Changes of nitric oxide synthase activity and free methylarginines contents in regenerating rat liver after partial hepatectomy

In the present study, liver regeneration rate (%) was increased up to 70% 3 days after partial hepatectomy (PH). Nitric oxide synthase (NOS) activity in liver tissue as well as serum nitrite/nitrate content had no timed response, revealing no significant difference between shamoperated and partially hepatectomized rat liver. Contents of free methylarginines in liver tissue were increased biphasically in a time-dependent manner after PH. However, those in serum did not exhibit the same patterns as in liver. Taken together, the results suggest that N^G-monomethyl-L-arginine (MMA) and N^G, N^G-dimethylarginine (DMA) play a role in inhibiting nitric oxide (NO) synthesis in regenerating rat liver because the increase of their contents was synchronized with NOS expression.     

Study of in vivo and in vitro resting vasodilator nitric oxide tone in normotensive and genetically hypertensive rats

The effects of N^G-nitro- -arginine ( -NNA) on mean arterial pressure and the effects of both -NNA and methylene blue on isolated aorta tone, were studied in order to elucidate potential alterations in vasodilator resting nitric oxide (NO) tone in genetic hypertension. -NNA produced a significantly greater increase of mean arterial pressure in spontaneously hypertensive rats (SHR) than in Wistar Kyoto (WKY) rats; in both cases, -arginine completely inhibited the -NNA hypertensive effect. Neither ganglion blockade with hexamethonium nor cyclooxygenase inhibition with indomethacin significantly modified the effect of -NNA in both rat strains. In intact aorta rings, after submaximally contraction with KCl (25 mM), both -NNA and methylene blue induced strong dose-dependent contractions. The maximum contractions were, however, significantly greater in WKY rats than in SHR. The mechanical elimination of endothelium markedly inhibited both -NNA and methylene blue maximum contractions. In intact rings, -arginine completely inhibited the -NNA effects in both rat strains; in rubbed rings, the -arginine inhibitory effects were strong in WKY rats but not important and erratic in SHR. -Arginine had no effect on the contractions induced only by KCl in any of the preparations. In WKY rat-rubbed rings, sodium nitroprusside was significantly more effective in relaxing the contractions in response to 25 mM KCl than the contractions in response to methylene blue. These results indicate that contractions induced by -NNA and methylene blue in isolated aorta are principally due to the inhibition of an important endothelial resting vasodilator NO tone. They also show that hypertension reduces the resting vasodilator NO tone in isolated rat aorta, in spite of enhancing the total vasodilator NO tone in anaesthetized rat.     

Possible role of nitric oxide in the antinociceptive action of intraventricular bradykinin in mice

The i.c.v. administration of bradykinin (4, 8 and 16 μg) induced antinociception in mice which was resistant to naloxone; furthermore, the induction of tolerance to morphine by a single s.c. injection (100 mg/kg, 24 h before test doses of the peptide) did not affect antinociception. Since bradykinin is known to increase nitric oxide (NO) in peripheral tissues, we studied the possibility that its antinociceptive action may be related to NO effects in the central nervous system. Bradykinin effects were antagonized by previous treatment with N^G-nitro- -arginine or concomitant i.c.v. administration of bradykinin and methylene blue. The immediate precursor of NO, -arginine, which by itself produces analgesia, also reduced bradykinin effects; moreover, tolerance to -arginine significantly decreased the response to the peptide. These results suggest that NO is involved in antinociception induced by i.c.v. administration of bradykinin.     

