The effect of indomethacin and substance P on the guinea pig urinary bladder

The effects of indomethacin on the responses of the guinea pig urinary bladder to nerve stimulation, acetylcholine, adenosine 5′ triphosphate and Substance P have been investigated. Indomethacin alone had no significant effect on responses of the bladder to nerve stimulation but did significantly reduce the atropine-resistant contractions. Responses of the tissue to acetylcholine were unaffected by indomethacin but responses to Substance P were significantly reduced. Only the highest dose of ATP (10^?3 M) was significantly reduced by indomethacin. The possibility that Substance P is the transmitter responsible for the atropine-resistant contractions of the urinary bladder to nerve stimulation is discussed.     

Prostaglandins modulate the renal actions of antidiuretic hormone in the Pekin duck

The present study was designed to determine whether the responses of the avian kidney to circulating arginine vasotocin (AVT), under different osmotic conditions, involve an interaction with prostaglandins (PGs). The renal effects of intravenously infused AVT at a dose of 0.1 ng.kg^–1.min^–1 for 45 min were compared in Pekin ducks given maintenance infusions of either 200 mosmol NaCl or glucose at 1 ml.min^–1, with and without PG inhibition by indomethacin. Birds infused with glucose responded with similar degrees of AVT-induced antidiuresis with and without indomethacin, however the urinary excretion of sodium was significantly reduced when PG production was prevented. In ducks receiving saline without indomethacin, the antidiuretic response to AVT was markedly less than that in the glucose-infused birds, however, indomethacin treatment increased the degree of antidiuresis to a level similar to that in the glucose-infused ducks. The results indicate that PGs have important renotropic actions in birds and in particular modulate the antidiuretic effect of AVT in salt- and volume-loaded animals.Abbreviations ANP atrial natriuretic peptide - AVT arginine vasotocin - PGs prostaglandinsCommunicated by I.D. Hume     

Indomethacin but not aspirin inhibits basal and stimulated lipolysis in rabbit kidney

The concurrent effect of indomethacin or aspirin on prostaglandins (PGs) biosynthesis and on cellular fatty acid efflux were compared. Studies with rabbit kidney medulla slices and with isolated perfused rabbit kidney showed a marked difference between the two non-steroidal anti-inflammatory drugs, with regard to their effects on fatty acid efflux from kidney tissue. While aspirin effect was limited to inhibition of PGs biosynthesis, indomethacin also reduced the release of free fatty acids. In medullary slices, indomethacin inhibited the Ca²⁺ stimulation of phospholipase A₂ activity and the resulting release of arachidonic and linoleic fatty acids. In the isolated perfused rabbit kidney, indomethacin inhibited the basal efflux of all fatty acids as well as the angiotensin II — induced selective release of arachidonate. Indomethacin also blunted the angiotensin II — induced temporal changes in the efflux of all other fatty acids. Neither indomethacin nor aspirin affected significantly the uptake and incorporation of exogenous (¹⁴C)-arachidonic acid into kidney total lipid fraction.Our tentative conclusion is that indomethacin inhibits basal as well as Ca²⁺ or hormone stimulated activity of kidney lipolytic enzymes. This action of indomethacin reduces the pool size of free arachidonate available for conversion to oxygenated products (both prostaglandin and non-prostaglandin types). The non-steroidal anti-inflammatory drugs can therefore be divided into two groups: a) $\text{aspirin-type compounds}$ which inhibit PGs formation only by interacting with the prostaglandin endoperoxide synthetase and b) $\text{indomethacin-type compounds}$ which inhibit PG generation by both reduction in the amount of available arachidonate and direct interaction with the enzyme.     

