Relaxin increases the accumulation of new epithelial and stromal cells in the rat cervix during the second half of pregnancy

Both cervical and vaginal growth are relaxin dependent during rat pregnancy. We recently reported a relaxin-dependent 1.5-fold increase in cervical and vaginal DNA content from midpregnancy until term. This finding indicated that relaxin probably promotes cervical and vaginal growth at least in part by promoting cellular proliferation. The objective of this study was to identify and quantify cells in the cervix and vagina that proliferate during the second half of rat pregnancy in response to relaxin. Primiparous pregnant rats were ovariectomized or sham ovariectomized (group C; n = 8) on day 9 of pregnancy (D9). Ovariectomized rats were then treated with physiological doses of progesterone plus estrogen (n = 7) or progesterone, estrogen, and porcine relaxin (n = 7). Cellular proliferation was determined by continuously administering a low dose of 5-bromo-2'-deoxyuridine (BrdU) via miniature osmotic pump from D9-D22. On D22, cervices and vaginas were collected, fixed in formalin, paraffin embedded, and serially sectioned (4 microm). Adjacent serial sections were either immunostained for BrdU to assess cell proliferation or stained with hematoxylin to determine total cell number. Cell proliferation was evaluated by counting BrdU-positive nuclei and total nuclei in the same area on adjacent sections. Cell counts were determined using computerized digital morphometric analysis at x575. In control rats, nearly 75% of the epithelial cells and 55% of the stromal cells within the cervix at term had proliferated during the second half of pregnancy. The accumulation of approximately half of the new cells was relaxin dependent. Within the cervical stroma, relaxin increased the accumulation of cells associated with blood vessels and also the number of isolated cells (probably fibroblasts). Relaxin did not appear to affect smooth muscle cell proliferation in the cervix. In contrast to the cervix, a minority of vaginal epithelial cells (45%) and stromal cells (20%) proliferated during the second half of pregnancy. Although relaxin appeared to have a tendency to increase the accumulation of new vaginal epithelial and stromal cells, morphometric analysis did not provide support for such an effect. In conclusion, this study demonstrates that relaxin promotes a marked increase in the accumulation of new epithelial cells and stromal cells within the cervix. The relaxin-induced increase in new epithelial and stromal cells probably contributes to relaxin's effects on growth and remodeling of the cervix that are required for rapid and safe delivery.     

Serum immunoreactive relaxin and softening of the uterine cervix in pregnant hamsters

Serum immunoreactive relaxin levels and ripening of the cervix were measured throughout pregnancy in hamsters. RIA relaxin rose from an undetectable level on day 7 to a maximum value of 29 ng/ml on day 15 of gestation and then fell prior to parturition. The cervix became progressively more dilatable from the 12th to the 16th day of pregnancy. It is suggested that the endogenous relaxin measured by RIA may induce the cervical softening. The absolute levels of immunoreactive relaxin appear to be 10 to 15-fold higher than those previously observed in rats, mice and guinea pigs.     

Monoclonal antibodies specific for rat relaxin. X. Endogenous relaxin induces changes in the histological characteristics of the rat vagina during the second half of pregnancy

This study employed morphometric analysis to evaluate changes in the histological characteristics that accompany relaxin-induced growth and softening of the vagina during the second half of rat pregnancy. There were three treatment groups (N = 4/group). Five milligrams of a monoclonal antibody for rat relaxin, designated MCA1, were injected i.v. daily on days 12-21 of gestation to treatment group MCA1. Control groups received either 5 mg of monoclonal antibody for fluorescein (MCAF; monoclonal antibody control) or 0.5 ml PBS (vehicle control). Vaginas were removed on day 22 of pregnancy, fixed in 10% neutral-buffered formalin, and embedded in paraffin. Tissue sections (5 microm) were stained with Gomori's trichrome to visualize collagen, or orcein to visualize elastin. Measurements were performed with a light microscope equipped with a video camera connected to a computer. Within the vaginal stroma, the density of collagen fiber bundles was lower, the length of elastin fibers was shorter, and the cross-sectional area and wall thickness of arteries were greater in relaxin-replete control rats than in relaxin-deficient MCA1-treated rats. These relaxin-induced changes in the stroma appear to account, at least in part, for the hormone's softening effect on the vagina. Within the epithelium, there were approximately 2-fold more basal and mucus-secreting cells in relaxin-replete control rats than in MCA1-treated rats. The relaxin-induced accumulation of epithelial cells appears to contribute to vaginal growth. We conclude that relaxin plays a role in preparing the vagina as well as the cervix for rapid and safe delivery in pregnant rats.     

