Effect of Topically Applied Cyclooxygenase-2-Selective Inhibitors on Arachidonic Acid- and Tetradecanoylphorbol Acetate-Induced Dermal Inflammation in the Mouse

The topical effects of cyclooxygenase-2 (COX-2)-selective inhibitors, flosulide (CGP 28238), L-745,337 and SC-57,666 were examined in AA- and TPA-induced ear dermal inflammation in the mouse. The doses that caused 50% inhibition in AA edema (ED₅₀) were 2.4, 0.45 and 0.35 mg/ear for flosulide, L-745,337 and SC-57,666, respectively. The respective ED_50s in TPA-edema were 1, 0.45 and 0.14. Indomethacin and zileuton showed higher activity than the COX-2-selective inhibitors in both models. Flosulide and L-745,337 inhibited the AA-induced increase in 6-keto-PGF₁, while SC-57,666 was inactive. 80% inhibition was seen with indomethacin while zileuton had no effect. COX-2 selective inhibitors and indomethacin had no effect on LTB₄ levels, while zileuton produced a 50% inhibition. The TPA-induced increase in 6-keto-PGF₁ was greatly inhibited by all COX-2 inhibitors while LTB₄was potentiated by both flosulide and L-745,337. Indomethacin inhibited 6-keto-PGF₁ and zileuton reduced 6-keto-PGF and strongly reduced LTB₄. The neutrophil influx induced by AA was lower than that of TPA. Myeloperoxidase (MPO) levels were lowered by flosulide and L-745,337 but not by SC-57,666. TPA-induced MPO increase was decreased by all COX-2 inhibitors. Indomethacin and zileuton had similar effect on AA and TPA-induced increase in MPO. The results indicate that COX-2-selective inhibitors showed lower topical anti-inflammatory activity than indomethacin or zileuton.     

Effects of Chronic Treatment with Indomethacin at Clinically Relevant Doses on Intestinal Tissue 6-Keto Prostaglandin F1α and Leukotriene B4 Level in Relation to Gastroenteropathy

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

Effect of proquazone and indomethacin on gastric prostaglandin synthesisin vitro andin vivo

Although proquazone is less ulcerogenic than indomethacin in rat and man, it inhibits more effectively than indomethacin gastric mucosal synthesis of 6-keto-prostaglandin (PG) F₁ in both species during incubationin vitro. The more pronounced inhibitory activity of proquazone can be observed on formation of 6-keto-PGF₁ from endogenous substrate by fragments of gastric mucosa as well as on conversion of exogenous arachidonic acid by a microsomal fraction of mucosal homogenates indicating high affinity of proquazone for gastric mucosal cyclo-oxygenase. After oral administration, however, both drugs exhibit equal inhibitory potency on gastric formation of 6-keto-PGF₁ in the rat. These findings indicate that pharmacokinetic properties of non-steroidal anti-inflammatory drugs (NSAID) contribute significantly to their inhibitory action on gastric PG formationin vivo. The comparable reduction of gastric 6-keto-PGF₁ synthesis observed after oral administration of proquazone and indomethacin in the rat suggests that the ulcerogenic effects of NSAID result not only from inhibition of the gastric PG system. Effects on other processes and other enzyme systems, e.g. the lipoxygenase pathway of arachidonic acid metabolism, may modulate drug-induced ulcerogenicity and deserve further investigation.     

The influence of anti-rheumatic drugs on hepatic mRNA levels of acute-phase proteins in rats with adjuvant arthritis

