Effect Of Prostaglandin Synthesis Inhibition Research Articles

Abstract 322: Cyclooxygenase (COX) Inhibition Prior to CPR Decreases Heart Rate Variability in Pigs

Background: Cyclooxygenase inhibitors (COX-1 and 2) are widely used and inhibit prostaglandin synthesis. COX inhibitors have been shown to increase overall cardiovascular risk. Heart rate variability (HRV) is a measure of the balance of autonomic nervous system and shown to be predictive of neurological outcome after cardiac arrest. Prostaglandins are cardioprotective and modulate HRV. We hypothesized that prostaglandin inhibition impacts short term CPR survival and outcomes based on HRV in swine. Methods: 24 animals (30±5kg) were randomized to pretreatment with indomethacin (I) 2mg/kg (COX-1 Inhibitor), Celecoxib (C) 2mg/kg (COX-2 inhibitor) or placebo (P). VF was induced and after 3 minutes all animals received chest compression and ventilation. After 18 minutes of VF, vasopressin given and defibrillation attempted. Electrocardiogram, echocardiogram and hemodynamic measurements done at baseline (BL), after infusions (Tx) and return of spontaneous circulation (ROSC) at 30 and 180 minutes. Results: ROSC was achieved; 3/8 (I) compared with 7/8 (C), and 7/8 (P). No differences in blood gases or hemodynamics pre, during or post CPR between groups. Echo showed decrease function post resuscitation in surviving animals but not significantly different among groups. COX-2 inhibition induced a significant decrease in linear (SDNN, RMSSD) and frequency (HF) measures of HRV towards greater sympathetic tone, post resuscitation. Compared to P, COX-2 inhibition increased Troponin I levels at 180 min after ROSC; P [84(4)] vs C [721(31)] mg/dl (p< 0.001). Conclusions: COX-1 inhibition decreases ROSC, whereas COX-2 inhibition significantly increases indices of myocardial tissue damage, and decreases HRV. The impact on long term outcome is unknown. Since many adults use COX-1 or COX-2 inhibitors, studies analyzing post resuscitation outcomes of patients should consider the effects of prostaglandin synthesis inhibitors as confounding variables.

The effect of prostaglandin synthesis inhibitors and diphosphonates on tumour-mediated osteolysis.

Previous studies have shown that the prostaglandin synthesis inhibitor indomethacin reduced osteolysis produced by the experimental VX2 carcinoma, probably by inhibiting the stimulation of osteoclasts by prostaglandin E2. This study was carried out to determine whether prostaglandin inhibitors affect the tumour osteolysis produced by human mammary carcinoma as well as the VX2 carcinoma. The effect of diphosphonates on reducing tumour osteolysis was also investigated, since diphosphonates directly affect bone resorption. The results indicated that various non-steroidal, anti-inflammatory agents which inhibit prostaglandin synthesis reduced the osteolysis produced by human mammary or rabbit VX2 carcinomas. The diphosphonate compounds also produced a significant inhibition of tumour osteolysis. The results confirm the findings of Powles and his colleagues (1) that aspirin (also a prostaglandin synthesis inhibitor) reduced the osteolysis induced by human mammary carcinoma. It is suggested that these agents be evaluated as adjuvant therapy in patients with apparently 'early' mammary cancer in a controlled clinical trial.

Inhibition of cyclooxygenase-2: effects on renin secretion and expression in fetal lambs.