Up-regulation of oxytocin receptor messenger ribonucleic acid and protein by estradiol in the cervix of ovariectomized rat

Oxytocin receptor (OTR) regulation has been extensively studied in uterine myometrium and endometrium. However, studies in the cervix are limited. The present studies utilized in situ hybridization and immunocytochemistry to localize OTR mRNA and protein distribution in cervices of nonpregnant ovariectomized (OVX) rats and examined the effect of combined and independent treatments with estradiol and progesterone on cervical OTR. Thirteen nonpregnant rats were bilaterally OVX under general anesthesia. At least 7 days later, the rats were exposed to one of four different treatments 24 h prior to necropsy: 1) estradiol (50 microg, n = 4); 2) progesterone (10 mg, n = 3); 3) both estradiol (50 microg) and progesterone (10 mg) (n = 3); 4) corn oil vehicle (n = 3). After 24-h estradiol treatment, OTR mRNA increased significantly (p < 0.05) in smooth muscle cells of the rat cervix as a result of increased copy numbers of OTR mRNA per cell as well as an increased population of OTR mRNA-positive cells. Progesterone alone had no effect on OTR mRNA expression; however, progesterone combined with estradiol significantly inhibited the up-regulation of OTR mRNA by estradiol alone. The increase of OTR mRNA in cervical epithelial cells was minimal in all situations. Intensity of cervical OTR immunostaining in both the epithelial cells and cervical smooth muscle cells was also elevated after estradiol treatment. The anti-rat OTR antiserum used for immunocytochemistry was validated by Western blot analysis. In conclusion, OTR and OTR mRNA were localized in smooth muscle cells and in epithelial cells of rat cervix. Estradiol-dependent activation of OTR gene expression and active OTR synthesis in smooth muscle cells account for the increased OTR level in rat cervix in vivo, in which progesterone acted as an antagonist of estradiol on OTR gene expression.     

Induction of labor by endocervical application of prostaglandins and intravenous infusion of oxytocin in postterm pregnancy

The study compares two contemporary modes of labor induction: intravenous application of Syntocinon and endocervical application of prostaglandins and examines their efficacy and safety. Ninety women were divided according to the degree of cervical maturation (shown by Bishop score) into two groups. In group I there were 60 women with unripe cervix (Bishop score < or = 5) and induction was performed by endocervical application of 0.5 mg Dinoprostone, and in group II there were 30 women with ripe cervix (Bishop score < or = 6) in which the induction was performed by intravenous application of Syntocinon (500 ml of 5% glycose with 10 iu of Syntocinon). After three hours the initially significantly different Bishop score values were equalized and it was possible to correlate the duration of the labor (Group I 545 min, Group II 338 min). The correlation of initial Bishop score values and the total duration of the labor was negative and high in both groups. All the neonates from both groups were in good condition and no serious complication was noted. Both methods of labor induction appear similarly effective and safe both for the fetus and the mother.     

The influence of metyrapone on the synthesis and release of prostaglandins from the pregnant rat uterus in vitro

1 Metyrapone (150 mg/kg, s.c. or i.p.) an inhibitor of corticosteroid biosynthesis, significantly reduced the release of prostaglandins of the F-type from isolated preparations of pregnant rat uteri in vitro, on day 22 - the expected day of delivery. 2 Metyrapone and indomethacin administered in vitro both inhibited the conversion of 14C-arachidonic acid to prostaglandin E2 by homogenates of day 22 pregnant rat uteri. Metyrapone was approximately 150 times less potent than indomethacin. Although indomethacin also inhibited prostaglandin F2alpha production, metyrapone stimulated synthesis of this prostaglandin. The differential inhibition of prostaglandin synthesis by metyrapone may reflect sensitivity of the inhibitor to changes in experimental conditions. 3 Inhibition of prostaglandin synthesis may explain the effects of metyrapone on parturition in the rat.     