Using specific cDNA probes, we have investigated drug-induced changes in hepatic mRNA levels of the major acute-phase proteins (APP) fibrinogen, ₂-macroglobulin (₂-MG), albumin and ₁-acid glycoprotein (₁-AGP) in male Lewis rats with adjuvant arthritis. Test compounds were given orally from day 0 to 20 and hepatic mRNA analysis was performed at day 21. Prednisolone (1,3, 10 mg/kg), Cyclosporine A (1, 3, 10 mg/kg) and cyclophosphamide (3 mg/kg) dose-dependently normalized hepatic mRNA levels of all four APP. Equipotent anti-inflammatory doses of indomethacin (0.3, 1 mg/kg) significantly downregulated ₂-MG mRNA levels but were much less effective in influencing albumin and ₁-AGP mRNA levels and even slightly increased hepatic fibrinogen mRNA levels. These results suggest that cytokine overproduction, which is thought to be responsible for the acute-phase response in rats with adjuvant arthritis, can be effectively downregulated by immunosuppressive drugs, but is distinctly less affected by the cyclooxygenase inhibitor indomethacin.     

Role of xanthine oxidase and eicosanoids in development of pancreatic ischemia-reperfusion injury

The implication of different eicosanoids and oxygen free radicals in the development of pancreatic injury after an ischemia-reperfusion process has been evaluated. For this purpose we have compared the effect of allopurinol and indomethacin administration on the pancreatic levels of eicosanoids in a rat model of pancreatic ischemia-reperfusion. After 60 min of pancreatic ischemia and 2 h of reperfusion, significant increases in 6-keto-PGF₁, PGE₂, and LTB₄ in pancreas tissue were detected. Allopurinol before the ischemic period reduced 6-keto-PGF₁, PGE₂, and LTB₄ levels to the range of basal values, while prior indomethacin treatment significantly reduced 6-keto-PGF₁ and PGE₂ levels, with LTB₄ remaining unmodified. Increased postischemic plasma lipases were also significantly reduced by allopurinol to the range of sham-operated animals whereas indomethacin did not modify these levels. The data suggest a role for lipoxygenase metabolites in the development of pancreatic injury and the importance of the enzyme xanthine oxidase as an inductor of eicosanoid biosynthesis.     

Prostaglandin excretion after furosemide in normal and low-renin essential hypertension

Summary We examined the urinary excretion of prostaglandin (PG)E₂ and PGF₂ before and 15 min after stimulation with the acutely vasodilating agent furosemide in 25 normotensive controls and 81 patients with essential hypertension (EH). After furosemide administration, PGE₂ excretion was lower in patients with EH (P<0.02). Excretion rates of PGF₂ and of sodium, and urinary volume in hypertensive patients were not significantly different from the values found in normotensive controls. Patients with low-renin essential hypertension (LREH) had a significantly reduced excretion of both PGE₂ and PGF₂ before and after administration of furosemide as compared to controls. The difference in PGF₂ excretion was also significant when LREH patients were compared to those with normal-renin essential hypertension (NREH). Patients with LREH were older and excreted less potassium than patients with NREH or normotensive controls. We conclude that the reduced PG excretion immediately after furosemide administration in patients with EH reflects a diminished capacity of the hypertensive kidney to generate prostaglandins which exert an overall vasodilating effect. Since renin secretion is under the control of renal PG formation, the decreased responsiveness of plasma renin activity (PRA) observed in patients with EH and predominantly in those with LREH may be the consequence of a decreased renal cortical PG generation. Alternatively, mechanisms that reduce both PRA and PG generation have to be considered.Supported by Deutsche Forschungsgemeinschaft     

Effect of Topically Applied Cyclosporin A on Arachidonic Acid (AA)- and Tetradecanoylphorbol Acetate (TPA)-Induced Dermal Inflammation in Mouse Ear

Topical cyclosporin A (CsA) was compared with dexamethasone, indomethacin and phenidone in edema, increases in vascular permeability, eicosanoids and cell-influx induced by arachidonic acid (AA) and tetradecanoylphorbol acetate (TPA) in mouse ears. CsA ED₅₀ on AA-edema (7.7 g/ear) was similar to dexamethasone and lower than indomethacin and phenidone. CsA ED₅₀ in TPA edema (21 g/ear) was higher than dexamethasone and lower than indomethacin or phenidone. All drugs equally reduce the AA-induced increase in vascular permeability, but CsA and dexamethasone had more activity on TPA. AA-increase in 6-keto-PGF₁ was reduced by dexamethasone, indomethacin and phenidone but not by CsA; only phenidone reduced LTB₄. TPA-increase in 6-keto-PGF₁ was reduced by CsA and indomethacin while CsA, dexamethasone and phenidone decreased LTB₄. CsA, indomethacin and phenidone, but not dexamethasone, suppressed AA-neutrophil influx. In TPA-ears all drugs produced similar reduction in neutrophil influx. CsA was shown to be a good topical anti-inflammatory drug.     