Distribution and metabolism of four different dimethylated arsenicals in hamsters

Arsenic toxicity and distribution are highly dependent on animal species and its chemical species. Recently, thioarsenical has been recognized in highly toxic arsenic metabolites, which was commonly found in human and animal urine. In the present study, we revealed the mechanism underlying the distribution and metabolism of non-thiolated and thiolated dimethylarsenic compounds such as dimethylarsinic acid (DMA^V), dimethylarsinous acid (DMA^III), dimethylmonothioarsinic acid (DMMTA^V), and dimethyldithioarsinic acid (DMDTA^V) after the administration of them into femoral vein of hamsters. DMA^V and DMDTA^V distributed in organs and body fluids were in their unmodified form, while DMA^III and DMMTA^V were bound to proteins and transformed to DMA^V in organs. On the other hand, DMA^V and DMDTA^V were mostly excreted into urine as their intact form 1 h after post-injection, and more than 70% of the doses were recovered in urine as their intact form. By contrast, less than 8-14% of doses were recovered in urine as DMA^V, while more than 60% of doses were distributed in muscles and target organs (liver, kidney, and lung) of hamsters after the injection of DMMTA^V and DMA^III. However, in red blood cells (RBCs), only a small amount of the arsenicals was distributed (less than 4% of the doses) after the injection of DMA^III and DMMTA^V, suggesting that the DMA^III and DMMTA^V were hardly accumulated in hamster RBCs. Based on these observations, we suggest that although DMMTA^V and DMDTA^V are thioarsenicals, DMMTA^V is taken up efficiently by organs, in a manner different from that of DMDTA^V. In addition, the distribution and metabolism of DMMTA^V are like in manner similar to DMA^III in hamsters, while DMDTA^V is in a manner similar to DMA^V.     

NG-nitro L-arginine methyl ester: systemic and pulmonary haemodynamics,tissue blood flow and arteriovenous shunting in the pig

Summary The effects of N^G-nitro-Lrarginine methyl ester (L-NAME), an inhibitor of the endothelial nitric oxide (NO) biosynthesis, on systemic and pulmonary haemodynamics, and tissue as well as arteriovenous anastomotic blood flows were investigated in the anaesthetized pig, using simultaneous injections of radioactive microspheres of two different sizes (diameter: 15 and 50m). L-NAME (1, 3 and 10 mg·kg^–1) reduced systemic and pulmonary artery conductance and cardiac output, but heart rate and mean arterial blood pressure remained unchanged. L-arginine reversed the systemic and pulmonary haemodynamic changes induced by L-NAME. As detected with 15 m microspheres, L-NAME (1 and 3 mg·kg^–1) decreased tissue blood flow to and vascular conductance in the eyes, lungs, atria, kidneys, adrenals and liver. Furthermore, the difference between blood flows simultaneously measured with 15 and 50 m microspheres, which can be equated to blood flow through arteriovenous anastomoses with a diameter between about 28 and 90 m, was reduced by L-NAME (3 mg · kg^–1) in the skin of head and gluteal regions and, as indicated by the microsphere content of the lungs, in the total systemic circulation. These results suggest that in the anaesthetized pig (i) NO is involved in the regulation of both systemic and pulmonary vascular conductance, (ii) the decrease in systemic vascular conductance is in part due to constriction of systemic arteriovenous anastomoses, and (iii) the decrease in pulmonary vascular conductance, leading to reduction of cardiac output, seems to negate the expected rise in arterial blood pressure observed, for example, in rats and rabbits following inhibition of NO-synthesis. Correspondence to P. R. Saxena at the above address     

Alkylation of RNA by vinyl bromide metabolites in vitro and in vivo

[1,2-¹⁴C]Vinyl bromide was incubated with rat liver microsomes, NADPH, and polyadenylic acid, polycytidylic acid, or RNA, respectively. Part of the adenosine moieties in RNA or in polyadenylic acid were alkylated and labelled 1,N⁶-ethenoadenosine structures were formed. Part of the cytidine moieties were converted into 3,N⁴-ethenocytidine. In addition, a further unidentified cytidine alkylation product was observed which was not seen in experiments using [1,2-¹⁴C]vinyl chloride. When rats were exposed to [1,2-¹⁴C]vinyl bromide, radioactive ethenoadenosine and ethenocytidine were present in hydrolysates of liver RNA. A further alkylation product was observed in the RNA hydrolysates which did not occur in experiments using [¹⁴C]vinyl chloride. The data show that vinyl bromide metabolites alkylate nucleic acids; although in general in this respect vinyl bromide and vinyl chloride behave similarly, some differences are observed in the alkylation behaviour of both compounds.     