Indomethacin inhibits the insulin-induced increases in RNA and protein synthesis in L6 skeletal muscle myoblasts

Rates of accretion of RNA and protein and rates of protein synthesis were measured in sub-confluent cultures of L6 myoblasts. Insulin (100 μU/ml) stimulated protein synthesis by 15% within 30 min and by 40% at two and six hours. By six hours insulin also increased the accretion of RNA (+ 15%). The cyclo-oxygenase inhibitor indomethacin did not reduce the basal rate of RNA or protein accretion in L6 cells but reduced the rate of protein synthesis by 16%. When added together with insulin, indomethacin inhibited the hormonally-stimulated rate of protein synthesis and also significantly reduced the accretion of RNA. Indomethacin still reduced the effects of insulin on protein synthesis when added by the incorporation of [³H]-uridine was also stimulated by insulin but was inhibited by indomethacin only when the drug was present throughout the incubation. Inhibition of protein synthesis by cyclo-oxygenase inhibitors may be the result of both a direct action on translational efficiency and an effect on RNA synthesis.     

Indomethacin inhibits the uptake of sodium by ovine trophoblastic tissue in vitro

Blastocysts from several species synthesize prostaglandins in vitro, but the exact functions of the prostaglandins are unknown. The purpose of this study was to determine if indomethacin, an inhibitor of prostaglandin synthesis, would inhibit the uptake of ²²sodium ([²²Na]) by ovine trophoblastic tissue. To determine the concentration of indomethacin that would inhibit the synthesis of PGF_2α and 13,14-dihydro-15-keto-PGF_2α (PGFM) by blastocysts, blastocysts were collected from ewes 16 days after mating, sliced into pieces approximately 2 mm in length and incubated for 48 h at 37°C in 2 ml of medium containing either 0, 0.2, 0.4, 0.8 or 1.6 mM of indomethacin. Concentrations of indomethacin mM reduced (P<.01) trophoblastic release (ng/μg DNA) of PGF_2α from

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, reduced PGFM from

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, and inhibited formation of trophoblastic vesicles. In a second experiment, blastocysts were recovered from ewes 16 days after mating and pieces of trophoblast were incubated with [²²Na] and either 0 or 0.4 mM of indomethacin. Indomethacin reduced the uptake of [²²Na], which is an indirect measure of the transport of water across epithelia, from 3680 ± 1118 to 934 ± 248 cpm/μg DNA (P<.03) and prevented formation of trophoblastic vesicles. Prostaglandins produced by ovine blastocysts might be involved in controlling uptake of water, which is essential for expansion of blastocysts.     

Endogenous prostaglandins are physiological regulators of endocrine cells in the gastroduodenal mucosa of the rat.

BACKGROUND/AIM: To investigate whether endogenous prostaglandins participate in the regulation of the gastrointestinal endocrine cell system. METHODS: Sprague-Dawley rats were treated with 1 mg/kg indomethacin subcutaneously or indomethacin subcutaneously and 500 microg/kg oral prostaglandin E2 or solvents for 2 months. Endocrine cells were visualized by using immunohistochemistry and by the Sevier-Munger silver stain on specimens from the gastroduodenal mucosa, and their total volume was estimated, using standard stereological methods. Plasma and gastrointestinal tissue concentrations of regulatory peptides were analyzed by radioimmunoassay. RESULTS: Fundic mucosa. The total volume of cells stained with the Sevier-Munger silver stain (enterochromaffin-like) was increased by indomethacin, but reduced by the administration of prostaglandin E2 (P < 0.05 vs. indomethacin). Indomethacin increased the total volume of somatostatin-immunoreactive. Similarly, rats given indomethacin and prostaglandin E2 had higher values than controls. Indomethacin increased the tissue concentration of somatostatin in the gastric fundus whereas prostaglandin E2 prevented such changes (P < 0.05 vs. indomethacin). Antral mucosa. The total volume of serotonin-immunoreactive cells was reduced by indomethacin, but increased by prostaglandin E2 (P < 0.05 vs. controls and indomethacin, respectively). Duodenal mucosa. The total volume of somatostatin-immunoreactive cells was reduced in the rats given indomethacin and prostaglandin E2 (P < 0.05 vs. controls and indomethacin). Indomethacin reduced and simultaneous administration of prostaglandin E2 increased the total volume of CCK-immunoreactive cells (P < 0.05 vs. controls and indomethacin). Indomethacin reduced the total volume of serotonin-immunoreactive cells whereas the simultaneous administration of PGE2 comparatively increased their total volumes (P < 0.05 vs. indomethacin), although they were still lower than the control values. The total volume of GIP-immunoreactive cells was slightly increased in the rats given both indomethacin and indomethacin + prostaglandin E2. The tissue concentration of somatostatin in the duodenum was reduced in rats given indometacin and prostaglandin E2 (P < 0.05 vs. controls and indomethacin). CONCLUSION: Endogenous prostaglandins, particularly prostaglandin E2, regulate CCK-, enterochromaffin-like-, somatostatin-, GIP- and enterochromaffin cells in the gastroduodenal mucosa of the rat.     

