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PubMed1983

Effects of cyclooxygenase inhibitors on the alterations in lung mechanics caused by endotoxemia in the unanesthetized sheep.

The effects of Escherichia coli endotoxin on lung mechanics, hemodynamics, gas exchange, and lung fluid and solute exchange were studied in 12 chronically instrumented unanesthetized sheep. A possible role for cyclooxygenase products of arachidonate metabolism as mediators of the endotoxin-induced alterations in lung mechanics was investigated by studying sheep before and after cyclooxygenase inhibition with sodium meclofenamate and ibuprofen. Sheep were studied three times in random order: (a) sodium meclofenamate (or ibuprofen) infusion alone; (b) E. coli endotoxin alone; and (c) meclofenamate (or ibuprofen) and endotoxin. Meclofenamate alone had no effect on any of the variables measured. Endotoxin alone caused early marked changes in lung mechanics: resistance to airflow across the lungs (RL) increased 10-fold, dynamic lung compliance (Cdyn) decreased 80% and functional residual capacity (FRC) decreased by greater than 30%. The alveolar-to-arterial oxygen difference (delta AaPO2) increased markedly following endotoxemia. In the presence of sufficient meclofenamate to inhibit accumulation of thromboxane-B2 and 6-keto-prostaglandin F1 alpha in lung lymph, endotoxin caused no increase in RL, Cdyn decreased by less than 40%, and FRC decreased by only 6%. Meclofenamate significantly attenuated the hypoxemia and early pulmonary hypertension caused by endotoxemia but had no effect on the late increases in lung fluid and solute exchange. Ibuprofen had similar effects to those observed with meclofenamate. We conclude that both the pulmonary hypertension and changes in lung mechanics observed after endotoxemia may be mediated, at least in part, by constrictor prostaglandins or thromboxanes and that gas exchange may be improved by preventing endogenous synthesis of these mediators.

6-Ketoprostaglandin F1 alpha↗
PubMed1984

Prostaglandins inhibit renal ammoniagenesis in the rat.

We describe the inhibitory effect of prostaglandins (PGs) on in vivo rat renal ammonia synthesis. The influence of systemic pH upon urinary PG excretion and ammoniagenesis was also investigated. Finally, PG production by incubated rat renal cortical slices was suppressed to investigate the PG-ammonia interplay in the absence of changes in renal blood flow, glomerular filtration rate, ambient electrolyte concentrations or extrarenal hormonal factors. In vivo ammonia synthesis doubled and PG excretion fell by 44% in normal rats, after intravenous administration of 1 mg/kg of meclofenamate. Higher doses of meclofenamate further augmented ammonia production and further reduced PG excretion. PG depletion was also associated with an increase in fractional excretion of ammonia (FENH3) that was independent of changes in urine flow rate or pH. Acute metabolic acidosis (AMA) increased total ammonia synthesis but also stimulated PG production. Administration of meclofenamate to rats with mild AMA markedly reduced urinary PG excretion, further augmented ammonia synthesis, and significantly increased the FENH3. Inhibition of stimulated PG synthesis during severe AMA did not increase ammoniagenesis or FENH3. Acute metabolic alkalosis did not alter production of PGs or ammonia, but reduced the FENH3 by 42%. Meclofenamate nearly normalized the FENH3 but stimulated synthesis to a lesser degree than was seen in nonalkalotic rats that received meclofenamate. Inhibition of PG synthesis in incubated rat renal cortical slices also stimulated ammoniagenesis. Conversely, stimulation of PG synthesis decreased ammonia production and acidification of the incubation medium increased prostaglandin F2 alpha production. Thus, in vitro findings support the in vivo results. We conclude that PGs inhibit ammonia synthesis in normal rats and in those undergoing mild AMA. Severe acidosis overrides this inhibitory effect of PGs, whereas metabolic alkalosis suppresses the stimulatory effect of PG synthesis inhibition.

Acidosis↗
PubMed1986

Evidence against the hypothesis that prostaglandins are the vasodepressor agents of pregnancy. Serial studies in chronically instrumented, conscious rats.

