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At least 343 records · Page 19Linked to original sources
PubMed1989

Differential effects of ibuprofen, indomethacin, and meclofenamate on prostaglandin endoperoxide H2 metabolism.

Previous studies have suggested the possibility that the non-steroidal antiflammatory drug (NSAID), ibuprofen, may inhibit thromboxane (TX) A2 synthase activity in addition to inhibiting cyclooxygenase activity. Microsomal fractions isolated from the cat lung contain cyclooxygenase as well as prostacyclin (PGI2) synthase, TX synthase, and a GSH-dependent prostaglandin (PG) E2 isomerase activities. When [1-14C] PG endoperoxide H2 (PGH2) was used as substrate, ibuprofen, indomethacin, and meclofenamate exhibited differential effects on terminal enzyme activities. Ibuprofen, at concentrations up to 1 mM, had no effect on the activities of PGI2 synthase, TXA2 synthase of GSH-dependent PGE2 isomerase, whereas indomethacin selectively inhibited PGI2 synthase activity at 5 X 10(-4) M and 10(-3) M. Meclofenamate selectively inhibited TXA2 synthase activity at 5 X 10(-4) M and 10(-3) M. At concentrations of 5 X 10(-3) M, this selectivity was not observed, and indomethacin and meclofenamate decreased the formation of both 6-keto-PGF1 alpha and TXB2. These data indicate that the choice of NSAID and the concentration employed may specifically alter PGH2 metabolism. This action may affect the physiologic consequences of the exchange of PGH2 between cells. The data further indicate that indomethacin has the potential for use as a tool to specifically attenuate PGI2 synthase activity in vitro.

6-Ketoprostaglandin F1 alpha↗
PubMed1979

Studies on the inhibitory effect of indomethacin and meclofenamate on the adrenalectomy-induced increase in plasma renin concentration.

Bilateral adrenalectomy combined with a sodium-deficient diet caused a time-dependent increase in plasma renin concentration in rats. Seventy-two hours after adrenalectomy the inhibitors of prostaglandin biosynthesis indomethacin and meclofenamate diminished the plasma renin concentration by about 50%. This effect was independent of the amount of renin released. Indomethacin and meclofenamate fully retained their ability to reduce the plasma renin concentration when the renal sympathetic nerves or the macular densa cells of the kidneys no longer contributed to renin release. It is concluded that in adrenalectomized rats renal prostaglandins effect the baro-receptor-mechanism in the afferent arterioles and thus enhance renin release.

Adrenalectomy↗
PubMed1984

Angiotensin III-induced modulation of neurogenic responses in the rabbit vas deferens and portal vein.

The effects of prostaglandin synthesis inhibitors on the presynaptic actions of angiotensin (ang) II and III were examined in isolated rabbit vasa deferentia and portal veins. Ang II caused dose-dependent potentiation of low frequency, nerve stimulation in vasa deferentia and portal vein. Indomethacin (26 microM) enhanced the electrically-induced contractions in the vasa deferentia only but did not alter the potency of ang II in either preparation. In contrast, ang III decreased contractions in vasa deferentia induced by nerve stimulation by up to 36% (10(-6) M) and potentiated these contractions at concentrations higher than 10(-6) M. The inhibitory action of ang III on vasa deferentia was converted to potentiation by pretreatment with indomethacin or mepacrine. Exogenous PGE2 blocked low frequency nerve stimulation and not responses to norepinephrine. This prostaglandin appeared to mimic ang III in the vas deferens. No effects of ang III were observed if the contractions were induced by exogenous alpha adrenergic agonists. [Sar1, Ala8] ang II antagonized all responses to the angiotensins, whereas [Sar1, Cys-CH3(8)] ang II selectively antagonized the angiotensin-induced potentiation. Responses in field-stimulated portal veins were potentiated by ang III and this response was unaffected by indomethacin. This investigation strongly suggests the existence of at least two ang receptors in the vas deferens and demonstrates for the first time selective responses to the octa- and heptapeptides in the same effector organ.

Angiotensin II↗
PubMed1984

Potentiation of leukotriene formation in pulmonary and vascular tissue.