Indomethacin and cyclosporin together produce marked renal vasoconstriction in humans

OBJECTIVE: To test the hypothesis that an imbalance in intrarenal prostaglandins plays a role in cyclosporin-induced nephrotoxicity. METHODS AND RESULTS: Indomethacin was given in combination with cyclosporin to healthy volunteers. Cyclosporin alone (10 mg/kg twice a day) for 4 days had no effect on effective renal plasma flow (ERPF) and glomerular filtration rate but 4 days of therapy with cyclosporin (10 mg/kg twice a day) and indomethacin (50 mg twice a day) in combination resulted in a 37% fall in glomerular filtration rate and a 32% fall in ERPF. This suggests that autoregulatory mechanisms, possibly involving renal prostaglandins, may participate in counteracting the tendency for cyclosporin-induced renal vasoconstriction in humans. Cyclosporin increased systemic blood pressure acutely, and this was not influenced by indomethacin even though indomethacin on its own caused sodium retention. This suggests that, in contrast to the renal vasculature, the systemic vascular response to cyclosporin is neither augmented nor buffered by prostaglandins. CONCLUSION: The reduction in intrarenal prostaglandins clearly played a key role in the development of cyclosporin-induced renal vasoconstriction, but we could not demonstrate a role for prostaglandins or for sodium retention in the initiation of cyclosporin-induced hypertension.     

Role of endogenous prostaglandins in secretin- and plaunotol-induced inhibition of gastric acid secretion in the rat

We investigated the role of endogenous prostaglandins in the inhibitory effect of exogenous secretin and the antiulcer agent plaunotol on gastric acid secretion in the rat. Intravenous infusion of secretin (0.05 CU/kg/h) and intraduodenal administration of the secretin-releasing agent, plaunotol (320 mg/h), resulted in significant inhibition of gastric acid secretion stimulated by intravenous infusion of pentagastrin (0.3 micrograms/kg/h), and this was accompanied by an increase in the prostaglandin E2 content of the gastric mucosa. Intraduodenal administration of plaunotol (320 mg/h) produced plasma secretin levels comparable to the levels achieved by intravenous infusion of secretin (0.05 CU/kg/h). Intravenous administration of prostaglandin synthesis inhibitor, indomethacin (2 mg/kg + 1 mg/kg/h), completely abolished both the inhibitory action of secretin and plaunotol on gastric acid secretion, and the increase in gastric mucosa prostaglandin E2 induced by secretin and plaunotol. The results indicate that endogenous prostaglandins play a significant role in the inhibitory action of exogenous and plaunotol-released endogenous secretin in the rat.     

Effect of exposure of cigarette smoke on mechanical properties and thermal behaviour of rat skin and tendon

Skin and tendon samples of male albino rat taken for analysis, on the 120th day of smoking showed that, compared to controls, the cigarette smoke exposed group showed an increase in tensile strength of both skin and tendon while extensibility of skin remained the same and that of the tendon increased. Thermal behaviour such as isometric tension and temperature at isometric tension increased in rat skin, while in tendon only isomeric tension increased. Shrinkage temperature of skin and tendon has showed no alteration in cigarette smoke exposed rats.     

Role of eicosanoids, nitric oxide, and afferent neurons in antacid induced protection in the rat stomach

The mechanism underlying the mucosal protective effect of antacids is still unclear. This study shows that in rats the aluminum containing antacid, hydrotalcit, induces dose dependent protection against gastric mucosal damage caused by ethanol or indomethacin which is considerably enhanced by acidification. Hydrotalcit did not increase gastric mucosal formation or the intraluminal release of prostaglandins, and did not prevent the increase in mucosal leukotriene C4 formation in response to ethanol. Pretreatment with indomethacin did not attenuate the protective effect of unmodified or acidified hydrotalcit. Furthermore, hydrotalcit significantly reduced the gastric damage caused by indomethacin even when it was administered up to 2 hours after the ulcerogen. In indomethacin treated rats, simultaneous administration of hydrotalcit did not affect the concentrations of indomethacin in serum or inflammatory exudates nor did it attenuate the inhibition of prostaglandin release into the exudates. In hydrotalcit treated rats there was no attenuation of the increase in sulphidopeptide leukotriene release or decrease in leukocyte influx into inflammatory exudates elicited by indomethacin administration. Functional ablation of afferent neurons and inhibition of endogenous nitric oxide partially antagonised the protective effect of unmodified, but not of acidified, hydrotalcit. It is concluded that (i) the protective effect of unmodified and acidified hydrotalcit is independent of the eicosanoid system; (ii) protection against indomethacin induced gastric lesions does not require treatment before dosing of the ulcerogen and does not interfere with absorption and anti-inflammatory actions of indomethacin; (iii) endogenous nitric oxide and afferent neurons contribute partly to the effect of unmodified, but not of acidified, hydrotalcit suggesting that different mechanisms mediate their mucosal protective activity.     