Renal hemodynamics increase dramatically during pregnancy, and pressor responsiveness to exogenous administration of vasoconstrictors is attenuated. We investigated whether or not vasodilatory prostaglandins mediate these phenomena. Trained, chronically instrumented, conscious pregnant rats were used. Control values of glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were elevated at midgestation (P less than 0.01 and P = 0.05 from prepregnant means, respectively), and effective renal vascular resistance was decreased (P = 0.05). Indomethacin (4.5-6.5 mg/kg body weight [BW]) failed to decrease renal hemodynamics at this stage of pregnancy; in fact, it raised GFR somewhat further (P less than 0.05). Systemic pressor responsiveness to bolus administration of norepinephrine and angiotensin II (AII) was significantly attenuated by at least gestational day 20. Neither indomethacin (7 mg/kg BW) or meclofenamate (6 mg/kg BW) affected the refractory response. The renal vasculature was also relatively unresponsive to an intravenous infusion of AII (5 ng X kg-1 X min-1) during late gestation (day 19); in particular, the fall in ERPF in response to AII (16 +/- 3%) was markedly less than that observed in the prepregnant condition (34 +/- 3%; P less than 0.05). Indomethacin (6 mg/kg BW) failed to restore this blunted response, and further attenuation was evident, despite the presence of the inhibitor (gestational day 21). We conclude that vasodilatory prostaglandins do not appear to mediate the rise in renal hemodynamics, and the attenuation of the systemic and renal pressor responsiveness observed during pregnancy, insofar as these phenomena were unaffected by acute cyclooxygenase inhibition in unstressed, conscious rats.

Angiotensin II↗
PubMed1994

Analysis of regional hemodynamic regulation in response to scald injury.

Ultrasonic probes were placed around dog femoral arteries to record blood flow. Hind paw scalding with boiling water (5 s) caused a marked increase in ipsilateral femoral blood flow that persisted for the 2-h observation period. Contralateral femoral blood flow and systemic and pulmonary vascular resistances were unchanged. Compared to scald only animals, methysergide pretreatment diminished and shortened the femoral vasodilator response to scald (109 +/- 14 vs 243 +/- 27 ml/min at 5 min; 59 +/- 14 vs 191 +/- 31 ml/min at 2 h). Pretreatment with ritanserin, BW A1433U83, atropine, ICI 118551, diphenhydramine, ranitidine, meclofenamate, L-nitro-arginine methyl ester, 3-amino-1,2,4-triazine, and U 37883A had no effect on the increased femoral blood flow response to scald, suggesting this vasodilator response is not dependent upon activation of serotonergic2, adenosineA1, muscarinic, beta 2-adrenergic, histaminergic1 or histaminergic2 receptors, on cyclooxygenase products, endothelium-derived relaxing factor derived from nitric oxide (NO) synthase III, NO derived from NO synthase II, or KATP channels, respectively. Methysergide given after burn immediately reduced the augmented femoral blood flow to preburn levels, suggesting the vasodilator response to scald is mediated through continual activation of local serotonergic1-like receptors, which may be target site(s) for therapeutic interventions to influence burn-induced hemodynamic alterations.

Adamantane↗
PubMed1982

Short-term treatment of osteoarthritis: a comparison of sodium meclofenamate and ibuprofen.

A double-blind crossover study compared sodium meclofenamate (300 mg daily) and ibuprofen (900 mg daily) in thirty patients with osteoarthritis. Each treatment period was of 3 weeks duration. Both drugs were effective in reducing the severity of joint symptoms and in improving the range of motion, with the exception of spine movement which did not show any changes from the baseline. Tolerance was good.

Aged↗
PubMed2001

Vasodilator responses to ATP and UTP are cAMP dependent in the mesenteric vascular bed of the cat.