The importance of prostaglandins in the regulation of the renin-angiotensin system during development is not known. These experiments were conducted to examine the effects of prostaglandin synthesis inhibitors on basal and isoproterenol-induced plasma renin concentration and renin gene expression in the late-gestation fetal lamb. Eighteen lamb fetuses ranging in gestational age from 129 to 138 days underwent surgical insertion of femoral arterial and venous catheters under general endotracheal anesthesia. After a period of recovery, animals underwent an infusion of isoproterenol after administration of a saline bolus (control experiments); 24-48 h later a second study was performed after administration of NS-398, a cyclooxygenase (COX)-2 inhibitor, or saline for a second control study. Administration of COX-2 inhibitor significantly reduced baseline plasma renin levels and attenuated responses in fetal renin secretion to isoproterenol infusions. Renal cortical cells from animals receiving COX-2 inhibitor had significantly lower levels of renin mRNA compared with animals receiving only saline. Renal cortical cells in culture from animals receiving only saline exhibited increased levels of renin mRNA when treated with isoproterenol, forskolin, or IBMX. Only forskolin increased renin mRNA levels in renal cortical cells in culture from animals receiving COX-2 inhibitor. We conclude that prostaglandins play a stimulatory role in the regulation of the renin-angiotensin system and are necessary for beta-adrenergic stimulation of renin secretion and gene expression in the late-gestation fetal lamb.

The role of nitric oxide in dilating the fetal ductus arteriosus in rats.

Prostaglandin E is a major dilator of the fetal ductus arteriosus (DA), but the role of nitric oxide in fetal ductal dilation has not been established. We studied the effects of a potent nitric oxide synthase inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME), on the fetal DA in rats. L-NAME was injected into the dorsum of pregnant rats, and fetal DA was studied 4 h later with a rapid whole body freezing method. The inner diameters of the DA and the main pulmonary artery were measured on a freezing microtome. The inner diameter ratio of DA to main pulmonary artery (DA/PA) was 1.02+/-0.03 (mean +/- SEM; number of fetuses [n], 21) in normal near-term fetuses. The effect of prostaglandin synthesis inhibition was studied after orogastric administration of indomethacin to pregnant rats. In near-term rats on the 21st day of gestation (term, 21.5 d), a large dose of L-NAME (100 mg/kg) caused only mild ductal constriction, with DA/PA reduced to 0.83+/-0.05 (n = 20). Indomethacin (1 mg/kg) caused moderate ductal constriction, and DA/PA was decreased to 0.65+/-0.05 (n = 21). Combined administration of L-NAME (10 mg/kg) and indomethacin (1 mg/kg) caused severe ductal constriction, with DA/PA of 0.26+/-0.03 (n = 16). In preterm rats on the 19th day of gestation, a moderate dose of L-NAME (10 mg/kg) caused severe ductal constriction, with a DA/PA of 0.32+/-0.05 (n = 24). Indomethacin (1 mg/kg) alone caused only mild ductal constriction, with DA/PA 0.86+/-0.02 (n = 16). In conclusion, prostaglandin has a major role and nitric oxide has a minor role in dilating the DA in the near-term fetal rat. In contrast, nitric oxide has a major role and prostaglandin has a minor role in dilating the DA in preterm fetal rats.

Effect of prostaglandin synthesis inhibition on macula densa-stimulated renin secretion.

The purpose of the present studies was to evaluate directly the role of prostaglandins in macula densa-mediated renin release. Individual juxtaglomerular apparatus specimens were microdissected from rabbit kidney and perfused with a solution containing either high NaCl (Na+ = 141 meq/l; Cl- = 122 meq/l) or low NaCl (Na+ = 26 meq/l; Cl- = 7 meq/l) concentration. With a step decrease in perfusate NaCl (high to low), renin secretion rate was markedly stimulated (from 15.06 to 63.1 nGU/min, P < 0.01), and the response was almost fully reversible. When specimens were bathed with cyclooxygenase inhibitors flurbiprofen (10(-5) M) or flufenamic acid (10(-4) M), this macula densa-activated increase in renin release was largely or completely abolished (flurbiprofen, 3.5-10.5 nGU/min, not significant; flufenamic acid, 9.0-12.3 nGU/min, not significant). Exposing the macula densa to a step increase in perfusate NaCl concentration (low to high) resulted in a significant and reversible suppression of renin secretion in control specimens, but no significant suppression was seen in specimens treated with flufenamic acid. These data provide direct evidence to support the hypothesis that locally produced prostaglandins may act as a primary mediator of the renin response to macula densa activation.