Release of prostaglandin I2-like activity from the rat aorta: effect of captopril, furosemide, and sodium

The effect of captopril, furosemide, indomethacin and intake of sodium on the production of PGI2-like material was studied in the rat aorta. Release of PGI2-like material from these vessels was estimated by its ability to inhibit ADP-induced platelet aggregation. Pretreatment with indomethacin (15 mg/kg/day) reduced the capacity of the aorta to release PGI2-like material. Pretreatment with captopril (10 mg/kg/day) had no effect. Intravenous furosemide (60 microgram/ml plasma volume) increased the capacity of the aorta to inhibit by 28% (p less than 0.25). The inhibitory capacity of aorta removed from rats on a low sodium diet did not differ from those on a high sodium diet. We conclude that the action of furosemide in reducing vascular tone may be related to stimulation of PGI2 synthesis in blood vessels whereas the effect of captopril and sodium in reducing vascular tone may involve a mechanism unrelated to PGI2 synthesis or may involve the synthesis of a prostaglandin other than PGI2.     

Phosphatidylcholines as mediators of adaptive cytoprotection of the rat duodenum

BACKGROUND/AIMS: Surfactant phospholipids impede diffusion of acid through the gastric mucus, but their relevance in the defense of the duodenum against luminal acid is not known. METHODS: Duodenal resistance to acid was tested in anesthetized rats by instillation of HCl using a tube implanted in the proximal duodenum. The effects of a detergent (Brij 35; Sigma, St. Louis, MO) and a lipid mixture flushed through the luminal surface on duodenal resistance to acid were studied. The lipid content in the mucus and the effects of acid, prostaglandins, and indomethacin on the lipid layer were also analyzed. RESULTS: Instillation of 100 mumol HCl or 5 micrograms/kg 16,16-dimethyl prostaglandin E2 increased resistance to acid, preventing duodenal lesions induced by 500 mumol HCl. However, 100 mumol HCl or 16,16-dimethyl prostaglandin E2 did not prevent lesions induced by 500 mumol HCl in rats undergoing perfusions with 5% Brij 35. Indomethacin suppressed acid-induced protection. A mixture of tripalmitin and dipalmitoyl-phosphatidylcholine protected against 500 mumol HCl, and the effect was also observed in rats receiving indomethacin. Finally, 100 mumol HCl increased the phosphatidylcholine content in the duodenal mucus but not in rats receiving 5% Brij 35 or indomethacin. CONCLUSIONS: Surface-active phospholipids are critical for adaptive cytoprotection to acid in the rat duodenum.     

Glomerular adaptations to chronic dietary salt restriction or excess

Micropuncture studies were performed in 33 Munich-Wistar rats maintained chronically either on dietary NaCl restriction (group 1) or excess (group 2). Values for single nephron (SN) and total kidney glomerular filtration rate (GFR) were identical in both groups. Nevertheless, because of preferential efferent vasoconstriction, glomerular capillary hydraulic pressure (PGC) was higher in group 1, offsetting the lower initial glomerular plasma flow rate (QA) also found in group 1. The pressor response to infusion of exogenous angiotensin II (AII) was less in group 1 than in group 2, suggesting that vascular receptors for AII may have been occupied by endogenous hormone, the latter leading to the efferent arteriolar vasoconstriction. In addition to AII, prostaglandins also appear to be involved in the adaptations of the glomerular microcirculation to chronic variations in salt intake. In group 1, indomethacin or meclofenamate infusion mimicked exogenous AII, causing declines in QA and SNGFR. These changes were lacking in group 2. Because of relative contraction of plasma volume, the vasodilatory effects of prostaglandins appear to be needed in low salt animals to sustain SNGFR and QA. In the high salt group, however, since plasma volume is not contracted, maintenance of SNGFR and QA appears to be less critically dependent on endogenous prostaglandins.     