Inhibition of cysteinyl-leukotriene production by azelastine and its biological significance

Azelastine is a phthalazinone derivative with a wide spectrum of pharmacological activities. Actively sensitized guinea pigs were used to examine the broncholytic effect of azelastinein vivo. Furthermore, the influence of azelastine on the production of arachidonic acid (AA) metabolites was investigatedin vitro and compared to the effects of nordihydroguaiaretic acid (NDGA), indomethacin and ketotifen.In vivo, azelastine protected actively sensitized guinea-pigs against ovalbumin-induced bronchospasm with an ID₅₀ of 0.08 mg/kg orally. Ketotifen was similarly active (ID₅₀=0.05 mg/kg). Antigen-induced contraction of isolated tracheal rings of sensitized guinea-pigs was concentration-dependently inhibited by azelastine and NDGA with IC₅₀-values of 94.1 and 34.2 mol/l, respectively. Ketotifen exerted only weak inhibitory activity (18% at 100 mol/l). The arachidonic acid-induced contraction of isolated guinea-pig tracheal rings was also inhibited both by azelastine (IC₅₀=92.6 mol/l) and NDGA (IC₅₀=20.4 mol/l). Ketotifen was inactive on this model. Antigen challenge of chopped lung tissue from sensitized guinea-pigs resulted in the release of cysteinyl-leukotrienes (LT) which were identified by reversed phase high pressure liquid chromatography (HPLC) as LTD₄ and LTE₄. The release of cysteinyl-LT from sensitized guinea-pig lung tissue induced by antigen challenge was concentration-dependently inhibited by azelastine (IC₅₀=35.2 mol/l) and NDGA (IC₅₀=8.4 mol/l) but not by ketotifen and indomethacin. By contrast, indomethacin caused a pronounced augmentation of cysteinyl-LT release. The concentration of indomethacin, which augmented cysteinyl-LT release by 50% was 0.19 mol/l. At the same concentration, indomethacin inhibited the release of 6-keto-PGF₁ and TXB₂ by about 50%. Azelastine negligible influenced 6-keto-PGF₁ and slightly diminished TXB₂ release from the chopped lung tissue after challenge. Its IC₅₀-values were >2 mmol/l and 443 mol/l, respectively. NDGA inhibited the release of 6-keto-PGF₁ and TXB₂ with IC₅₀-values of 47.3 and 38.3 mol/l, respectively. Ketotifen was ineffective in inhibiting the release of cyclo-oxygenase products of AA metabolism. It seems likely that inhibition of release of 5-lipoxygenase-derived products of AA metabolism by azelastine contributes to its antiallergic and antiasthmatic activity.Author for correspondence.     

Arachidonic Acid (AA) and Tetradecanoylphorbol Acetate (TPA) Exert Systemic Effects When Applied Topically in the Mouse

We studied the systemic actions of topically applied arachidonic acid (AA) and tetradecanoylphorbol acetate (TPA) in the mouse. AA or TPA-induced ear edema, increases in vascular permeability, eicosanoid levels, neutrophil and mononuclear influx were determined in both phlogogen-treated and contralateral vehicle-treated ear of each mouse and were compared with vehicle-treated ears from control mice. Edema and vascular permeability increases appeared only in AA- or TPA-applied ears. Moreover, in contralateral ears from AA-treated mice an increase in 6-keto-PGF₁ and LTB₄ was found. Only LTB₄ increased in the contralateral ear after TPA. Contralateral ears from AA- or TPA-treated mice also showed a significant increase in MPO levels. The increased levels of 6-keto-PGF₁ but not those of LTB₄ in contralateral ears were reduced by indomethacin applied simultaneously with the phlogogen. AA also increased plasma and serum levels of LTB₄, but not those of 6-keto-PGF₁. In contrast, TPA increased plasma and serum levels of 6-keto-PGF₁ and LTB₄. The results show that both AA and TPA applied topically exert systemic effects.     