Leukotriene (LT) release from vascular and pulmonary tissue was assessed by a radioimmunoassay for peptide leukotrienes (i.e., LTC4, LTD4 and LTE4). The calcium ionophore A-23187 at 1-3 micrograms/ml and platelet activating factor (PAF) at 10 micrograms/ml produced marked formation of peptide leukotrienes in minced cat pulmonary tissue. This was also confirmed by bioassay of the incubates in isolated perfused cat coronary arteries. Rat pulmonary tissue was comparable to cat with regard to LT production, but guinea-pig lung produced about 30-50% less on a weight basis. In addition, aortic and coronary artery vessel walls produced significant amounts of LTs. The time course for maximal leukotriene production occurred at 45-60 min of incubation at 37 degrees C in both the radioimmunoassay and the bioassay. Cat coronary artery constricted markedly to LTC4 or LTD4 (30-40 mm Hg) and to the lung or blood vessel incubate. This constriction was virtually totally blocked by the leukotriene antagonist FPL-55712, but not by the thromboxane receptor antagonist, pinane thromboxane A2, the alpha-adrenergic receptor antagonist, phenoxybenzamine, or the angiotensin receptor antagonist, saralasin. Thus, pulmonary and vascular tissue produce leukotrienes that appear to exert coronary constrictor effects on specific leukotriene receptors. These results indicate that the ischemia of shock and anaphylaxis may be accentuated by the release of peptide leukotrienes.

Animals↗
PubMed1988

Effect of inhibitors of prostaglandin synthesis on the furosemide action in the loop Henle of rat kidney.

Inhibitors of prostaglandin synthesis such as indomethacin and meclofenamate may attenuate the diuretic response to furosemide. The purpose of the present study was to clarify whether an inhibition of furosemide's action in the loop of Henle is involved in this interaction. In a first set of experiments, the effect of indomethacin and meclofenamate on the diuretic response to furosemide was re-evaluated in anaesthetized rats. Single loops of Henle of rat kidneys were perfused in vivo in a second group of rats. Furosemide was added to the perfusion fluid and the effect of indomethacin (5 mg/kg i.v.) and meclofenamate (5 mg/kg i.v.) on furosemide's action in the loops was tested. In the absence of furosemide, indomethacin and meclofenamate did not significantly affect urine flow and sodium chloride excretion, or the loop's sodium and chloride reabsorption. Both prostaglandin inhibitors, however, significantly attenuated the diuretic effect of furosemide (1 mg/kg i.v.) and the inhibitory action of the diuretic, at a concentration of 10(-4) M, on the loop's sodium and chloride transport. The results identify the loop of Henle as a tubular site of interaction between furosemide and prostaglandin inhibitors. The interaction may be related to a furosemide-induced stimulation of renal prostaglandins.

Animals↗
PubMed1983

Induction of prostaglandin synthesis-dependent suppressor cells with endotoxin: occurrence in patients with thermal injuries.

The induction of lymphocyte suppressor activity with bacterial endotoxin is well documented. While most of the evidence has been obtained using animal models and has required large doses of endotoxin, we have demonstrated that additions of as little as 1.0 ng of chromatographically purified endotoxin [from Escherichia coli 055:B5, E. coli 0111:B4, Pseudomonas aeruginosa (Fisher-Devlin immunotype 1), Serratia marcescens, or Salmonella minnesota] to human mixed lymphocyte or to mitogen-stimulated cultures produced statistically significant suppression. In each case, endotoxin was most suppressive when present in the culture system prior to the introduction of the alloantigen or mitogen. Suppressive effects were dependent upon the participation of peripheral blood monocytes and could be blocked by the addition of the prostaglandin synthetase inhibitor indomethacin or meclofenamate sodium. Prostaglandin production by monocytes appeared to induce a population of "short-lived" suppressor cells, identified by the immediate and delayed addition of lymphocyte cocultures to endotoxin-preincubated cells. The suppressive behavior of endotoxin-primed lymphocytes was identical to the behavior of burn patient serum-primed lymphocytes or to lymphocyte populations derived from a subpopulation of burn patients whose serum was Limulus positive. We, therefore, feel that endotoxin plays a significant immunologic role in these patients.

Adult↗
PubMed1985

Prevention of cerebral vasospasm with OKY-046 an imidazole derivative and a thromboxane synthetase inhibitor. A preliminary co-operative clinical study.