Desmopressin versus indomethacin treatment in primary nocturnal enuresis and the role of prostaglandins

OBJECTIVES: To compare the efficacy of desmopressin and indomethacin and also determine the prostaglandin E2 (PGE2) concentrations in the patient and control groups. METHODS: Eighty-five children with primary nocturnal enuresis were followed up for a baseline period of 4 weeks, during which they recorded wet and dry nights. After this period, the patients were divided into three groups that used desmopressin, indomethacin, or placebo for 4 weeks. The dosage of desmopressin (group A, n = 31 ) was 20 microg/day and the dosage of indomethacin (group B, n = 29) was 100 mg/day. The placebo group (group C) consisted of 25 patients. We determined the serum PGE2 and urine PGE2 concentrations before and after treatment in the three groups and in a control group. RESULTS: Treatment with desmopressin and indomethacin resulted in significantly more dry nights during the 4 weeks of observation than did placebo (P <0.005). The number of dry nights was also significantly different in the desmopressin group than in the indomethacin group (P <0.01). In the total patient group, the mean serum and urine PGE2 concentrations were significantly different from the control group's serum and urine PGE2 concentrations (P <0.001). There was a significant decrease in the serum and urine PGE2 concentrations in group A and group B after the treatment period (P <0.01). CONCLUSIONS: Desmopressin and indomethacin were found to be more effective than placebo. We conclude that prostaglandins have an important role in the pathophysiology of primary nocturnal enuresis.     

The effect of oxytocics on the human cervix during midtrimester pregnancy

Observations of the effects of oxytocics on the human pregnant cervix have been made in vivo using a double open ended catheter technique. Prostaglandin E, prostaglandin F2alpha and oxytocin had similar but no specific effects upon the intracervical canal pressure; ergometrine caused contractions of the cervix. The significance of these findings is discussed in relation to cervical rupture and cervico-vaginal fistulae that have been reported following second trimester abortion induced with prostaglandins.     

Effect of lithium on ionic balance and polyphosphoinositide metabolism during larval vegetalization of the sea urchin Paracentrotus lividus

BACKGROUND: Intragastric hypertonic (2 mol/L) saline produces injury in the gastric mucosa and a significant increase in gastric blood flow (hyperemia) in anesthetized rats. We studied the mechanism of this hyperemia. METHODS: Rats were treated with intravenous boluses of NG-nitro-L-arginine methyl ester (3 mg/kg) to block synthesis of endogenous nitric oxide, pyrilamine (1 mg/kg) to inhibit H1 receptors, or indomethacin (5 mg/kg) to block synthesis of endogenous prostaglandins during blood flow studies or with subcutaneous capsaicin (125 mg/kg) 10-14 days before blood flow studies to ablate capsaicin-sensitive afferent nerves. Gastric mucosal blood flow was measured by hydrogen gas clearance before and during intragastric administration of 2 mol/L saline. RESULTS: The gastric hyperemia induced by intragastric 2 mol/L saline was completely blocked only by indomethacin. The associated gastric mucosal damage was increased significantly. CONCLUSIONS: In the rat stomach, the gastric hyperemia induced by intragastric 2 mol/L saline is mediated by endogenous prostaglandins and plays a protective role. Endogenous nitric oxide, H1 receptors, and capsaicin-sensitive afferent nerves are not involved in this protective hyperemia.     

Gameprost, sulproston and dinoproston for induced abortion in the 15th-24th week of pregnancy