Converting enzyme inhibitor ramipril stimulates prostacyclin synthesis by isolated rat aorta: Evidence for a kinin-dependent mechanism

Summary The present study was performed to investigate the effect of the angiotensin I-converting enzyme inhibitor ramipril on vascular synthesis of prostacyclin (PGI₂). Administration of ramipril (Hoe 498) to rats significantly stimulated prostacyclin (PGI₂) synthesis, quantified by radioimmunoassay of its stable hydrolysis product 6-keto-PGF₁, by portions of the animals' isolated aorta. This effect was maximal at a dose range of 10^–7 mol/kg ramipril. The addition of the active ramipril metabolite ramipril diacid directly into the incubation buffer at final concentrations of 10^–9, 10^–6, and 10^–4 M resulted in a dose-dependent stimulation of 6-keto-PGF₁ released by isolated aortic tissue. Pretreatment of rats with aprotinin (40,000 U s.c. 60 min before the incubations) attenuated the ramipril-induced effect on aortic 6-keto-PGF₁ synthesis. Our results show that the angiotensin I-converting enzyme inhibitor ramipril stimulates PGI₂ synthesis in vascular tissue and that this effect may be secondary to changes in the activity of the kinin system.Abbreviations ACE angiotensin I-converting-enzyme - PG prostaglandin - PGI₂ prostacyclin Dedicated to Prof. Dr. F. Krück on the occasion of his 65th birthday     

Effects of indomethacin,triamcinolone, and dexamethasone on recombinant human interleukin-1-induced substance P and prostaglandin E2 levels in rabbit knee joints

Intra-articular (i.a.) injection of recombinant human interleukin-1 alpha (rHuIL-1) in rabbit knees induced both an inflammation, as determined by increases in leukocytes in the joint fluid, and cartilage degradation, as measured by loss of proteoglycan. Substance P (SP) and prostaglandin E₂ (PGE₂) levels in the joint lavage are also elevated. Treatment with 5 mg indomethacin/kg, p.o., b.i.d., 2 mg triamcinolone i.a., and 10 mg dexamethasone/kg, p.o., reduced synovial lavage leukocyte counts, as well as PGE₂ and SP lavage concentrations induced with IL-1 injection. However, none of the treatments inhibited rHuIL-1-induced proteoglycan loss.     

Hydrogen peroxide-induced alterations in prostaglandin secretion in the rat colon in vitro

Although the specific cause(s) of inflammatory bowel diseases (IBD) has not been identified, one theory suggests ischemia as the early event that occurs in IBD and reperfusion causes sustained release of oxyradicals, leading to inflammation and ulceration. In this study, we have confirmed that H₂O₂ in the concentration seen during ischemia/reperfusion is primarily responsible for cellular membrane damage in the rat colonic fragments in vitro. Hydrogen peroxide caused a time and dose-dependent increase in 6-keto-PGF₁ and TXB₂ release. Hydrogen peroxide-stimulated 6-keto-PGF₁ release was blocked (50%) by phospholipase A₂ (PLA₂) inhibitors quinacrine and dimethyleicosodienoic acid at 5 min. Hydrogen peroxide-stimulated 6-keto-PGF₁ release was completely blocked by idomethacin, significantly blocked (69%) by nordihydroguiaretic acid, and completely blocked by catalase. superoxide dismutase and uric acid failed to inhibit H₂O₂-stimulated 6-keto-PGF₁ release. Endogenous catalase inhibitors 3-aminotriazole and sodium azide further enhanced the release of 6-keto-PGF₁ stimulated by H₂O₂ by 29% and 73%, respectively. Xanthine-xanthine oxidase also increased 6-keto-PGF₁ release from the fragments by 110%. This release was not inhibited by superoxide dismutase and uric acid, but was completely inhibited by catalase. These studies suggest a direct effect of H₂O₂ on colonic fragments leading to submicroscopic cellular membrane damage and excess prostanoid production utilizing a PLA₂/cyclooxygenase and catalase-sensitive pathway without the formation of toxic hydroxyl ions. The quick release of 6-keto-PGF₁ also suggests an early manifestation of H₂O₂-induced damage in rat colonic fragments.     