The prevention of cerebral vasospasm with OKY-046, an imidazole derivative and a thromboxane synthetase inhibitor, was studied co-operatively at ten neurosurgical services. Intravenous administrations of 2, 5 or 10 mu/kg/minute of OKY-046 were given continuously from the earliest possible day to the 14th SAH-day to 82 patients with ruptured cerebral aneurysm. Sixty-eight patients (83%) showed moderate to high high-density (SAH) in their initial CTs. Angiographic vasospasms were seen in 58 patients, representing 71% of all cases or 81% of the 72 cases for which angiograms were available: the vasospasms of 45 patients (55 or 63%) were moderate to severe. Symptomatic vasospasm occurred, however, only in 27 patients (33%): in 18 of those cases, moreover, the symptoms were mild or transient. The conditions of the patients at one month after the SAH were classified into 9 grades from 0 (normal) to 8 (deceased). Fifty-two patients (63%) were classified as 0 or 1, and 64 (78%) as better than 3 (possible daily life unaided). The administration of OKY-046 was proven to decrease TXB2 in the blood. This paper emphasizes the effectiveness of the drug for symptomatic vasospasm, and supports our previous contention that cerebral microthrombosis may play an important role in the pathogenesis of cerebral vasospasm.

Acrylates↗
PubMed1994

Differential effects of prostanoid synthesis inhibitors on cicletanine-induced relaxation of isolated human epigastric arteries.

We have examined the influence of prostanoid synthesis inhibitors on the relaxation responses induced by cicletanine in ring preparations of isolated human epigastric arteries following precontraction induced by 10(-7) M noradrenaline. Cicletanine caused concentration-dependent relaxations, uninfluenced by the cyclooxygenase inhibitors, meclofenamate (1, 10 microM) and indomethacin (1, 10 microM) but significantly (p < 0.05) attenuated by the specific prostacyclin synthesis inhibitor, tranylcypromine (0.1-10 microM) (n > 6 in each). In contrast, cromakalim-induced relaxations were significantly attenuated by indomethacin, meclofenamate and tranylcypromine. The tranylcypromine-sensitive cicletanine-induced relaxation suggests, at least in part, the involvement of prostacyclin in the vasodilator action of cicletanine.

Abdominal Muscles↗
PubMed1976

Meclofenamate does not reduce chronic hypoxic pulmonary vasoconstriction.

There was no reduction in the pulmonary pressor response to hypoxia following inhibition of prostaglandin synthesis in rats exposed to chronic hypoxia. A fall in left ventricular weight suggested that systemic pressure may have been reduced after inhibition of prostaglandin synthesis in normoxic rats.

Altitude↗
PubMed1994

Methods to prevent colonic injury in pelvic radiation.

PURPOSE: Radiation has become an adjunct in the treatment of pelvic malignancies. Attempts to prevent adjacent tissue injury have met with varying degrees of success, and the purpose of this study was to investigate potential radioprotective effects of an elemental diet, sodium meclofenamate, and vitamin A in an animal model of acute and chronic pelvic radiation previously described. METHODS: Female Sprague-Dawley rats, 200-250 grams, were anesthetized and then received 900 rads of pelvic radiation once per week for five weeks for a total of 4500 rads. Animals were divided into five groups. Treatment groups received radiation and elemental diet, radiation and vitamin A, radiation and sodium meclofenamate. Control animals received anesthesia only and no radiation. Vitamin A was given as a supplement to (662 IU/kg) standard rat chow. Elemental diet was given as a commercially available formula, whereas sodium meclofenamate was given as a postoperative supplement (5 mg/kg/day). All animals were given these treatments during the course of radiation therapy only. Histology of distal colon was measured at one week, five weeks, six months, and one year postradiation therapy. The distal two cm of colon were removed at necropsy and fixed in 10 percent formalin at each of the above time points. Histologic grade was determined by a previously described grading scale. RESULTS: Results showed a qualitative radiation injury that could be documented at one and five weeks postradiation. Elemental diet, vitamin A, and sodium meclofenamate prevented histologic changes that occurred at these time points. No difference in histologic grade was seen between any groups at six months and one year postradiation therapy. CONCLUSION: In summary, our model of pelvic radiation produces a definable radiation injury within the colon at one and five weeks postradiation. Use of elemental diet, vitamin A, and sodium meclofenamate prevented these changes.