Inhibition of Proteolysis by a Cyclooxygenase Inhibitor,Indomethacin

The effect of indomethacin, a non-steroidal anti-inflammatory drug upon purified calpain has been studied. Also, its effects upon Ca²⁺-mediated degradation of cytoskeletal proteins (neurofilament) in spinal cord homogenate has been investigated. A dose-dependent inhibition of purified calpain activity was observed. A 50% inhibition of ¹⁴C-caseinolytic activity was obtained with less than 1.1 mM of indomethacin while the activity was completely inhibited at 3.3 mM concentration. The inhibitory effect of ketorlac, another non-steroidal anti-inflammatory drug, upon calpain was weaker than that of indomethacin. The degradation of myelin basic protein (MBP) by cathepsin B, a lysosomal cysteine protease, was significantly inhibited by indomethacin. It also inhibited the Ca²⁺-mediated degradation of neurofilament protein (NFP) in spinal cord homogenate. The extent of NFP degradation was analyzed by SDS-PAGE and the inhibition shown by indomethacin was weaker than that observed with leupeptin and the calpain inhibitor E64-d. The inhibitory effect of indomethacin on the activity of multicatalytic proteinase complex was negligible. These results suggest that indomethacin, a non-steroidal anti-inflammatory drug and cyclooxygenase inhibitor also inhibits proteinases, including cathepsin B and calpain.     

Adaptation of rat gastric tissue against indomethacin toxicity

Indomethacin is used in the treatment of inflammatory diseases. But the drug toxicity limits its usage. This study investigated whether adaptation occurred after various dosages of repeated (chronic) indomethacin in rats to the gastro-toxic effects of indomethacin. It also examined whether the adaptation was related to oxidant–antioxidant mechanisms and oxidative DNA damage in gastric tissue. To illuminate the adaptation mechanism in the gastric tissue of rats given various dosages of chronic indomethacin, the levels of oxidants and antioxidants (GSH, MDA, NO, SOD and MPO), activities of COX-1 and COX-2 enzymes and oxidative DNA damage (8-OHd Gua/10⁵ Gua) were measured. Results were compared to 25-mg/kg single-dose indomethacin group, and the role of oxidant and antioxidant parameters and oxidative DNA damage in the adaptation mechanism was evaluated. The average ulcer areas of gastric tissue of the 0.5-, 1-, 2-, 3-, 4-, and 5-mg/kg dosages of chronic indomethacin given to rats were 19.5 ± 3.7, 12.5 ± 3.3, 10 ± 5.2, 4.5 ± 3.6, 8.6 ± 2.4, and 9.5 ± 2.1 mm², respectively. This rate was measured as 21.3 ± 2.6 mm² in the single-dose indomethacin group. Consequently, after various dosages of repeated (chronic) indomethacin administration in rats, it was observed that a clear adaptation developed against gastric damage and that gastric damage was reduced. The best adaptation was observed in the gastric tissue of the 3-mg/kg chronic indomethacin group. In parallel with the damage reduction, the oxidant parameters (MDA and MPO) and oxidative DNA damage (8-OHd Gua/10⁵ Gua) were reduced, and the antioxidant parameters (GSH, NO and SOD) were increased. There is no relation between COX enzymes and adaptation mechanism. This circumstance shows that not COX-1 and COX-2 enzymes, oxidant and antioxidant parameters may play a role in the adaptation mechanism.     