Regional distribution of prostanoids in rat brain: effect of insulin and 2-deoxyglucose

Summary Prostaglandin synthesis in the brain has been suggested as a component in the control mechanism of the cerebral circulation. During insulininduced hypoglycemia there is a significant increase in local cerebral blood flow in various brain regions, however, regional loss of autoregulation occurs under these conditions. In the present study the regional distribution of PGE₂, TXB₂ (the stable metabolite of thromboxane) and 6-keto-PGF₁ (the stable metabolite of prostacyclin) was determined in rat brain following decapitation. Three groups of rats were treated with either saline, insulin or 2-deoxyglucose and their brains were rapidly removed one hour later. Samples from the cortex hypothalamus, hippocampus, striatum, nucleus accumbens and cerebellum were assayed by RIA for the content of PGE₂, TXB₂ and 6-keto-PGF₁ The levels of all three compounds in control rats were the lowest in the striatum and cerebellum, while in the cortex and hippocampus their levels were 4–6 times higher. Insulin had selective effect on the post decapitation levels of prostanoids. It increased PGE₂ in the n. accumbens and TXB₂ in the hippocampus, and reduced 6-keto-PGF₁ and TXB₂ in the cortex. 2-DG reduced all PGs in the cortex and 6-keto-PGF₁ in the hypothalamus and hippocampus. The results demonstrate that discrete brain areas have a differential capacity to accumulate PGs following decapitation. This capacity is selectively affected by insulin and 2-DG.     

Experimental diabetes: No effects on prostacyclin release from the vessel wall and renal cortex

Diabetes is commonly complicated by thrombosis and atherosclerosis. In humans, diabetes mellitus has been associated with a decreased synthesis of prostacyclin, which could partly explain the prothrombotic state. Experimental diabetes has been diverging in this aspect, and endothelial damage has been proposed to be an early event. To analyse whether the effect of inducing diabetes had any influence on prostacyclin release from diabetic tissue, streptozotocin-induced diabetic rat aortas and renal tissue were incubated in Hank's balanced salt solution. The stable degradation product for prostacyclin 6-keto-PGF₁ was determined by radioimmunoassay. There was no difference in the release of 6-keto-PGF₁ from aorta and renal tissue in diabetic animals compared to controls, and insulin given to diabetic animals also had no effect.In order to study only the intraluminal release of prostacyclin, aortas and caval veins from alloxan-diabetic rabbits were perfused for five 15 min periods. Diabetic animals had the same release of 6-keto-PGF₁ from the aorta and caval vein as control animals.Scanning electron microscopy of the luminal side of the perfused vessels revealed the same degree of endothelial coverage with approximately 75% coverage after perfusion.It is concluded that experimental diabetes of 6 months' duration does not alter the vascular and renal prostacyclin release in response to exogenous trauma like incubation or perfusion.     