Effect of prostaglandin synthesis inhibitors on spontaneous and endotoxin-induced abortion in mice

The putative role of prostaglandin E 2(PGE 2) in suppressing rejection of the ‘fetal allograft’ (resorption) in C3H/HeJ and CBA/J allopregnant mice was tested by administration of the prostaglandin synthesis inhibitors indomethacin (INDO) and acetylsalicylic acid (ASA). When the resorption rate was low, INDO fed at a dose of 15 μg/ml in drinking water after implantation had a slight augmenting effect when the endogenous resorption rate was <30%, but had no effect when the endogenous rate was higher or when bacterial lipopolysaccharide (LPS) was given. ASA fed at 50 μg/ml had no augmenting effect and did not increase sensitivity to the abortogen LPS in either CBA/J (LPS sensitive) or C3H/HeJ (LPS resistant) mice. Both INDO and ASA fed to CBA/J mice significantly reduced endogenous PGE 2 extractable from the uteri of hormonally pseudopregnant mice after deciduoma induction. Feeding INDO at doses up to 30 μg/ml from day 2.5 of pregnancy impaired but failed to completely block implantation in CBA/J mice, and with daily administration, some of the mice became sick: all of the implants in sick mice resorbed. INDO at doses of 150–200 μg per day known to inhibit implantation in vivo by sufficiently blocking PGE 2 synthesis, was injected on one or more days beginning after the time of implantation. This failed to cause abortion in CBA/J mice and although some mice became ill, provided this happened after day 8.5 of pregnancy when sensitivity to the abortogenic effects of injected LPS decreased substantially in these mice, all implants in the sick mice were ‘healthy’ (i.e. non-resorbing). We were unable to increase the rate of resorption in syngeneically pregnant CD1 mice above 13% with 15 ml INDO in drinking water. Our data do not support the view that PGE 2 represents an important intrauterine suppressor molecule blocking the processes mediating embryo death at the time of abortion. Spontaneous abortion in DBA/2-mated CBA/J mice appears to be determined by the level of bacterial LPS (endotoxin) and treatment with antibiotics or intralipid (which enhances endotoxin clearance), reduces the abortion rate. A sufficient dose of INDO may cause abortion, but the data taken together suggest this may be due to effects on the gut whereby permeability to bacterial LPS is increased.

Effect of prostaglandin synthesis inhibition on the tubuloglomerular feedback control in the rat kidney.

It is known that intact prostaglandin synthesis is of some importance for tubuloglomerular feedback (TGF). In this study the effects of cyclooxygenase inhibition by oral fenflumizole, an imidazole derivative, on TGF in rats after acute elevation of ureteral pressure were investigated by comparison with the TGF mechanism in untreated rats. The effects of fenflumizole on the TGF mechanism were also compared with those of indomethacin injection. To characterize the TGF mechanism proximal tubular stop-flow pressure (Psf) was measured during perfusion of the loop of Henle with an artificial perfusion solution with a composition resembling that of the proximal fluid. The perfusion rate was varied from 0 to 40 nl.min-1, in steps of 2.5-5 nl.min-1, permitting measurement of the maximal pressure response delta Psf, to increased tubular perfusion, and the perfusion rate which elicited a half-maximal drop in Psf, designated the turning point (TP). Both cyclooxygenase inhibitors caused a significant increase in TP from a control value of 21 to approximately 27 nl.min-1. TP remained at this level in fenflumizole-treated rats, even after elevation of ureteral pressure, a situation in which TGF is normally not detectable. From these and earlier investigations we conclude that the prostaglandin system is of importance for a normally operating TGF control mechanism, both under normal conditions and, especially, in conditions in which resetting of TGF is observed.

