in collagen synthesis of the follicular wall in relation to the ovulatory process, we measured prolyl hydroxylase (PH), as well as lysyl oxidase (LO) activity and the content of hydroxyproline (Hyp) in ovarian follicles of the rabbits treated by hCG, hCG/indomethacin (IM) and hCG/IM/various PGs. The experimental groups consisted of; 1) untreat control group 2) ovulatory group receiving hCG 3) non-ovulatory group given PGs 4) ovulatory group given hCG and PGs 5) group in which hCG-induced ovulation was inhibited by IM (4 mg/kg) 6) group in which IM-inhibited ovulation was recovered by PGF2 alpha (1.5 mg/kg) 7) group in which IM-inhibited ovulation was not restored by PGE1 (0.1 mg/kg) and PGE2 (0.7 mg/kg). The peak activities of PH and LO in ovarian follicles were observed at 12-13 hr after hCG injection, namely, immediately after ovulation. Significant changes of these activities after hCG administration were specific to the ovaries. PH activity in the ovaries was suppressed by the administration of IM, but LO activity was not significantly suppressed. In the hCG/IM/PGF2 alpha-treated ovulatory rabbits (Group 6), PH activity recovered to nearly the level of the hCG-treated rabbits (Group 2). By addition of PGE2, ovulation did not recover but PH activity was restored to about 70% of the hCG-treated rabbits. PGE1 did not have any effect on the reversal of ovulation-blockage or restoration of PH activity. The amount of Hyp after hCG administration tended to decrease from 6 hr to 10 hr but was significantly increased from 10 hr to 13 hr. This increase of Hyp after ovulation significantly correlated with the increase of PH and LO activities. In the hCG/IM/PGF2 alpha-treated rabbits (Group 6), the changes of Hyp were similar to those the hCG-treated rabbits (Group 2). In conclusion, collagen synthetic activity, found to be regulated by PH and LO activities in the ovarian follicles, was activated after follicle rupture, resulting in reconstruction of collagen fibers, and PGs play an important role in the ovulatory process by modifying collagen synthesis.     

Effects exerted by prostaglandins and indomethacin on the immune response during aging

The effect of in vitro addition of indomethacin, an inhibitor of the cyclooxygenase pathway, and of prostaglandin E1 and E2 on the proliferative capacity of phytohemagglutinin- and concanavalin A-stimulated spleen lymphocytes from young and old, long-lived (C3H X C57BL/10 RIII)F1 mice was investigated. Mitogen-activated splenocytes from old mice showed a different sensitivity to these drugs than splenocytes from young animals. Additionally, our data indicate that drugs can act either as inhibitors or as stimulators of mitogenesis, depending on the mitogen used, the dose of the drug, the age of the cell donor and the length of time in culture. It is suggested that prostaglandins of the E series may play a role in the pathogenesis of age-associated immune impairment.     

Effect of indomethacin on serum lipids, lipoproteins, prostaglandins and the extent and severity of atherosclerosis in rhesus monkeys.

The present study evaluated indomethacin therapy--a nonsteroidal anti-inflammatory drug--on experimental hyperlipidemia and atherosclerosis in Rhesus monkeys. Twenty-four monkeys were divided randomly into four groups of six. Two groups received stock pellet diet and two were given an atherogenic diet for six months. After this period, one stock diet-fed group and one atherogenic diet-fed group were treated with oral indomethacin (2.5 mg) on alternate days for a further six months. Serum lipids and lipoproteins were markedly elevated in atherogenic diet-fed monkeys. Generally, indomethacin did not exert a hypocholesterolemic effect; however, liver cholesterol was decreased (P less than 0.05) in atherogenic diet-fed monkeys treated with indomethacin. High density lipoprotein cholesterol was increased in stock diet-fed, indomethacin-treated monkeys but not in atherogenic diet-fed, indomethacin-treated monkeys. Apoprotein A-I was not affected by indomethacin in either stock or atherogenic diet-fed monkeys; however, the drug produced a significant (P less than 0.01) reduction of serum thromboxane B2 in stock diet-fed monkeys, without restoring the 6-keto-prostaglandin F1 alpha to pretreatment levels. A protective role of the drug was noted on both the extent and severity of aortic and coronary atherosclerosis.     

An investigation into the role of prostaglandins in zebrafish oocyte maturation and ovulation