Acute Disease↗
PubMed1984

Influence of various prostaglandin synthesis inhibitors on DMH-induced rat colon cancer.

To evaluate the influence of inhibitors of prostaglandin synthesis on the incidence of DMH-induced colon cancer, 90 male Sprague-Dawley rats were randomly assigned to: indomethacin 20 mg per liter drinking water, meclofenamate 50 mg per liter drinking water, or normal drinking water (control group). Dimethylhydrazine was given by weekly subcutaneous injections (20 mg/kg body weight) during the first 20 weeks. Thirty-two weeks after the start of treatment and carcinogen exposure, the animals were killed and examined for the number, size, location, and spread of intestinal tumors. Colon cancer incidence was significantly lower in animals receiving indomethacin (56 per cent) compared with the control group (88 per cent) and with the meclofenamate group (90 per cent) (P less than 0.005). The corresponding figures for tumors in the small intestine were 31, 46, and 35 per cent, respectively. The tumors in indomethacin-treated animals did not differ in number, size, location, or spread from tumors of the other groups, suggesting that indomethacin might influence the carcinogenic process itself, rather than the natural course of the established disease. We conclude that indomethacin significantly reduces the incidence of large-bowel cancer in this animal model and that this observation may have some potential for future chemopreventive studies in human high-risk groups (e.g. ulcerative colitis, familial polyposis).

1,2-Dimethylhydrazine↗
PubMed1990

Effect of cyclic guanosine monophosphate on hypoxic and angiotensin-II-induced pulmonary vasoconstriction.

We examined, in isolated blood perfused rat lungs, the effect of the cell permeable 8-bromo derivative of cGMP on pulmonary vasoconstriction induced by either alveolar hypoxia or angiotensin II. 8-Bromo cGMP dose-dependently reduced both hypoxia-(IC50 = 2.2 X 10(-5) M) and angiotensin-II-induced pulmonary vasoconstriction (IC50 = 5.0 X 10(-5) M). This effect of 8-bromo cGMP on pulmonary vasoconstriction was not affected by cyclooxygenase blockade. M & B 22948 (0.1 mM), an inhibitor of cGMP-phosphodiesterase, reduced synergistically with 8-bromo cGMP the hypoxia or angiotensin-II-induced vasoconstriction. The cGMP-phosphodiesterase inhibitor M & B 22948, by itself, selectively reduced hypoxia-induced vasoconstriction, suggesting a modulating effect of endogenous cGMP during hypoxic vasoconstriction.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2006

Alpha2-adrenoreceptor mediated sympathoinhibition of heart rate during acute hypoxia is diminished in conscious prostacyclin synthase deficient mice.

Acute hypoxia increases ventilatory drive in conscious animals, resulting in tachycardia. Sustained hypoxia changes the initial chemoreflex ventilatory increase to secondary ventilatory depression, which then evokes a gradual secondary heart rate (HR) reduction. Prostacyclin (PGI(2)) release is known to potentiate alpha(2)-adrenoreceptor (alpha(2)-AR) mediated inhibition of sympathoactivation during ischaemia and hypoxia. We examined whether alpha(2)-AR mediated sympathoinhibition was responsible for limiting hypoxic heart rate increases during initial sympathoactivation, and subsequent secondary HR depression, and if PGI(2) is required for sympathoinhibition of HR. The responses of unrestrained PGI(2) synthase deficient (PGID) and wild type (WT) mice to acute hypoxia (10% O(2) for 30 min) were investigated by simultaneous telemetry, whole body plethysmography and open-flow respirometry. PGID mice exhibited potentiated .V(E) (p < 0.007) after intraperitoneal vehicle injection (n = 8), but not so HR responses compared to WT mice during sustained hypoxia. Idazoxan (alpha(2)-AR antagonist, i.p. bolus 3 mg/kg) pretreatment did not change hypoxic ventilatory response in either group, but significantly elevated hypoxic HR in WT mice only (p < 0.013). Sodium meclofenamate (cyclooxygenase inhibition, i.p. bolus 25 mg/kg) pretreatment eliminated the potentiated .V(E) of PGID and caused significant basal hypotension that led to a transient hypertensive response to hypoxia. From these results, we suggest that alpha(2)-AR activation is required for coupling HR to central inspiratory drive during acute hypoxia, and that PGI(2) is required to enhance the inhibition of sympathoactivation.