In a randomized, prospective study at the Dept. of Obstetrics and Gynecology of the University Hospital of Giessen 4 different ways of inducing abortions with prostaglandins were tested between the 15th and 24th week of gestation. The aim of the study was to determine the best approach to inducing abortion in order to minimize the psychological and physical stress to the patient. Subjects randomized to the first two groups got a single cervical installation of either 0.5 mg Dinoprostongel (Prepidil, N = 22) or 0.5 mg Sulprostongel (Nalador, N = 21). Six hours later, i.v. infusion with Sulproston (8.3 micrograms/min) was started and continued until the abortion was complete. Patients randomized to the third and fourth group received either 0.5 mg Dinoprostongel intracervically (N = 15) or 1 mg Gemeprost vaginal suppositories (Cergem, N = 21) every 6 hours until the cervix was 1-2 cm dilated. Subsequently the patients received an i.v. infusion with Sulproston until the abortion was complete. In the first group with intracervical application of Sulproston the total time until abortion was 17.8 h +/- 7.8 h. This was shorter than following a single application of Dinoprostongel (22.5 h +/- 14.7 h). Although there was a five hours difference, the between-group differences were not statistically different because of a wide range in values following Dinoproston treatment. This range could not be explained by the age of the mother, week of gestation or parity. In the group receiving multiple intracervical applications of Dinoproston the time till expulsion was twice as long as that after multiple vaginal suppositories of Gemeprost (33.8 h +/- 13.9 h vs. 15.6 +/- 6.0 h, p < 0.01). The time span until a cervical dilatation of 1-2 cm was 27.0 h +/- 13.7 h in the group with repeated Dinoproston application. This period of time was more than twice the time span seen in the group with repeated Gemeprost application (12.5 h +/- 4.2 h, p < 0.01). On the average four treatments with intracervical Dinoprostongel were required while the average with Gemeprost vaginal suppositories was two to achieve a cervical dilatation of 1-2 cm. Furthermore in 7 of 21 cases treatment with Gemeprost achieved the expulsion of the fetus without Sulproston infusion (11.4 h +/- 5.2 h). Comparing single versus repetitive prostaglandin application we could demonstrate that the duration of Sulproston infusion was cut in half after repeated therapy with Gemeprost. We conclude that repetitive application of Gemeprost vaginal suppositories decreases the time to abortion and subject discomfort tremendously. The application of Gemeprost suppositories provides the easiest and most efficient therapeutic approach for both patients and staff. Furthermore the regiment that provided the best results was also the most cost-effective (range 180,-DM to 317,- DM per case).     

Characteristics of gene 28 product, the constituent of the central part of bacteriophage T4 baseplate

This study investigated the effects of indomethacin at clinically relevant doses and its chronic usage on intestinal pathology, survival time and intestinal tissue 6-keto prostaglandin F1 alpha and leukotriene B4 level in rats during various periods with different doses. Indomethacin was administered ranging from 0.625 to 5 mg/kg. When used in doses of 0.625 and 1.25 mg/kg, indomethacin caused no apparent intestinal lesions or death during a treatment period of 30 days. On the other hand, all rats died in 7 days when 5 mg/kg of indomethacin was given. Mortality rate reached 53.3% in seven days in the group where 3.75 mg/kg indomethacin was given. The minimal dose of indomethacin, which induced intestinal ulcer and death, was 2.5 mg/kg. The main pathological findings were intestinal ulcers, but no macroscopic and microscopic changes were observed in the stomach. Intestinal tissue 6-keto prostaglandin F1 alpha and leukotriene B4 levels were quantified by enzyme immunoassay after homogenisation and extraction of tissue. In dose-dependent studies, only the dose of indomethacin, 3.75 mg/kg, significantly inhibited intestinal tissue 6-keto prostaglandin F1 alpha levels during seven days application period (197.39 +/- 24.26 vs 383.66 +/- 46.68 ng/g tissue, treatment vs control). 2.5 mg/kg of indomethacin caused no intestinal ulceration on 4th day, however, it significantly inhibited intestinal tissue 6-keto prostaglandin F1 alpha levels on 4th day in time-dependent studies (190.3 +/- 26.62 vs 383.66 +/- 46.68 ng/g tissue, treatment vs control). Neither dose-dependent nor time-dependent indomethacin administration changed intestinal tissue leukotriene B4 level. The results of this study indicated that indomethacin produced enteropathy rather than gastropathy when used chronically in clinically relevant doses in rats. Inhibition of prostaglandin synthesis, which was estimated by quantification of intestinal tissue 6-keto prostaglandin F1 alpha level, seemed not to be a prerequisite for its enteropathic effect.     

Prostaglandins in blood of diabetic versus non-diabetic humans

We have found a higher concentration of prostaglandins in blood from the diabetic patient under long-term indomethacin therapy as compared with blood from non-diabetics. These findings are generally (qualitatively) similar to previous reports with studies of blood serum from diabetic patients, not on indomethacin treatment, compared with non-diabetics. Certain rationale are presented in an effort to explain the reason why blood prostaglandins in the diabetic are not lowered when the patients are treated with a drug which is clearly established as a blocker of prostaglandin synthesis.