BACKGROUND: This study was designed to examine the responses to and the mechanism by which purinergic agonists decrease vascular resistance in the mesenteric vascular bed of the cat. METHODS AND RESULTS: Injections of ATP, UTP, and 2-MethylThioATP (2-MetSATP) into the mesenteric perfusion circuit elicited dose-dependent decreases in perfusion pressure while injections of beta,gamma-MethylATP (beta,gamma-MetATP) produced a biphasic response with an initial vasopressor response followed by a vasodilator response. The order of potency of the vasodilator response was 2-MetSATP > ATP > UTP > beta,gamma-MetATP. The vasodilator responses to ATP, UTP, 2-MetSATP, and beta,gamma-MetATP were increased in duration by the cAMP phosphodiesterase inhibitor, rolipram. However, vasodilator responses were not altered by the adminstration of a nitric oxide synthase inhibitor, a cGMP phosphodiesterase inhibitor, or a cyclooxygenase inhibitor. Treatment with PPADS, a P2X(1), P2Y(1), and P2Y(4) receptor antagonist, did not alter vasodilator responses to the purinergic agonists; however, the vasopressor component of the response to beta,gamma-MetATP was decreased. CONCLUSIONS: These data suggest that ATP, UTP, 2-MetSATP, and beta,gamma-MetATP dilate the mesentary vascular bed in the cat by a cAMP dependent mechanism, and that nitric oxide or prostaglandin release, cGMP accumulation, or activation of P2X(1), P2Y(1), or P2Y(4) receptors play little or no role in mediating vasodilator responses to the purinergic agonists in this regional vascular bed. In addition, these results suggest that the pressor component of the response to beta,gamma-MetATP is mediated by the activation of P2X(1) receptors.

Adenosine Triphosphate↗
PubMed2003

Identification of gap junction blockers using automated fluorescence microscopy imaging.

Gap junctions coordinate electrical signals and facilitate metabolic synchronization between cells. In this study, the authors have developed a novel assay for the identification of gap junction blockers using fluorescence microscopy imaging-based high-content screening technology. In the assay, the communication between neighboring cells through gap junctions was measured by following the redistribution of a fluorescent marker. The movement of calcein dye from dye-loaded donor cells to dye-free acceptor cells through gap junctions overexpressed on cell surface membranes was monitored using automated fluorescence microscopy imaging in a high-throughput compatible format. The fluorescence imaging technology consisted of automated focusing, image acquisition, image processing, and data mining. The authors have successfully performed a high-throughput screening of a 486,000- compound program with this assay, and they were able to identify false positives without additional experiments. Selective and pharmacologically interesting compounds were identified for further optimization.

Animals↗
PubMed1977

Comparison of sodium meclofenamate and indomethacin in rheumatoid arthritis.

A double-blind crossover study was conducted in 15 patients with classical definite rheumatoid arthritis to compare the effect of sodium meclofenamate (300 mg daily) with placebo and indomethacin (100 mg daily). Each treatment was administered for 1 week to patients assigned at random to treatment sequences. The active drugs were shown to be significantly superior to placebo. Sodium meclofenamate alone reduced the articular index. Patient preference, however, was in favour of indomethacin.

Adult↗
PubMed1983

Clinical therapeutic trial of sodium meclofenamate and naproxen in rheumatoid arthritis, with comments on the use of placebos in clinical trials.

Forty patients with active rheumatoid arthritis were entered into a single-blind study of 12-weeks' duration to compare the efficacy and tolerance of 100 mg sodium meclofenamate 3-times daily and 250 mg naproxen twice daily. Disease activity was defined by the presence of a Ritchie Articular Index score of greater than 15. Patients were assessed at 4-week intervals. Analysis of variance of the data from those patients who completed 12 weeks in the trial showed that in the sodium meclofenamate group there was a significant improvement in articular index, left grip strength, pain severity and patients' global assessment over the course of the study. In the naproxen group, there was a significant improvement in articular index, grip strength and pain severity over the study. Pairwise comparisons showed that morning stiffness improved significantly from baseline to 12 weeks only, in both treatment groups. There were no significant differences between the two treatment groups for any of the measurements at any time period during the study. In the sodium meclofenamate group, there were 4 drop-outs due to inadequate efficacy and 6 in the naproxen group. Four patients in the sodium meclofenamate group and 2 patients in the naproxen group dropped out of the study because of side-effects, primarily nausea. These results suggest that sodium meclofenamate was equally well tolerated and as effective as naproxen in the treatment of rheumatoid arthritis in this group of patients.