Anti-inflammatory and gastrointestinal effects of nabumetone or its active metabolite, 6MNA (6-methoxy-2-naphthylacetic acid): Comparison with indomethacin

6MNA, the active metabolite of the non-acidic anti-inflammatory drug nabumetone, was investigated using intravenous administration for effects on (a) carrageenan paw oedema and gastric irritancy compared to either oral nabumetone or both oral and intravenous indomethacin when given acutely and (b) gastrointestinal irritancy when given in repeat dosing studies. An oral dose of nabumetone or intravenous 6MNA produced effective anti-inflammatory activity together with significant inhibition of paw exudate PGE₂. An anti-inflammatory oral dose of nabumetone or intravenous 6MNA produced minimal effects on gastric 6-keto-PGF₁ production, with an absence of gastric damage, in contrast to indomethacin. In repeat dose studies, 6MNA failed to induce gastrointestinal damage even at doses where general toxicity was evident. These results show that in the rat 6MNA, the active metabolite of nabumetone, is an effective anti-inflammatory drug but, even in very high intravenous doses, does not have the propensity to induce gastrointestinal damage.     

Phenyl isothiocyanate pleurisy in rats—a model for the evaluation of anti-exudative substances

Orally administered phenyl isothiocyanate (PITC) induces profuse exudation into the rat pleural cavity, exudates up to 12 ml being observed. The prerequisite for this damage is a body weight of about 190 g in female and 250 g in male rats.Exudation begins about 28 h after provocation, reaches its maximum after 40 h and remains constant until 48 h after PITC administration. Pleural exudate is no longer detectable 70 h after PITC provocation.Taking, ±9 ml exudate as the criterion, the ED₅₀ 40 h after PITC was 63.9 mg/kg p.o. in female rats, aged 98 days. In male rats aged 88 days, where the criterion was ±7 ml exudate, the corresponding ED₅₀ was 73.8 mg/kg p.o. The LD₅₀ in female rats aged 72 days was 86.9 mg/kg p.o. and in male rats aged 81 days 110 mg/kg p.o.Based on a criterion of ±50% inhibition of exudate compared with control rats (female, aged 70 days) the ED₅₀ of acetylsalicylic acid 40 h after PITC (50 mg/kg p. o.) was 155 mg/kg p.o., of aescin 0.42 mg/kg i.v. and of hydrocortisone 12.0 mg/kg i.v.Following intoxication with PITC using doses of 50 mg/kg p.o. (female rats) and 65 mg/kg p.o. (male rats) the plasma and exudate showed the following significant findings: The haematocrit value and the number of leucocytes in the plasma were increased; K⁺ and protein concentration in the plasma decreased whereas Na⁺ concentration remained unchanged. The exudate contained 20%–25% of the leucocytes normally present in plasma and 26–38×10³/ml, mast cells. No erythrocytes were detected in the exudate. Electrophoretic separation of the plasma proteins revealed shifts from albumin to ₁-globulin, whereas the percentages of -and -globulins remained the same.Thus, the PITC-pleurisy model distinctly reveals both the initial (exudation) and the later phase of inflammation (leucocyte migration), the initial phase being especially pronounced. The efficacy of either decidedly antiexudative substances, such as aescin, or substances which influence the later phases of inflammation (acetylsalicylic acid, hydrocortisone) can be evaluated using this model.     

Involvement of brain histamine in basal and stress-induced release of prolactin in the rat

We investigated whether inhibition of brain histamine (HA) synthesis by -fluoromethylhistidine (-FMH) can influence basal or stimulated prolactin (PRL) release in male rats. -FMH was administered either into the carotid (i.a., 20 and 100 mg/kg) or intracerebroventriculary (i.c.v., 200 g/rat) into freely moving rats with indwelling catheters. Plasma PRL levels were measured 90, 120, 180 min later. Both i.a. and i.c.v. administration of -FMH significantly inhibited basal PRL secretion at 120 and 180 min. When PRL secretion was stimulated by exposing rats to restraint stress, -FMH administered 3 h before the stress (20 and 100 mg/kg, i.a.; 200 g/rat, i.c.v.) was able to prevent the PRL surges at 10 and 20 min after stress. These results suggest that endogenous brain HA has a facilitatory role in the control of PRL secretion in rats.     