Indomethacin blocks gonadotropin stimulation of ovarian ornithine decarboxylase activity by inhibiting protein synthesis

Both gonadotropins and prostaglandins stimulate the ornithine decarboxylase (ODC) activity of porcine granulosa cells (1,2). To investigate a possible intermediary role of prostaglandins in this gonadotropin action, the effects of indomethacin on gonadotropin-induced ODC activity were studied. Indomethacin had no effect at concentrations lower than 10⁻⁵ M; at higher concentrations indomethacin exerted a dose-dependent suppression of LH-stimulated ODC activity which was essentially complete at 5 × 10⁻⁴ M. The effects of PGE₂ and 8-Bromo-cAMP, potent stimulators of ODC, were also blocked by indomethacin (5 × 10⁻⁴ M). This effect did not represent direct inhibition of enzyme activity, but appeared to be due to inhibition of protein synthesis by the drug. Thus, incorporation of ¹⁴C-leucine into proteins by these cells was blocked by indomethacin with a dose-response curve similar to that for ODC suppression. This distal effect of indomethacin may complicate the interpretation of some experiments if the inhibitor is assumed to act only at the prostaglandin synthetase step.     

Prostaglandin E2 is a Potential Mediator of Extracellular ATP Action in Osteoblast-Like Cells

Extracellular ATP dose dependently stimulated ⁴⁵Ca²⁺ influx even in the presence of nifedipine, a Ca²⁺ antagonist that inhibits voltage-dependent Ca²⁺ channel, in osteoblast-like MC3T3-E1 cells. ATP stimulated arachidonic acid release and the synthesis of prostaglandin E₂ (PGE₂). However, the ATP-induced arachidonic acid release was significantly reduced by chelating extracellular Ca²⁺ with EGTA. On the other hand, ATP induced DNA synthesis of these cells in a dose-dependent manner in the range between 1μM and 1 mM. The pretreatment with indomethacin, a cyclooxygenase inhibitor, suppressed both ATP-induced PGE₂ synthesis and DNA synthesis in these cells. The inhibitory effect by 50μM indomethacin on the DNA synthesis was reversed by adding 10μM PGE₂. These results strongly suggest that extracellular ATP stimulates Ca²⁺ influx resulting in the release of arachidonic acid in osteoblast-like cells and that extracellular ATP-induced proliferative effect is mediated, at least in part, by ATP-stimulated PGE₂ synthesis.     

A copper-complex reduced gastric damage caused by acetylsalicylic acid and ethanol

We investigated the effect of oral administration of CuNSN, a bis(2-benzimidazolyl)thioether (see structure 1) on gastric lesions induced in rats by acetylsalicylic acid (ASA) or ethanol. The involvement of endogenous eicosanoids and nitric oxide in protection by CuNSN was evaluated with indomethacin and N^G-nitro-L-arginine (L-NNA), inhibitors of prostaglandin and NO synthesis respectively. L-arginine and its enantiomer D-arginine were also used. Pretreatment with graded doses of CuNSN inhibited ASA- and ethanol-induced mucosal injury. CuNSN increased PGE₂ output in rat ex vivo gastric mucosal pieces after administration of 100 mg/kg of ASA. Pretreatment with indomethacin only partially counteracted the protective activity of CuNSN against ethanol-induced damage. L-NNA did not attenuate the protection by CuNSN, which was reduced but not prevented by indomethacin, suggesting that prostanoids contribute to the CuNSN protective effect, together with some mechanism(s) other than NO synthesis.     