Adult↗
PubMed1984

Effects of meclofenamate on pulmonary vascular resistance correlate with postnatal age in young piglets.

We administered sodium meclofenamate, a prostaglandin synthetase inhibitor, to 15 piglets (ages 5-70 d) to test the hypothesis that endogenous prostaglandin pulmonary vasodilators influence total pulmonary resistance under both normoxic and hypoxic conditions. No significant differences in hemodynamic measurements were found between the control group and drug-treated animals more than 12-d-old. When six experimental animals less than 12 d of age were compared with six age-matched controls, meclofenamate produced a small but significant increase in mean pulmonary artery pressure (110 +/- 9 versus 97 +/- 10%, P less than 0.05) and total pulmonary resistance (135 +/- 23 versus 102 +/- 12%, P less than 0.03). The magnitude of the change in total pulmonary resistance produced by 2 mg/kg of meclofenamate during normoxia correlated inversely with postnatal age (r = 0.83, P less than 0.01). Individual changes in pulmonary hemodynamics produced by acute hypoxia after meclofenamate treatment were the same as pretreatment values and were similar in both young and older animals.

Animals↗
PubMed1991

Prostaglandin inhibition prevents the fall in pulmonary vascular resistance as a result of rhythmic distension of the lungs in fetal lambs.

Prostaglandins (PG) are vasoactive factors involved in the regulation of pulmonary vascular resistance at birth. However, their physiologic importance is unclear. We hypothesized that PG are important regulators of pulmonary vascular resistance during static and rhythmic distension of the lungs. To test this hypothesis, we studied seven near-term fetal lambs treated with meclofenamate (a PG synthetase inhibitor) and six controls. The fetal lambs were instrumented on a long-term basis with vascular catheters to measure pulmonary arterial pressures, left atrial pressures, and pulmonary blood flow (radionuclide-labeled microsphere method). The fetal airway was intubated, and the ductus arteriosus wall was infiltrated with formalin to assure full patency during the study period. Pulmonary vascular resistance was calculated during baseline and during sequential in utero static distension of the fetal lungs, rhythmic distension, and ventilation with oxygenation. We found that during rhythmic distension, inhibition of PG synthesis abolished the 4-fold decrease in pulmonary vascular resistance seen in the control group. In contrast, during static distension, pulmonary vascular resistance did not change in either group, and during ventilation with oxygenation, pulmonary vascular resistance decreased 12-fold in both groups. We conclude that PG are important regulators of pulmonary vascular resistance during rhythmic distension but are not essential for the regulation of pulmonary vascular resistance during static distension or during ventilation with oxygenation.

Animals↗
PubMed1981

The role of renal prostaglandins in the renin response to isoproterenol in the rat in vitro.

Renal prostaglandins (PGs) have been considered to be important mediators of renin release. However, the mechanism and the site of action have not been clarified. To investigate the role of PGs in the control of isoproterenol-induced renin release, we studied the effect of two inhibitors of PG synthesis, indomethacin and meclofenamate, on the renin release stimulated by isoproterenol and dibutyryl cAMP. We used an in vitro superfusion system of rat renal cortical slices. Neither indomethacin nor meclofenamate affected basal renin release. Isoproterenol (8 x 10(-7) M) increased renin and PGE2 release which was blocked by indomethacin (10(-4) M) and meclofenamate (10(-4) M). Dibutyryl cAMP stimulated renin release significantly, and this effect was not blocked by indomethacin (10(-4) M). Moreover, dibutyryl cAMP did not stimulate PGE2 release. In view of the fact that we have previously shown that PG-stimulated renin release is not blocked by propranolol and is enhanced by phosphodiesterase inhibitors, our present experiments suggest that the site of action of PGs on renin release is located between the beta-adrenergic receptor and the generation of cAMP.