NG-nitro-L-arginine (N5-[imino(nitroamino)methyl]-L-ornithine) impairs endothelium-dependent dilations by inhibiting cytosolic nitric oxide synthesis from l-arginine

Summary We studied the effects of the l-arginine analogue N^G-nitro-l-arginine (l-NNA), in comparison with its d-isomer (d-NNA), on endothelium-dependent dilations of rabbit femoral arteries (RFA) and on the release of endothelium-derived relaxant factor (EDRF) from native and cultured endothelial cells. In addition, we examined the effects of l- and d-NNA on the l-arginine- and NADPH-dependent synthesis of nitric oxide (NO) in the cytosol of porcine aortic endothelial cells. l-NNA enhanced the noradrenaline-induced contraction of endothelium-intact, but not of endothelium-denuded segments of RFA, indicating an inhibition of basal EDRF release. l-NNA also inhibited significantly the endothelium-dependent dilations to acetylcholine (ACh). Both effects of l-NNA were attenuated by l-arginine. l-NNA rapidly inhibited the release of EDRF from cultured and native endothelial cells stimulated with thimerosal or ACh. l-NNA concentration-dependently and reversibly antagonized the l-arginine- and NADPH-dependent activation of a purified soluble guanylate cyclase (GC) by cytosol from.Sreshly harvested porcine aortic endothelial cells, suggesting a direct competition between l-NNA a l-arginine at the level of endothelial NO-synthesis. d-NNA was ineffective in all instances. These results prove l-NNA to be a stereospecific inhibitor of the cytosolic NO formation from l-arginine in endothelial cells. Therefore, l-NNA will be a useful tool to elucidate the molecular mechanism of mammalian NO synthesis. Send offprint requests to A. Mdlsch at the above address     

Effect of NG-nitro-L-arginine methylester (L-NAME) on functional and biochemical alpha 1-adrenoceptor-mediated responses in rat blood vessels.

1. The modulation by NG-nitro-L-arginine methylester (L-NAME) of alpha 1-adrenoceptor-mediated contraction was investigated on isolated segments of rat tail artery and aorta. The influence of L-NAME on inositol phosphates accumulation by alpha 1-adrenoceptor agonists was also investigated to elucidate the intracellular mechanism responsible for this modulation. 2. In aorta but not in tail artery L-NAME (30 microM) enhanced the sensitivity (3.3 times) and the maximum contraction (Emax) induced by the full agonist, phenylephrine. 3. St-587, a partial alpha 1-adrenoceptor agonist, behaved as a weak agonist in the aorta (22.2% of phenylephrine Emax). However, when the same agonist was studied in tail artery rings a maximum contraction that was 78.4% of the phenylephrine induced Emax was reached. 4. L-NAME increased (3.3 times) the Emax for St-587 contraction in the aorta but not in the tail artery. Sensitivity to St-587 was slightly but significantly (P < 0.001) enhanced (1.9 times) by L-NAME in tail artery segments. 5. Contractile responses to phenylephrine after partial alkylation with phenoxybenzamine were analyzed by the nested hyperbolic null method. To elicit 50% of Emax for contraction only 1.1% of the receptors in the tail artery and 21% of the receptors in the aorta need to be occupied. These results indicate a higher receptor reserve for the tail artery than the aorta. 6. In the tail artery but not in the aorta, St-587 activates phosphoinositide turnover. The presence of L-NAME was without effect on inositol phosphates accumulation induced by this partial alpha 1-adrenoceptor agonist. 7. The maximum contraction induced by phenylephrine, after partial alpha-adrenoceptor alkylation, was enhanced by L-NAME in tail artery rings. However, the NO synthase inhibitor was unable to modify the phenylephrine-induced accumulation of inositol phosphates in the presence of phenoxybenzamine. 8. These results indicate that the differences in St-587-induced contraction and the modulation by L-NAME of alpha 1-adrenoceptor-mediated contraction observed between the tail artery and aorta are associated with differences in receptor reserve. In addition, our biochemical studies indicate that the potentiating effect of L-NAME is independent of intracellular calcium release via phosphatidylinositol turnover.     