This study explored the potential for ovarian-derived prostaglandins (PGs) to be involved in the regulation of oocyte maturation and ovulation in zebrafish. It was demonstrated that cultured vitellogenic follicles have the capacity to produce prostaglandin E₂ (PGE₂) and PGF_2α in response to arachidonic acid (AA) in a concentration-dependent manner, and that AA stimulates the in vitro production of 17β-estradiol (E₂). The production of AA-stimulated PGF_2α was significantly reduced by treatment with the non-selective cyclooxygenase (COX) inhibitor, indomethacin (INDO). Treatment of full-grown follicles with AA did not induce oocyte maturation as assessed by germinal vesicle breakdown, but INDO significantly decreased the rate of spontaneous maturation. Using Real-Time PCR, it was shown that follicles of different developmental size classes (primary growth and pre-vitellogenic, early-vitellogenic, and mid- to full-grown vitellogenic) express enzymes that release (cytosolic phospholipase A₂ (cPLA₂); phospholipase Cγ1) or metabolize (COX-1, COX-2, and prostaglandin synthase-2) AA to PG metabolites. The expression of cPLA₂ was found to be significantly greater in full-grown follicles compared to follicles of the pre- and early-vitellogenic stages. In vivo studies demonstrated that breeding groups of zebrafish exposed to 100 μg/L INDO exhibited reduced spawning rates and clutch sizes compared with control and 1 μg/L INDO exposed fish. In other studies, it was shown that naturally spawning groups of females exhibit increased ovarian levels of PGF_2α, E₂, and 17α,20β-dihydroxy-4-pregnen-3-one (a maturation-inducing hormone in zebrafish) near the time of ovulation compared with non-breeding females. Collectively, these experiments indicate that the AA pathway in zebrafish ovaries is involved in the regulation of oocyte maturation and ovulation and a non-selective inhibitor of COX disrupts these processes.     

Effect of carprofen and indomethacin on gastric function and the content of prostaglandins E2 and F2 alpha in human gastric juice

The effect of indomethacin (2 X 50 mg daily) and carprofen (2 X 150 mg daily) on gastric secretion and the generation of prostaglandins PGE2 and PGF2 alpha in gastric juice, was investigated in a single blind cross-over study in eight healthy volunteers lasting one week. We observed no statistically significant change in basal and pentagastrin-stimulated gastric secretory parameters (outputs of gastric acid, N-acetyl-neuraminic acid and pepsin) before and after treatment with indomethacin and carprofen. However, an inhibitory effect was found on the output of PGE2 and PGF2 alpha after pentagastrin stimulation. While both drugs diminished the output of PGF2 alpha to a similar extent, carprofen exerted a markedly weaker inhibitory effect on the output of PGE2 than did indomethacin. It is suggested that the gastric tolerability of non-steroidal anti-inflammatory drugs (NSAIDs) is related to their inhibitory potency on PGE2 formation, in the sense that weak inhibitors of PGE2 cause less damage to the gastric mucosa than do strong inhibitors.     

Oxytocin influences preovulatory follicular development and advances ovulation in rats

Oxytocin has been shown to advance gonadotropin secretion in pro-estrus rats. The effects that oxytocin-induced changes have on the ovary were investigated in this study. Oxytocin administered to rats at proestrus 09.00 h, 10.00 h and 11.00 h advanced follicular growth, progesterone secretion, and the time of ovulation. However, both treated and control groups of rats ovulated similar numbers of oocytes and the oocytes released were of similar fertility. Because oxytocin has been shown to induce early LH and FSH release the effects of oxytocin administration on the ovary were possibly an indirect action involving the pituitary. The results of this investigation indicate that exogenous oxytocin alters the timing but not the fertility of periovulatory events.     

Influence of prostaglandins, omeprazole, and indomethacin on healing of experimental gastric ulcers in the rat

We investigated whether the trophic actions of prostaglandins, omeprazole, and indomethacin on gastric mucosa lead to accelerated healing of gastric ulcers in the rat. Cryoulcers were produced in the corpus area and treated with 16,16-dimethyl prostaglandin E2 (5 or 100 micrograms/kg b.i.d., intragastrically), omeprazole (40 mumol/kg once daily, subcutaneously), indomethacin (2 mg/kg b.i.d., subcutaneously), or placebo. At the end of the treatment, plasma gastrin, cell labeling index (autoradiography with [3H]thymidine), and the size and depth of mucosal defects were measured. Compared with placebo, omeprazole accelerated ulcer healing as indicated by a smaller ulcer area [1.1 +/- 0.2 vs. 4.8 +/- 1.2 mm2 (mean +/- SEM)] and smaller ulcer depth (383 +/- 31 vs. 488 +/- 41 microns) after 10 days of treatment. Prostaglandins did not affect ulcer healing despite thickening of gastric corpus mucosa. Indomethacin delayed ulcer healing and reduced the labeling index. Omeprazole induced a marked hypergastrinemia (208 +/- 12 vs. 66 +/- 12 pmol/L on day 5, and 469 +/- 23 vs. 58 +/- 16 pmol/L on day 10). The results indicate that abolishment of acid secretion by omeprazole accelerates healing. Trophic actions and "cytoprotective" effects by prostaglandins are not relevant for ulcer healing in this model.     