Renal Functional Effects of Prostaglandin Synthesis Inhibition in Patients with Insulin-Dependent Diabetes Mellitus of Long Duration without Nephropathy

The short-term effects of prostaglandin synthesis inhibition (PGSI; single dose 500 mg of naproxen) on renal function were studied in six women (age: 21.9 +/- 2.4 yrs) with insulin dependent diabetes mellitus (IDDM) of 14.3 +/- 2.8 yrs' duration, and in nine age- and sex-matched controls. The diabetics had no overt signs of nephropathy (Albustix neg, normal serum creatinine, and blood pressure). The clearance of inulin (CIn) and PAH; the filtration fraction (FF); and the excretion of Na, albumin and PGE2 were studied under water diuresis on two separate mornings, first without and then with PGSI. With PGSI all individuals has lower PGE2 excretion. The CIn and FF were significantly (p less than 0.05) higher in the diabetics than in the controls both without (129.4 +/- 23.9 ml/min/1.73 m 2 and 23.4 +/- 2.8% vs. 107.6 +/- 10.3 and 19.7 +/- 1.6) and with (133.7 +/- 29.4 and 22.6 +/- 2.1, vs. 106.8 +/- 10.3 and 20.1 +/- 1.5) PGSI. The diuresis and Na excretion were significantly lower with PGSI, than without, in both groups. The albumin excretion was significantly higher in the diabetics under both conditions (29.9 +/- 16.6 and 34.2 +/- 19.9 micrograms/min/100 ml GFR, vs. 14.5 +/- 10.6 and 12.9 +/- 8.3 in controls). We conclude that the hyperfiltration in this stage of IDDM does not appear to be PG dependent, and that PGSI does not give any immediate effects on the albumin excretion.

Reduced prostaglandin release from the stunned porcine heart--significance for attenuated reactive hyperaemia

Since both reactive hyperaemia and membrane phospholipids are altered even after short lasting ischaemic periods, the release of PGE2 and PGI2 in the basal state and during early reperfusion was examined to determine whether it was changed in the stunned myocardium. The effect of prostaglandin synthesis inhibition on reactive hyperaemia was also examined. The distal left anterior descending coronary artery was occluded for brief periods and coronary flow was recorded by Doppler flowmetry. In subgroups: (1) a shunt was established draining the ischaemic region for determination of myocardial prostaglandin release associated with 2 min of ischaemia before and after a 10 min occlusion; (2) prostaglandin synthesis was blocked between two 2 min occlusions by infusing indomethacin into the left anterior descending artery; and (3) segment lengths were measured in the left anterior descending artery region subjected to consecutive periods of 2, 10, and 2 min of ischaemia, and in a control region. 21 pentobarbitone sodium anaesthetised pigs, weight 21-30 kg, were used. 30 min after the 10 min occlusion, systolic shortening was reduced by 38(18-57)% (median +95% confidence interval; p less than 0.05). Concomitantly, basal PGE2 and PGI2 release was reduced by 69(30-77)% (p less than 0.05) and 58(7-81)% (p less than 0.05), respectively. During early reperfusion after 2 min of ischaemia, PGE2 release was reduced by 53(17-86)% (p less than 0.05) after development of stunning, whereas PGI2 release remained unaltered. Blockade of prostaglandin synthesis did not affect reactive hyperaemia either in normal or in stunned myocardium. Prostaglandin release from the stunned myocardium is reduced. Since indomethacin did not affect reactive hyperaemia, the attenuated PGE2 release during early reperfusion in stunned myocardium cannot explain the concomitant reduction in reactive hyperaemia.

Indomethacin Treatment in Newborn Canine Endotoxic Shock.

Prostaglandins have been reported to play an important role in endotoxic shock. However, the beneficial effects of prostaglandin synthesis inhibitors for the treatment of newborn endotoxic shock have been controversial. This study was performed to evaluate the effects of indomethacin on the hemodynamics during fulminant endotoxic shock in newborn dogs. After E. coli lipopolysaccharide (LPS) injection, mean arterial pressure was maintained for the first 60 min, and then declined from 53 +/- 2 to 27 +/- 2 mmHg at 120 min. Cardiac output dropped from 0.37 +/- 0.03 to 0.24 +/- 0.03 L/min/kg 5 min after LPS injection and continued to decline to 0.12 +/- 0.01 L/min/kg at 120 min. Indomethacin treatment 20 min prior to LPS injection attenuated the hypotension (50 +/- 3 mmHg at 120 min, p less than 0.05) and the decrease of cardiac output (0.18 +/- 0.02 L/min/kg at 120 min, p less than 0.05). Indomethacin treatment 5 min after LPS injection also attenuated the hypotension (55 +/- 4 mmHg at 120 min, p less than 0.05) and the decrease of cardiac output (0.21 +/- 0.02 L/min/kg at 120 min, p less than 0.05). Survival times were increased by the indomethacin treatments. Thus, indomethacin appears to be beneficial for the treatment of fulminant hemodynamic deterioration in newborn endotoxic shock.