Evidence against prostaglandin modulation of cardioaccelerator nerve activity in the anesthetized dog

The hypothesis that prostaglandins have a modulatory role in adrenergic neurotransmitter release was tested in the anesthetized dog. Inhibition of prostaglandin synthesis with indomethacin (10 mg/kg, i.v.) did not alter positive chronotropic responses to cardioaccelerator nerve stimulation or blood pressure responses to exogenous norepinephrine. In the presence of indomethacin, infusions of PGE₂ (0.01 and 0.1 μg kg⁻¹ min⁻¹) also failed to influence the responses to cardioaccelerator nerve stimulation although the blood pressure responses to exogenous norepinephrine were reduced in a dose-related manner. It was concluded that endogenous prostaglandins and exogenous PGE₂, the purported physiological inhibitor of neurotransmitter release in cardiac tissue, do not play a role in modulating chronotropic responses during cardioaccelerator nerve stimulation in the anesthetized dog.     

Effects of two-vessel forebrain ischemia and of administration of indomethacin and quinacrine on Na<Superscript>+</Superscript>, K<Superscript>+</Superscript>-ATPase activity in various rat brain areas

The effect of a two-vessel forebrain ischemia (induced by occlusion of carotid arteries and hypotension), subsequent reperfusion, and administration of indomethacin and quinacrine on the Na⁺,K⁺-ATPase activity and diene conjugate content was studied in various rat forebrain fields. The most pronounced metabolic alterations were observed during ischemia and reperfusion. Under these effects, there was a statistically significant reduction of the Na⁺,K⁺-ATPase activity in the brain cortex and striatum and an increase of the diene conjugate content in the rat brain cortex in comparison with sham-operated animals. Injection of indomethacin, a cyclooxygenase inhibitor, to rats subjected to ischemia and reperfusion, resulted to a statistically significant increase of the Na⁺,K⁺-ATPase activity in the brain cortex, hippocampus, and striatum (p < 0.02) as compared with control animals. The diene conjugate content in the rat brain cortex during brain ischemia and reperfusion was statistically significantly lower in the rats injected with indomethacin. The effect of quinacrine (a blocker of phospholipase A₂) was similar to that of indomethacin in the rat cortex, whereas in the rat striatum and hippocampus, the quinacrine effect during ischemia and reperfusion was less marked than that of indomethacin. The obtained data indicate the ability of inhibitors of the arachidonic pathway of free radical formation to normalize the Na⁺, K⁺-ATPase activity during brain ischemia. There also revealed local peculiarities of metabolic disturbances in different regions of the rat forebrain during ischemia and reperfusion.Translated from Zhurnal Evolyutsionnoi Biokhimii i Fiziologii, Vol. 41, No. 1, 2005, pp. 33–38.Original Russian Text Copyright © 2005 by Molchanova, Moskvin, Zakharova, Yurlova, Nosova, Avrova.     

Structure of Cu2(indomethacin)4 and the reaction with superoxide in aprotic systems

The copper complex of indomethacin (1-(p-chlorobenzoyl)-5-methoxy-2-methyl-indole acetate), a common anti-inflammatory drug, was prepared and characterized. Crystal structure determination revealed the dimeric form of the 1:2 complex, namely Cu₂(indomethacin)₄ · L₂, in the unit cell. Suprisingly, the copper-copper distance (263 pm) was very close to metallic copper (256 pm). The two coordination sites in the copper-copper axis can be readily replaced by superoxide. An intriguing similarity to Cu₂(acetate)₄ was seen.Due to the lipophilic nature of the indomethacin ligand, this copper complex reacted with superoxide in aprotic solvents. The superoxide dismutating activity was successfully demonstrated in Me₂SO/water and acetonitrile/water mixtures using the nitro-blue tetrazolium assay and pulse radiolysis. The second-order rate constant of 6 · 10⁹ M^?1 · s^?1 in strictly aqueous systems dropped only slightly to 1.1 · 10⁹ M^?1 · s^?1 when aprotic solvents were used. This is the fastest rate constant ever observed for a copper-dependent dismutation of superoxide. The KO₂-induced lipid peroxidation in both erythrocytes and liver microsomes was suppressed by 70% in the presence of 1 · 10^?10 mol · ml^?1 of Cu₂(indomethacin)₄. The inhibitory action dropped to 25% when Cu₂Zn₂superoxide dismutase was employed. The formation of copper · indomethacin in rat serum after administration of indomethacin was shown in vitro and in vivo.     