Antisecretory effects of indomethacin on rabbit ileal mucosa in vitro

Prior in vivo studies have shown that indomethacin, which inhibits prostaglandin (PG) synthesis, affects fluid transport in the small bowel, enhancing spontaneous fluid absorption and reducing the amount of fluid that accumulates in response to cholera toxin and other secretory stimuli. To further explore the mechanisms involved, we determined the effects of indomethacin on ion transport, cAMP concentration, and PGE2 production in rabbit ileal mucosa in vitro. Indomethacin (1 mM), when added alone, had no significant effect on short-circuit current (either basal or glucose-stimulated), Cl fluxes, or cAMP concentration. Indomethacin did, however, inhibit the ion transport changes caused by several secretagogues: Effects of theophylline, Ca-ionophore A23187, and arachidonate were reversibly inhibited by at least 65%, whereas effects of dibutyryl cAMP, 16,16-dimethyl PGE2, cholera toxin, and heat-stable Escherichia coli enterotoxin were inhibited by about 30%. Indomethacin also inhibited the theophylline-evoked increase in cAMP concentration. Indomethacin decreased PGE2 production under basal conditions and in the presence of theophylline and A23187, which may partly explain the antisecretory action of the drug. Since arachidonate increased PGE2 release from the mucosa more than 10-fold and indomethacin did not inhibit this effect, indomethacin at high concentration (0.5-1 mM) appears to also inhibit the action of intestinal secretagogues by a prostaglandin-independent mechanism. This study also demonstrates that the antisecretory effect of indomethacin is not simply due to stimulation of an unrelated absorptive process.     

The effects of dexamethasone and indomethacin on the outcome of pregnancy in the rabbit.

Pregnant rabbits were treated with indomethacin (8-10 mg/kh/day) or dexamethasone (1-2-1-8 mg/kh/day) during late gestation. The effects of these treatments on the concentrations of progesterone and prostaglandin F (PGF) in the peripheral plasma, and the outcome of gestation was studied. Treatment with indomethacin significantly prolonged the length of gestation (P smaller than 0-01) compared iwth control, untreated animals. In these treated animals, the plasma progesterone levels declined at a similar time to that in control rabbits but the increase in systemic PGF normally seen during late pregnancy was reduced. Dexamethasone treatemnt reliably induced premature delivery within 3-6 days. The plasma progesterone concentration fell rapidly during the first 24 h of dexamethasone administration, but in no animal was this associated with a significant increase in the plasma levels of PGF. These results are consistent with the suggestion that prostaglandins are involved in the normal initiation of parturition in the rabbit. They do not support the hypothesis that the effect of dexamethasone on the length of gestation is mediated through an increase in the production of prostaglandin F.     

Alternating proliferative capacity in the rat gastrointestinal mucosa. Effects of E2 prostaglandins and indomethacin

Having previously observed an apparent uneven distribution of proliferating cells in the gastric corporic mucosa of the rat, we examined the mitotic distribution along 8-mm sections of gastric and jejunal epithelia. Metaphases were arrested with vincristine to facilitate mitotic count, and the effects of treatment with a prostaglandin E2 analogue and a cyclooxygenase blocker were examined. Clusters of mitotic figures alternating with non-proliferating areas were observed in the gastric corporic epithelium of control rats. During 4 h mitotic activity was absent over 21% of the corporic mucosa. Extending the examined area to about 240 glands reduced substantially the error of mitotic counts. An uneven distribution of mitoses was found in the antral and jejunal epithelium, but areas without proliferating cells were uncommon. Treatment with the prostaglandin E2 analogue reduced the number of mitosis-free areas in the gastric corpus to 13%, and clusters were less easily identified. The total mitotic count was unaffected by treatment. In the jejunum prostaglandin increased the absolute number of mitoses. The mitotic span was also increased, reflecting the uneven distribution. Indomethacin produced the opposite effects to the prostaglandin analogue, including reduction of epithelial height. Of the gastric corporic mucosa 35% was non-proliferating during the observation period, but the clustering phenomenon was still apparent. Absence of dose relationship was attributed to ulcerogenic actions of high doses of indomethacin. It is concluded that mitoses are unevenly distributed in the upper gastrointestinal epithelium of the rat and that safe estimates of mitotic count require examination of large corporic areas.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of dose and time of melatonin injections on the diurnal rhythm of immunity in chicken

The effect of daily melatonin injections on the diurnal rhythm of immune parameters was examined in White Leghorn cockerels, kept from hatching in L:D 12:12 conditions. Subcutaneous injections of melatonin were made at the beginning of darkness or 4 h earlier for four weeks starting from one week of life. The melatonin dosage in one group was raised (10, 13, 16, and 20 ng per bird daily, respectively) during four consecutive weeks. The two other doses were 10 and 500 times higher and were increased every week as well. Control birds received equivalent injections of vehicle. Three-week-old chickens were immunized ip with sheep red blood cells and reimmunized one week later. Five-week-old birds were sacrificed during a 24 h period every 4 h. The existence of the diurnal rhythm was evaluated by cosinor analysis. The diurnal rhythm of total white blood cells and serum agglutinins was more dependent on the time of melatonin injections than on the hormone used. The effect of melatonin injections on the level of immune parameters examined was also dependent on the time of sample collection. Results obtained indicate the participation of pineal gland in the regulation of the diurnal rhythm of the examined indices of avian immune system function that exhibit diurnal changes in sensitivity to exogenous melatonin.