Glomerular and tubular adaptive responses to acute nephron loss in the rat. Effect of prostaglandin synthesis inhibition.

These studies, using in vivo micropuncture techniques in the Munich-Wistar rat, document the magnitude of changes in glomerular and tubular function and structure 24 h after approximately 75% nephron loss (Nx) and compared these results with those obtained in sham-operated rats. The contribution of either nephron hypertrophy or renal prostaglandin to these adjustments in nephron function was also explored. After acute Nx, single nephron GFR (SNGFR) was increased, on average by approximately 30%, due primarily to glomerular hyperperfusion and hypertension. The approximately 45% reduction in preglomerular and the constancy in postglomerular vascular resistances was entirely responsible for these adaptations. Although increases in fluid reabsorption in proximal convoluted tubules correlated closely with increase in SNGFR, the fractional fluid reabsorption between late proximal and early distal tubular segments was depressed. Nephron hypertrophy could not be substantiated based on either measurements of protein content in renal tissue homogenates or morphometric analysis of proximal convoluted tubules. However, acute Nx was associated with increased urinary excretory rates per functional nephron for 6-keto-PGF1 alpha and TXB2. Prostaglandin synthesis inhibition did not affect function in control nephrons, but this maneuver was associated with normalization of glomerular and tubular function in remnant nephrons. The results suggest that enhanced synthesis of cyclooxygenase-dependent products is one of the earliest responses to Nx, and even before hypertrophy the pathophysiologic effects of prostaglandin may be important contributors to the adaptations in remnant nephron function.

No effect of prostaglandin synthesis inhibition on muscle reflexes in fetal lambs

The effects of inhibiting prostaglandin (PG) synthesis on fetal breathing movements and on the amplitude of reflex contraction of the digastric muscle (five trials) or hindlimb semitendinosus muscle (seven trials) has been studied in six fetal lambs at 123-139 days gestation. Infusion of either indomethacin (100 mg) or acetaminophen (300 mg) in 30 ml saline over 30 min resulted in an increase in the amplitude and incidence of breathing movements for 3-18 h in the different trials, but there was no change in the mean amplitude of either reflex or in the normal variation of reflex amplitude with changes in electrocortical activity. It is concluded that PGs modulate fetal breathing movements by an action on the brain stem chemoreceptors but do not alter the excitability of neural pathways subserving some cranial and spinal reflexes.

Effects of various prostaglandin synthesis inhibitors on pancreatic carcinogenesis in hamsters after initiation with N-nitrosobis(2-oxopropyl)amine

The effects of prostaglandin synthesis inhibitors on development of N-nitrosobis(2-oxopropyl)amine (BOP)-initiated pancreatic tumors were investigated. Female Syrian golden hamsters were given five weekly s.c. injections of BOP (10 mg/kg body weight) during the first 5 weeks and then given 20 p.p.m. indomethacin in the drinking water, 0.25% phenylbutazone in the diet, 1% aspirin in the diet, or no treatment (control group). The resultant incidence of pancreatic carcinoma at week 32 was significantly lower (P less than 0.05) in animals receiving phenylbutazone (36.8%) than in the controls (71.4%) and the numbers of carcinomas per hamster were significantly reduced by indomethacin (0.63) and phenylbutazone (0.58) treatment compared with the control group value (1.29). Aspirin also showed a tendency to decrease pancreatic tumor incidence, but this was not significant. Thus, prostaglandin synthesis inhibitors reduce the development of pancreatic cancer when administered during the post-initiation phase in this animal model.