Influence of dipyridamole and its combination with NO donor or NO synthase inhibitor on adjuvant arthritis

The anti-arthritic and anti-inflammatory effects of dipyridamole and the possible involvement of NO in the dipyridamole action are not yet clear. The aim of this study was to evaluate the effects of dipyridamole alone and in combination with either the nitric oxide donor, sodium nitroprusside (SNP) or the non-selective nitric oxide synthase inhibitor, L-NG- monomethyl arginine (L-NMMA), on pathogenesis of adjuvant-induced arthritis model in rats. The results of the present work showed that prophylactic administration of dipyridamole alone and dipyridamole administration in combination with either low dose of SNP or L-NMMA significantly ameliorated pathogenesis of adjuvant arthritis in rats as evidenced by significant decrease in arthritis index, hind paws volume, loss of body weight, hyperalgesia compared with control vehicle (1% DMSO) treated adjuvant arthritic rats. Inflammatory cellular infiltrate in synovium of ankle joint and pannus formation were also markedly inhibited. Interleukin-10(IL-10) levels were significantly increased in these groups of animals. In contrast, a high dose of SNP counteracted the anti-inflammatory and anti-arthritic effects of dipyridamole. The inhibitory effect of therapeutic administration of dipyridamole alone on adjuvant arthritis syndrome was not significantly different from that of vehicle administration. In conclusion, dipyridamole has prophylactic but not therapeutic anti-arthritic and anti-inflammatory effects that appear to be dependent on inhibition of NO synthase. A synergistic combination between dipyridamole and NO synthase inhibitor or low dose of NO donor may have prophylactic and therapeutic values in autoimmune diseases like RA.     

Distribution and metabolism of gastrodin in rat brain

Gastrodin is the major and bioactive component in Tianma (Gastrodia elata Bl.) and has sedative, anticonvulsive and neuroprotective effects. Since little is known about its neuropharmacokinetics and brain metabolism, this study was undertaken to investigate the kinetic inter-relationship of gastrodin in rat plasma, cerebrospinal fluid (CSF) and brain microdialysate (frontal cortex, hippocampus, thalamus and cerebellum). Gastrodin was administered via the femoral vein at a dose of 200mg/kg, and blood, CSF and brain microdialysate were collected at timed intervals for the measurement of gastrodin concentrations by high-performance liquid chromatography. The samples were analyzed on a Diamonsil C18 column (5 microm, 250 mm x 4.6mm i.d.) with a mobile phase consisting of acetonitrile-water (5% acetonitrile for brain microdialysate, 2.5% acetonitrile for plasma and CSF), and detected with a UV detector at 221 nm. The distribution of gastrodin in rat showed that levels of gastrodin declined rapidly after drug administration, and the entry of gastrodin into the brain was rapid. However, the ratios of AUC(brain)/AUC(plasma) were not high. The individual ratios of the AUC in the CSF, frontal cortex, hippocampus, thalamus and cerebellum to the AUC in the plasma were 4.8+/-2.4%, 3.3+/-1.2%, 3.0+/-0.7%, 3.3+/-1.3% and 6.1+/-1.9%, respectively. The AUC in the cerebellum was significantly higher than that in other brain regions (P<0.05). The concentrations of p-hydroxybenzyl alcohol, the main metabolite of gastrodin, were very low both in the CSF and plasma.     