Animals↗
PubMed1982

Progesterone and estrogen control of the response of rat uterine lysosomal cathepsin D activity to a deciduogenic stimulus.

Endometrial sensitization to deciduogenic stimuli and destruction of luminal epithelial cells during the uterine decidual reaction may depend upon the control of endometrial lysosome function by progesterone and estradiol. These experiments examined progesterone and estrogen control of the levels of uterine cathepsin D and the response of cathepsin D activity to a deciduogenic stimulus. The progestin medroxyprogesterone acetate increased rates of uterine cathepsin D synthesis, but these rates were not enhanced by estradiol pretreatment. The response of cathepsin D activity to a deciduogenic stimulus, however, required progestin pretreatment, followed by estrogen treatment. Decreases in cathepsin D activity after a deciduogenic stimulus required estrogen stimulation for approximately 12 h, and this estrogen effect could be suppressed by treatment with dexamethasone or inhibitors of prostanoid synthesis. These results indicate that destruction of luminal epithelial cells during the uterine decidual reaction involves the coordinated control of the cathepsin D content by progesterone and of intracellular lysosome activity by estradiol.

Animals↗
PubMed1986

Role of brain prostaglandins in the control of vasopressin secretion in the conscious rat.

Administration of 10 micrograms prostaglandin D2 (PGD2), the primary PG identified in the rat brain, into the lateral cerebral ventricle of conscious rats resulted in a significant elevation in the plasma vasopressin (AVP) concentration, without a change in mean arterial blood pressure or heart rate. The central administration of indomethacin (100 micrograms) resulted in a significant attenuation of the AVP response to a peripheral osmotic stimulus (iv 2.5 M NaCl; 100 microliters/kg X min for 30 min), but had little effect on the AVP response to hemorrhage (two successive 10% reductions in the estimated blood volume). Administration of another PG synthetase inhibitor, meclofenamate (100 micrograms, into the lateral cerebral ventricle), resulted in a significant attenuation of the AVP response to both the osmotic stimulus and hemorrhage. It is concluded that brain PGs play a central role in the control of AVP secretion.

Animals↗
PubMed1986

Rabbit uterine oxytocin receptors and in vitro contractile response: abrupt changes at term and the role of eicosanoids.

We examined the relation between increased uterine oxytocin receptor concentration and increased in vivo sensitivity of the rabbit uterus to oxytocin at the end of gestation. We determined oxytocin receptor concentrations in myometrium and decidua on different days near term of gestation and postpartum. We also examined the in vitro contractile response to oxytocin on days 30 and 5 days postpartum, when the uterus is unresponsive in vivo, and on day 31 (term), when the uterus is exquisitely sensitive to this hormone in vivo. In addition, we tested the role of endogenous eicosanoids and decidual oxytocin receptors in the myometrial contractile response to oxytocin by examining the contractile response in the presence of the cyclooxygenase/lipoxygenase inhibitor sodium meclofenamate or in muscle strips from which the decidua had been removed by scraping. The concentration of specific binding sites for [3H]oxytocin in myometrial and also decidual membrane preparations was determined. We demonstrate that contractile sensitivity to oxytocin increases at least 4-fold between days 30 and 31 (term) of gestation, and this is accompanied by a nearly 10-fold increase in the concentration of oxytocin-binding sites in both decidua and myometrium. The lesser sensitivity to oxytocin on day 30 was, however, only apparent in the presence of meclofenamate, which suggests that endogenous eicosanoids contribute to the preterm response to oxytocin measured in vitro. The maximal response to oxytocin (integrated area) increased 2-fold between day 30 and term. Thus, an increase in both sensitivity and maximal response to oxytocin could be demonstrated at term in vitro. Five days after parturition, maximal response and uterine sensitivity measured in the presence of meclofenamate had returned to those of the preterm uterus, and the concentration of oxytocin-binding sites had declined. In contrast, sensitivity and maximal response to the cholinergic agonist carbamylcholine declined between day 30 and term. These results support a highly regulated physiological role for oxytocin in parturition which depends primarily on changes in receptor concentration.