Effectiveness of prostaglandin F2α in restoration of HMG-HCG induced ovulation in indomethacin-treated rhesus monkeys

Six mature female rhesus monkeys were treated with HMG-HCG in control cycles at doses adjusted to induce ovulation while avoiding superovulation. Occurrence of ovulation was determined by observation of fresh ovulation points at laparotomy 48 to 120 hours following HCG. In subsequent cycles animals were treated with indomethacin (treatment days 4 through 10) together with the established dose of HMG_HCG. In 8 cycles indomethacin 5 mg/kg was given i.m. once daily; in 9 cycles 10 mg/kg i.m. was administered in 2 divided doses. Following this, PGF_2^α (3 mg t.i.d. s.c.) was administered for 3 days together with indomethacin 10 mg/kg and HMG-HCG, beginning on the day prior to HCG. Determinations of progesterone were performed by RIA on treatment days 4, 7, 10, and 11. Eleven of the 13 control cycles were ovulatory. With indomethacin 5 mg/kg/day, 5 of 8 cycles were ovulatory but ovulation was delayed in 2 instances. Of 9 cycles using indomethacin 10 mg/kg/day only 1 was ovulatory. When PGF_2^α was administered in subsequent cycles along with indomethacin (10 mg/kg) and HMG-HCG, ovulation occurred in 13 of 19 cycles. These data suggest that local ovarian PGF_2^α may be essential in the mechanics of follicle rupture in gonadotropin-treated rhesus monkeys.     

The in vitro effect of indomethacin on basal bone resorption, on prostaglandin production and on the response to added prostaglandins

Mouse calvaria were maintained in organ culture without serum additives. Basal active resorption, as measured by ⁴⁵Ca and hydroxyproline release, was significantly inhibited to 74% control levels by indomethacin (1.4 × 10⁻⁷ M). Prostaglandin F and prostaglandin E₂ production, determined by radioimmunoassay, were both significantly lowered by this concentration of indomethacin. DNA, protein and hydroxyproline synthesis, as indices of cell toxicity, were unaffected by low concentrations of indomethacin, while concentrations of 1.4 × 10⁻⁶M inhibited protein synthesis (p<0.005). In the presence of indomethacin (1.4 × 10⁻⁷M) both PGE₂ and PGF_2α stimulated resorption in a dose-dependent manner, with PGE₂ being the more potent. Neither prostaglandin affected hydroxyproline synthesis at low concentrations, but PGE₂ had a marked inhibitory action at a higher concentration (10⁻⁶M). In combination, the effects of PGE₂ and PGF_2α showed no evidence of synergism or any antagonistic action. The study shows that in vitro calcium and hydroxyproline resorption in the unstimulated mouse calvaria are inhibited by indomethacin at concentrations measured in serum during human therapy. The decreased PGF and PGE₂ production associated with this decreased bone resorption in the presence of non-toxic concentrations of indomethacin would suggest a role for these prostaglandins in maintaining the basal resorption of cultured bone.     

A novel chemiluminescence sensor for the determination of indomethacin based on sulfur and nitrogen co‐doped carbon quantum dot–KMnO4 reaction

We report on a simple and sensitive sulfur and nitrogen co‐doped carbon quantum dot (S,N‐CQD)‐based chemiluminescence (CL) sensor for the determination of indomethacin. S,N‐CQDs were prepared by a hydrothermal method and characterized by fluorescence spectra, Fourier transform infrared spectroscopy and transmission electron microscopy. To obtain the best CL system for determination of indomethacin, the reaction of S,N‐CQDs with some common oxidants was studied. Among the tested systems, the S,N‐CQD–KMnO₄ reaction showed the highest sensitivity for the detection of indomethacin. Under optimum conditions, the calibration plot was linear over a concentration range of 0.1–1.5 mg L^?1, with a limit of detection (3σ) of 65 μg L^?1. The method was applied to the determination of indomethacin in environmental and biological samples with satisfactory results.     