Dose- and time-dependence of L-NAME neuroprotection in transient focal cerebral ischaemia in rats

1. In this study the effect of the dose and administration time of N^G-nitro-L-arginine methyl ester (L-NAME), an NO-synthase inhibitor, in a model of transient focal cerebral ischaemia in rats was investigated.
2. Two injections of L-NAME were given, of 1, 3 and 10 mg kg⁻¹, 5 min and 3 h after the onset of ischaemia. None of the doses gave any striatal neuroprotection, but 1 and 3 mg kg⁻¹ L-NAME reduced the infarcted volume in the cortex (by 26%, P<0.01 for 1 mg kg⁻¹ and 21%, P<0.05 for 3 mg kg⁻¹), whereas 10 mg kg⁻¹ had no neuroprotective effect.
3. Single injections of L-NAME 1 mg kg⁻¹, given 5 min or 3 h after ischaemia onset, had similar neuroprotective effects on the cortical infarction as did the repeated injections.
4. L-NAME 1 mg kg⁻¹ given 3, 6 or 9 h after ischaemia induction reduced the cortical infarct volume by 19% (P<0.01) when given 3 h after ischaemia, by 21% (P<0.01) when given at 6 h, and by 16% (P<0.5) when given at 9 h, but had no neuroprotective activity when given 12 h after ischaemia.
5. Thus a low dose of L-NAME is neuroprotective in a model of transient focal ischaemia, with a wide therapeutic window, much larger than that found for MK-801.

     

Phase II trial of ZD1694 (TomudexTM) in patients with advanced pancreatic cancer

SummaryBackground Currently available therapies for advanced pancreatic cancer offer only palliative benefits, and patients with this disease have a poor prognosis. We undertook a phase II trial of ZD1694 (Tomudex^TM), a quinazoline folate analogue that is a potent and selective thymidylate synthase inhibitor, to determine this analogue's efficacy and safety in patients with advanced pancreatic adenocarcinoma.Patients and methods ZD1694, 3.0 mg/m², was administered to 42 adult patients with pancreatic adenocarcinoma as a 15-minute intravenous infusion every 3 weeks for up to 6 doses. Objective tumor response was assessed every 6 weeks; clinical examinations, adverse event assessments, and clinical laboratory tests were performed every 3 weeks.Results ZD1694 produced an overall response rate of 5% (95% confidence limits [CI], 1% to 16%) in the study group. Of 42 patients, 2 (5%) had a partial response, 12 (29%) had stable disease, 21 (50%) had disease progression, and 5 (11%) could not be evaluated for response. Grade 3 vomiting, grades 3 and 4 fever, grade 3 leukopenia, grade 4 thrombocytopenia, and grades 3 and 4 liver function elevations were reported. Toxic effects with ZD1694 were reversible and manageable.Conclusions ZD1694 has an acceptable safety profile but limited activity in patients with advanced pancreatic cancer.Tomudex is a tradename, the property of Zeneca Limited. Supported by a grant from Zeneca Limited.     

Nitric oxide synthase inhibitor decreases NMDA-induced elevations of extracellular glutamate and intracellular Ca2+ levels via a cGMP-independent mechanism in cerebellar granule neurons

These studies were designed to examine the differential effect of nitric oxide (NO) and cGMP on glutamate neurotransmission. In primary cultures of rat cerebellar granule cells, the glutamate receptor agonist N-methyl-D-aspartate (NMDA) stimulates the elevation of intracellular calcium concentration ([Ca2+]i), the release of glutamate, the synthesis of NO and an increase of cGMP. Although NO has been shown to stimulate guanylyl cyclase, it is unclear yet whether NO alters the NMDA-induced glutamate release and [Ca2+]i elevation. We showed that the NO synthase inhibitor, N(G)-monomethyl-L-arginine (NMMA), partially prevented the NMDA-induced release of glutamate and elevation of [Ca2+]i and completely blocked the elevation of cGMP. These effects of NO on glutamate release and [Ca2+]i elevation were unlikely to be secondary to cGMP as the cGMP analogue, dibutyryl cGMP (dBcGMP), did not suppress the effects of NMDA. Rather, dBcGMP slightly augmented the NMDA-induced elevation of [Ca2+]i with no change in the basal level of glutamate or [Ca2+]i. The extracellular NO scavenger hydroxocobalamine prevented the NMDA-induced release of glutamate providing indirect evidence that the effect of NO may act on the NMDA receptor. These results suggest that low concentration of NO has a role in maintaining the NMDA receptor activation in a cGMP-independent manner.     