Effects of eicosanoids on the water and sodium balance of the neonate

Experimental and clinical evidence support the assumption that eicosanoids affect the morphological development and the functional behaviour of the kidney during the intra-uterine and newborn periods. Inhibition of prostaglandin (PG) synthesis in the pregnant rhesus monkey resulted in renal hypoplasia in the offspring. The plasma levels of PGs are high in the newborn. Production of PGE2 by the cortical collecting duct was found to be similar in newborn and adult rabbit but the affinity of the renal tissue of the newborn for this eicosanoid was higher than that of the renal tissue of the adult rat. Based on findings in adult animals this would be expected to blunt the effect of antidiuretic hormone and account, in part, for the limited ability of the newborn to concentrate the urine. Yet, administration to unanaesthetized newborn rats of acetaminophen, a drug that inhibits the synthesis of PGE2 and thromboxane B2, blocked, rather than enhanced, the increment in urine osmolality produced by 1 h of water deprivation. The effect was absent in weaning and adult rats. A similar experimental manoeuvre increased sodium excretion in newborn but not in weaning or adult rats. Age-related differences are also evident with regard to side effects of PG synthesis inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of indomethacin on glomerular permselectivity and hemodynamics in nephrotoxic serum nephritis

The present study was undertaken to determine the effects of prostaglandin synthesis inhibition on glomerular hemodynamics in nephrotoxic serum nephritis and to elucidate the mechanisms by which prostaglandin synthesis inhibition reduces proteinuria in nephritic rats. Dextran sieving studies were performed before and after intravenous administration of indomethacin to control rats and to nephritic rats with heavy proteinuria. Indomethacin did not significantly alter mean arterial pressure, glomerular filtration rate or proteinuria in control rats nor were significant changes in dextran sieving observed. By contrast, in nephritic rats indomethacin significantly reduced glomerular filtration rate (2.58 +/- 0.50 vs. 1.39 +/- 0.27 ml/min, P less than 0.001), proteinuria (0.198 +/- 0.079 vs. 0.048 +/- 0.019 mg/min, P less than 0.05) and filtration rate-corrected proteinuria (0.059 +/- 0.033 vs. 0.031 +/- 0.013 mg/ml GFR, P less than 0.05). The fractional clearance of neutral dextrans with molecular radii exceeding 42 A were elevated above control values in nephritic rats (P less than 0.05). After administration of indomethacin, the fractional clearance of neutral dextrans uniformly declined toward control values and remained elevated only for molecular radii exceeding 54 A. Assessment of glomerular hemodynamics in nephritic rats before and after indomethacin showed significant declines in single nephron filtration rate (31.5 +/- 3.0 vs. 21.2 +/- 2.5 nl/min, P less than 0.02), glomerular plasma flow rate (99.5 +/- 6.7 vs. 68.5 +/- 7.8 nl/min, P less than 0.05) and glomerular ultrafiltration coefficient (0.0430 +/- 0.0033 vs. 0.0339 +/- 0.0032 nl.sec-1.mm Hg-1, p less than 0.05). Indomethacin did not significantly change these parameters in control rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Direct evidence for the local generation of vascular angiotensin II and its prostaglandin-mediated release from isolated hind legs in the rat

We examined the effect of prostaglandin synthesis inhibitors (indomethacin and meclofenamate) on the release of immunoreactive angiotensins I (irAng I) and II (irAng II) from isolated perfused rat hind-leg vasculature in order to delineate the possible relevance of prostaglandins to the vascular renin-angiotensin system in vitro. Isolated rat hind-legs were perfused with Krebs-Ringer solution and release of irAng I and irAng II into the perfusate was directly measured by using a Sep-Pak C18 cartridge connected to the perfusion system. The spontaneous release of irAng I and irAng II was as high as 600-700 pg per 30 min and was stable for at least 3 h. Addition of indomethacin and meclofenamate (10(-8) to 2 X 10(-6) mol/l) to the perfusion medium suppressed the release of both irAng I and irAng II to a similar extent in a dose-dependent fashion (P less than 0.001); the maximal percentage inhibition of irAng II release that was evoked by these inhibitors (2 X 10(-6) mol) was 60 +/- 6% (P less than 0.001) for indomethacin and 50 +/- 4% (P less than 0.001) for meclofenamate. There was a highly significant positive correlation between the amount of irAng I released and the amount of irAng II that was altered by indomethacin (r = 0.91) or meclofenamate (r = 0.94). These results provide direct proof of the local generation and subsequent release of Ang II by peripheral vascular tissue and suggest that prostaglandin plays an important role in the regulation of vascular Ang II release.