Effect of sparteine sulfate on uterine prostaglandin F in the rat

Indomethacin, an inhibitor of prostaglandin synthetase, added to an bath in a concentration of 1, 5, and 10 × 10⁻⁶ g/ml reduced sparteine-induced contractions of isolated uterine segments from pregnant rats. Contractions induced by prostaglandin F₂α and acetylcholine were not reduced.Sparteine increased the prostaglandin F content of the blood and uterine tissue in the pregnant but not in the nonpregnant rat. This increase was significantly reduced by the administration of indomethacin (10 mg/kg). The present study suggests that the mechanism of sparteine action is mediated through a prostaglandin F system.     

Pre-junctional inhibitory action of prostaglandin E2 on excitatory neuro-effector transmission in the human bronchus

The effects of prostaglandin E₂ (PGE₂) and indomethacin on excitatory neuro-effector transmission in the human bronchus were investigated by tension recording and microelectrode methods. PGE₂ (10⁻¹⁰–10⁻⁹M) suppressed the amplitude of twitch contractions and excitatory junction potentials (e.j.ps) evoked by field stimulation at a steady level of basal tension obtained by the combined application of indomethacin (10⁻⁵M) and FPL55712 (10⁻⁶M). In doses over 10⁻⁸M, PGE₂ reduced the muscle tone and dose-dependently suppressed the amplitude of twitch contractions. Indomethacin (10⁻⁵ or 5 × 10⁻⁵M) reduced the muscle tone and enhanced the amplitude of twitch contractions and e.j.ps evoked by field stimulation in the presence of FPL55712. PGE₂ (10⁻⁹M) had no effect on the post-junctional response of smooth muscle cells to exogenously applied acetylcholine (ACh) (4 × 10⁻⁷M). However, indomethacin (10⁻⁵M) significantly enhanced the ACh-induced contraction of the human bronchus. These results indicate that PGE₂ in low concentrations has a pre-junctional action to inhibit excitatory neuro-effector transmission in addition to a post-junctional action, presumably by suppressing transmitter release from the vagus nerve terminals in the human bronchial tissues.     

The role of endogenous prostaglandins in the regulation of gastric secretion in rhesus monkeys

Prostaglandins (PG) are known to alter a variety of gastrointestinal functions, but the physiological role of endogenous PG remains unclear. This experiment was designed to evaluate chanes in gastric secretion following both acute and chronic inhibition of PG synthesis with indomethacin (5 mg/kg s.c.). Gastric juice was collected by continuous aspiration in 8 concious chair-adapted male rhesus monkeys following treatment with saline or indomethacin for one or four days. The gastric juice was anzlyzed for H⁺, Na⁺, K⁺ and Cl⁻ concentrations. The amount of soluble mucus in the gastric juice was estimated using Alcian Blue dye binding of acidic glycoproteins and Periodic Acid Schiff reaction with neutral glycoproteins. PG levels were measured in the plasma and in biopsy samples of fundus, antrum and duodenum. Both one and four days of indomethacin significantly (p < 0.05) decreased tissue PG levels in the fundus, antrum and duodenu. Plasma levels of PGF_2α were significantly (p < 0.05) decreased after both one and four days of indomethacin, while PGE₂ and 6-keto PGF_1α were significantly inhibited only after four days of indomethacin. Both acute and chronic inhibition of PG synthesis was accompanied by a decrease in the concentration of sodium and mucus in the gastric juice but by an incrase in the output and concentration of hydrogen ion. These changes suggest a possible mechanism by which endogenous PG play a role in the regulation of gastric secretion and in the protection against gastrointestinal damage.