Acute Disease↗
PubMed1996

Blockade of nitric oxide formation inhibits the stimulation of the renin system by a low salt intake.

This study aimed to investigate the possible involvement of endothelial autacoids such as nitric oxide or prostaglandins in the well-known stimulatory effect of a low salt intake on renin secretion and renin gene expression in the kidney. To this end, plasma renin activity (PRA) and kidney renin mRNA levels were determined in male Sprague-Dawley rats fed either a normal (0.6% w/w) or a low (0.03%) NaCl diet for 10 days. To inhibit nitric oxide formation, the animals received L-nitro-argininemethylester (L-NAME, 40 mg/ kg twice a day), to inhibit prostaglandin formation the animals received meclofenamate (8 mg/kg twice a day) during the last 2 days. In animals fed a normal salt diet, L-NAME decreased PRA from 6.5 to 4.9 ng angiotensin I x h(-1) x ml(-1) and decreased renin mRNA levels by about 15%. Meclofenamate did not change PRA or renin mRNA in animals fed on normal salt diet. In vehicle-treated animals fed a low salt diet, PRA increased from 6.5 to 20.2 ng ANGI x h(-1) x ml(-1) and renin mRNA levels increased by 100%. Meclofenamate treatment did not alter these changes of PRA and renin mRNA during the intake of a low salt diet. In animals treated with L-NAME, PRA increased to only 7.2 ng ANGI x h(-1) x ml(-1) and renin mRNA increased by 20%. These findings indicate that inhibition of nitric oxide formation but not of prostaglandin formation substantially attenuates the stimulatory effect of a low salt intake on the renin system, suggesting that nitric oxide is required for this process.

Animals↗
PubMed2006

Starch-based microspheres produced by emulsion crosslinking with a potential media dependent responsive behavior to be used as drug delivery carriers.

This paper describes the development and characterization of starch microspheres for being used as drug delivery carriers in tissue engineering applications. The developed starch microspheres can be further loaded with specific growth factors and immobilized in scaffolds, or administrated separately with scaffolds. Furthermore and due to the processing conditions used, it is expected that these microspheres can be also used to encapsulate living cells. The aim of this study was to evaluate the efficacy of this methodology for further studies with biologically active agents or living cells. The starch microspheres were prepared using an emulsion crosslinking technique at room temperature to allow for the loading of biologically active agents. A preliminary study was performed to evaluate the incorporation of a model drug (nonsteroidal anti-inflammatory drug-NSAID) and investigate its release profile as function of changes in the medium parameters, such as ionic strength and pH. The developed starch-based drug delivery system has shown to be dependent on the ionic strength of the release medium. From preliminary results, the release seems to be pH-dependent due to the drug solubility. It was found that the developed microspheres and the respective processing route are appropriate for further studies. In fact, and based in the processing conditions and characterization, the developed system present a potential for the loading of different growth factors or even living cells on future studies with these systems for improving bone regeneration in tissue engineering, especially because the crosslinking reaction of the microspheres takes place at room temperature.

Absorption↗
PubMed1982

Effects of meclofenamate and captopril on adrenal blood flow: contrasts in conscious rabbits at rest and after hemorrhage.

The role of prostaglandins and angiotensin II or kinins in maintaining adrenal blood flow was studied using the prostaglandin cyclo-oxygenase inhibitor meclofenamate and the kininase inhibitor captopril in resting and hemorrhaged (10 ml/kg) conscious rabbits. Meclofenamate (6 mg/kg intravenously) reduced adrenal blood flow after 3, 15 and 30 minutes by 26, 28 and 17 percent, respectively. Captopril increased adrenal flow by 20 percent, an effect subsequently reversed by meclofenamate. In contrast, hemorrhaged rabbits maintained adrenal blood flow following meclofenamate and captopril despite substantial reductions in renal blood flow with meclofenamate given before and after captopril. It is concluded that (1) adrenal blood flow at rest is modulated by vasodilator prostaglandins and to a lesser extent angiotensin II or bradykinin. (2) The adrenal effects of meclofenamate and captopril are overriden by hemorrhage, perhaps reflecting the need to increase adrenal hormones during hypovolemic stress. (3) The decrease in plasma catecholamines seen with meclofenamate at rest may be due to reduced adrenal blood flow.

Adrenal Glands↗