Stereoselectivity in metabolism of ifosfamide by CYP3A4 and CYP2B6

The aim was to identify the hepatic cytochromes P450 (CYPs) responsible for the enantioselective metabolism of ifosfamide (IFA). The 4-hydroxylation, N²- and N³-dechloroethylation of IFA enantiomers were monitored simultaneously in the same metabolic systems using GC/MS and pseudoracemate techniques. In human and rat liver microsomes, (R)-IFA was preferentially metabolized via 4-hydroxylation, whereas its antipode was biotransformed in favour of N-dechloroethylation. CYP3A4 was the major enzyme responsible for metabolism of IFA enantiomers in human liver. The study also revealed that CYP3A (human CYP3A4/5 and rat CYP3A1/2) and CYP2B (human CYP2B6 and rat CYP2B1/2) enantioselectively mediated the 4-hydroxylation, N²- and N³-dechloroethylation of IFA. CYP3A preferentially supported the formation of (R)-4-hydroxyIFA (HOIF), (R)-N²-dechloroethylIFA (N2D) and (R)-N³-dechloroethylIFA (N3D), whereas CYP2B preferentially mediated the generation of (S)-HOIF, (S)-N2D and (S)-N3D. The enantioselective metabolism of IFA by CYP3A4 and CYP2B1 was confirmed in cDNA transfected V79 cells.     

N-Nitro-L-arginine protects against ischaemia-induced increases in nitric oxide and hippocampal neuro-degeneration in the gerbil

To assess the effects of the nitric oxide synthase inhibitor N^G-Nitro-L-arginine on behavioural, biochemical and histological changes following global ischaemia, the Mongolian gerbil was used. Ischaemia was induced by bilateral carotid occlusion for 5 min. N^G-Nitro-L-arginine was administered i.p. at either 1 or 10 mg/kg 30 min, 6, 24, and 48 h after surgery. 5 min bilateral carotid occluded animals were hyperactive 24, 48 and 72 h after surgery. N^G-Nitro-L-arginine caused some attenuation in this hyperactivity. The activity of nitric oxide synthase was increased in the cerebellum, brain stem, striatum, cerebral cortex and hippocampus of 5 min bilateral carotoid occluded animals. N^G-Nitro-L-arginine reversed the increase in nitric oxide synthase activity in all brain regions. Extensive neuronal death was observed in the CA₁ layer of the hippocampus in 5 min bilateral carotid occluded animals 96 h after surgery. N^G-Nitro-L-arginine significantly protected against the neuronal death of cells in the CA₁ layer.     

Comparative pharmacokinetics of Nω-hydroxy-nor-L-arginine,an arginase inhibitor,after single-dose intravenous,intraperitoneal and intratracheal administration to brown Norway rats

Abstract

1. Rodent studies have documented that N^ω-hydroxy-nor-L-arginine (nor-NOHA), an arginase inhibitor, has therapeutic potential in the treatment of cardiovascular and obstructive airway diseases. However, its bioavailability and pharmacokinetics have not been described so far.

2. Anesthetized brown Norway rats were administered single doses of nor-NOHA (10, 30 or 90?mg/kg) intravenously (i.v.), intraperitonealy (i.p.) or via intratracheal (i.t.) instillation of aerosol. Plasma nor-NOHA was assayed using a validated HPLC method.