Effect of prostaglandin synthesis inhibitors on morphine-induced gastric protection in rats

Effect of prostaglandin synthesis inhibitors on morphine-induced gastric protection in rats

Prostaglandins and cellular reaction in uterine flushings. II. Effect of PG synthesis inhibition in IUD users.

The effect of oral administration of indomethacin (100 mg/day), a potent inhibitor of prostaglandin (PG) biosynthesis, on the PG levels and cellular profile in the uterine flushings in response to the use of an IUD (Lippes Loop size C) was studied in sixty women. Indomethacin reduced the cell counts in both follicular and luteal phases of menstrual cycles before and after IUD insertion. The anti-inflammatory drug decreased PGE2 and PGF2 alpha levels in both phases of the cycle before IUD insertion. After insertion, it inhibited only the formation of PGF2 alpha and its 13,14-dihydro-15-keto metabolite in the luteal phase but not in the follicular phase. In long-term users, however, the drugs reduced the levels of all PGs studied in the luteal phase and only PGF2 alpha and its metabolite in the follicular phase. The implications of these findings in the mechanisms of contraceptive action of IUDs and their side effects are discussed.

Effect of indomethacin and propranolol on the blood pressure and renin response to atriopeptin III in conscious rats

The effect of prostaglandin synthesis inhibition and of β-adrenoceptor blockade on the blood pressure and renin response to the synthetic atrial natriuretic peptide atriopeptin III was assessed in unanesthetized normotensive rats. This peptide was infused i.v. for 30 min at a rate of 1 μg/min in rats pretreated either with indomethacin (5 mg i.v.) or propranolol (1 mg i.v.). The blood pressure reducing effect of atriopeptin III was attenuated neither by indomethacin nor by propranolol. Atriopeptin III per se did not modify plasma renin activity. Both the administration of indomethacin and of propranolol had a suppressing effect on renin release during atriopeptin III infusion. These data suggest that the vasodilating properties of atrial natriuretic peptides do not depend in the conscious normotensive rats on the production of prostaglandins. They also provide evidence that during infusion of such peptides, both prostaglandins and β-adrenergic mechanisms are still involved in the regulation of renin secretion.

Effect of prostaglandin synthesis inhibition in vivo on the immune response following hepatitis B vaccination in normal subjects

Prostaglandin E 2 has been shown in several studies to have immunomodulatory properties. We have now studied the in vitro and in vivo effects of piroxicam, a nonsteroidal antiinflammatory drug with potent prostaglandin-synthetase inhibitory activity, on immune responses in healthy subjects ( n=50). All subjects received three injections of hepatitis B vaccine with a 1 month interval. From 3 days before until 7 days after each vaccination they also received piroxicam or placebo in a double blind way. There was no difference in the humoral immune response to hepatitis B surface antigen between the two groups. Oral intake of piroxicam did not affect in vitro proliferation of T-cells in response to OKT3 monoclonal antibody. However, addition of piroxicam in vitro to cultures of peripheral blood mononuclear cells significantly enhanced OKT3-induced T-lymphocyte proliferation ( P<0.001). The enhancement was observed even in subjects taking piroxicam orally, demonstrating that in vivo piroxicam treatment leaves the cells susceptible to the in vitro immunomodulating effect of this drug. We conclude that, although piroxicam in vitro enhances T-cell functionality, oral intake of this prostaglandin synthetase inhibitor — at least by normal subjects — does not enhance antibody formation to a protein antigen and has no demonstrable effect on T-cell function.