Animals↗
PubMed1986

Angiotensin peptides and prostaglandin E2 synthesis: modulation of neurogenic responses in the rabbit vas deferens.

Isolated rabbit vasa deferentia were used to study the neuromodulation induced by angiotensins II and III (AII and AIII) upon both phases of the electrically stimulated contraction (ESC). AIII (10(-8)-10(-7) M) was shown to inhibit the ESC at low frequencies (2-10 Hz), while AII tended to potentiate both phases. Since AIII had no effect on contractions induced by exogenous ATP (twitch, putative transmitter), or norepinephrine (NE; tonic, neurotransmitter), AIII effects were presumed to be presynaptic. AIII neuromodulation was reversed by indomethacin, and prostaglandin E2 (PGE2) mimicked the inhibitory effects of AIII on ESC. The response to AIII was blocked by [Sar1,Ala8]AII (10(-6) M), an angiotensin antagonist. AIII (10(-9)-10(-5) M) stimulated PGE2 synthesis in a concentration-dependent manner. AII (10(-9)-10(-7) M) produced a dramatic rise in PGE2 synthesis, which declined sharply at higher AII concentrations. AII increased the overflow of [3H]NE approximately 50% (P less than 0.01; in the absence of indomethacin); similar concentrations of AIII did not affect [3H]NE release. However, 4 X 10(-8) M AIII in the presence of 26 microM indomethacin significantly (P less than 0.05) increased [3H]NE overflow. Thus, AIII inhibited ESC presynaptically by stimulating PGE2 synthesis, while AII potentiated these contractions presynaptically by enhancing NE release during nerve stimulation. Despite the greater inhibitory effect of AIII on force, AII was more potent than AIII in stimulating PGE2 production.

Adenosine Triphosphate↗
PubMed1990

Tumor necrosis factor and interleukin-1 may regulate renin secretion.

Cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1) are not only immunoregulatory polypeptides, but may have endocrine functions. We have studied the direct effects of recombinant and purified TNF and IL-1 on renin secretion using both static incubations and perifusions of rat renal cortical slices. Ultrapure human IL-1 (hIL-1) at concentrations as low as 5 U/ml (3 X 10(-12) M) significantly stimulated renin secretion (control, 98 +/- 4%; hIL-1, 153 +/- 13%; P less than 0.01). TNF similarly induced renin release [control, 97 +/- 6%; TNF (10 U/ml), 151 +/- 13%; P less than 0.005]. TNF and recombinant human IL-1 beta (rhIL-i beta) also blocked the inhibitory actions of angiotensin-II (AII) on renin release [control, 100 +/- 3%; AII (2 X 10(-7) M), 80 +/- 5%; AII plus TNF (20 U/ml), 102 +/- 7%; AII plus rhIL beta (10 U/ml), 106 +/- 6%; both P less than 0.02 vs. AII]. A cyclooxygenase (CO) blocker, meclofenamate (M), which does not significantly alter basal renin release, attenuated the TNF- and rhIL-1 beta-induced renin secretion [TNF (20 U/ml), 132 +/- 11%; TNF plus M (5 X 10(-5) M), 100 +/- 3% (P less than 0.01); rhIL-1 beta (10 U/ml), 135 +/- 9%; rhIL-1 beta plus M, 105 +/- 10% (P less than 0.05)]. The stimulatory effects of TNF and IL-1 on renin were reversible. These results suggest that IL-1 and TNF are renin secretagogues and can also block the inhibitory actions of AII on renin. Since the effect of TNF and IL-1 on renin can be blocked by a (CO) inhibitor, the studies indicate a role of prostaglandins in their action. Therefore, locally produced TNF and IL-1 may play an important paracrine role in regulation of the renin-angiotensin system.

Angiotensin II↗