Effects of selective histamine H3-receptor ligands on prolactin and growth hormone secretion in the rat

The effects of intracarotid (i.a.) administration of the histamine (HA) H₃-receptor agonist (R)--methyl-histamine (MeHA) and of the H₃-antagonist thioperamide, (THIO) on basal or morphine (M)-induced prolactin (PRL) and growth hormone (GH) secretion were studied in male rats. M was administered 3 h after the H₃-drugs. Neither THIO (2.5 mg/kg) nor MeHA (10 mg/kg) changed basal PRL levels and only THIO enhanced the PRL-releasing effect of M (6 mg/kg). Basal GH secretion was not modified by THIO. MeHA slightly increased GH secretion. THIO significantly decreased M-stimulated GH secretion (1 mg/kg, i.a.) and MeHA slightly increased it. These results, in agreement with previous evidence obtained after central HA administration, indicate that endogenous brain HA facilitates PRL and inhibits GH secretion.     

Effects of chronic NSAIDs on gastric mucosal injury related to mucosal prostanoids, and plasma drug concentrations in human volunteers

The relationship between endoscopically observed gastric mucosal damage, elicited following repeated oral intake for 7 d of four NSAIDs, to theie effects on antral and fundic production of PGE₂, 6-keto-PGF₁ and TxB₂ (assayed by GC-MS), mucosal histology and plasma concentration profiles was studied in 40 normal males. Subjects received azapropazone (APZ) 600 mg b.i.d., indomethacin (IND) 50 mg t.i.d., naproxen (NAP) 500 mg b.i.d., piroxicam (PIR) 20 mg qq.d., or one placebo capsude t.i.d (N=8/group). Plasma NSAIDs (HPLC) levelled at 7 d. Mucosal damage occurred in the antrum region with IND and NAP. APZ and PIR exhibited no differences compared to placebo. NAP and IND reduced all three prostanoids in the antrum while APZ and PIR were ineffective. Fundic PGE₂ was reduced by IND, NAP and PIR; APZ had no effects. Thus, mucosal damage relates to effects on prostanoid production in the antrum but not in the fundus.     

The effect of inhibition of prostaglandin synthesis on tubuloglomerular feedback in the rat kidney

To further clarify the mechanism mediating the reduction of nephron filtration rate in response to an increase of loop of Henle flow rate we have studied the effect of prostaglandin inhibition on tubuloglomerular feedback in rats. Following inravenous administration of 2 or 5 mg/kg indomethacin feedback responses expressed as the percent reduction of early proximal flow rate (EPFR) during flow elevation from 0–40 nl/min decreased from control values of –54.3±4.3% (mean ± S.E.) and –39.5±3.9% to –27.9±2.8% (P<0.001) and –5.0±4.9% (P<0.001) respectively. A significant reduction in the feedback response was also seen following intravenous administration of 2 or 5 mg/kg Ro 20-5720 (–28.8±5.8% and –7.8±3.8% respectively), 10 mg/kg meclofenamate (–15±4%), and 2 mg/kg eicosa-5,8,11,14-tetraynoic acid (–16.2±4.8%). In contrast to control animals injection of 5 mg/kg indomethacin had no effect on the feedback response in rats kept on a low salt diet. After applying a single dose of 5 mg/kg indomethacin or Ro 20-5720 feedback responses were reduced to –5.4±4.3% and –3.0±4.36% in the period 0–80 min, but were normal in the period 81–160 min after injection (–36.1±2.83% and –44.3±2.82% respectively). A dose dependent inhibition of the feedback response was also noted when indomethacin was applied intraluminally with full inhibition being established at a concentration of 0.5 mM. Urinary excretion rates of PGE₂ and PGF₂ fell from control values of 286.1±73.7 and 143.5±25.9 pg/min to 31.2±9.9 and 23.6±9 pg/min following 2 mg/kg indomethacin and to 36.8±4.4 and 8.9±1.9 pg/min following 5 mg/kg Ro 20-5720. Reduction of PG excretion was not reversible during the time of the experiment. Our results demonstrate a consistent decrease of tubuloglomerular feedback responses during inhibition of prostaglandin biosynthesis.Supported by the Deutsche Forschungsgemeinschaft