3. Upon i.v. administration, the mean concentration showed a biphasic decline and its value dropped below 10% of the maximum after 20?min. The pharmacokinetics were linear with the total and inter-compartmental clearances of 33 and 17?mL/min/kg, central and peripheral volumes of distribution of 0.19 and 0.43?L/kg and terminal half-life of 30?min.

4. The average absolute bioavailability of nor-NOHA after i.p. and i.t. delivery was 98% and 53%, respectively. The absorption from the airways was rate-limiting and its extent decreased with the dose.

5. In conclusion, nor-NOHA is rapidly cleared from the plasma in concordance with the short time window of its in vivo inhibitory activity reported in the literature. I.t. instillation of aerosol for topical effects of nor-NOHA in the airways is characterized with significant systemic availability.     

Formation of 3,N4-ethenocytidine moieties in RNA by vinyl chloride metabolites in vitro and in vivo

Rats were exposed to [1,2-¹⁴C] vinyl chloride. Liver RNA was isolated, hydrolyzed, and the nucleosides separated on Aminex-A-6. Besides the physiological bases and 1,N⁶-ethenoadenosine, radioactivity was also incorporated into 3,N⁴-ethenocytidine. Radioactive 3,N⁴-ethenocytidine moieties were also formed on incubation of polycytidylic acid with rat liver microsomes, NADPH and [¹⁴C] vinyl chloride. These alkylation mechanisms are consistent with the mutagenic and cancerogenic properties of vinyl chloride.

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Zusammenfassung RNS wurde aus der Leber von Ratten, die einer Atmosphäre mit [1,2-¹⁴C] Vinylchlorid ausgesetzt waren, isoliert. Nach enzymatischer Hydrolyse und Trennung der Nukleoside auf Aminex-A-6 wurde außer den physiologischen Nukleosiden und dem bereits beschriebenen 1,N⁶-Äthenoadenosin auch ein Radioaktivitätseinbau in 3,N⁴-Äthenocytidin gefunden. Eine Bildung von 3,N⁴-Äthenocytidinresten wurde auch beobachtet, wenn Polycytidylsäure, Rattenlebermikrosomen, NADPH-regenerierendes System und [¹⁴C] Vinylchlorid inkubiert wurden.

     

Different effects of dexamethasone and the nitric oxide synthase inhibitor L-NAME on caerulein-induced rat acute pancreatitis, depending on the severity

Effects of dexamethasone and N^G-nitro-L-arginine methyl ester (L-NAME), the nitric oxide (NO) synthase inhibitor, on caerulein-induced acute pancreatitis were examined in rats. Acute pancreatitis was induced by caerulein (20 μg/kg, s.c.) given repeatedly 2 or 4 times every hour, and serum amylase levels, pancreas weight and myeloperoxidase (MPO) activity were measured 6 h after the first injection of caerulein. Dexamethasone (3 mg/kg) and L-NAME (30 mg/kg) were administered p.o. 30 min before the first injection of caerulein. Caerulein caused moderate or severe pancreatitis, depending on the times of injections, resulting in different degrees of increase in serum amylase levels and pancreas weight, and the marked elevation of MPO activity was observed only after injections of caerulein given 4 times per hour. Both dexamethasone and L-NAME suppressed the severity of pancreatits, yet the effect of L-NAME as compared with dexamethasone was more potent against mild pancreatitis but less potent against severe pancreatitis. These results suggest that caerulein-induced acute pancreatitis shows different responsiveness to L-NAME and dexamethasone, depending on the severity; the former is more effective against pancreatitis with less inflammation, while the latter is more effective against pancreatitis with severe inflammation. It is assumed that endogenous NO may be involved in oedema formation as the early event in the development of acute pancreatitis.     

Enhancement of the anti-inflammatory and anti-arthritic effects of theophylline by a low dose of a nitric oxide donor or non-specific nitric oxide synthase inhibitor

Background and purpose:

Although there are many new specific phosphodiesterase inhibitors with anti-inflammatory activity, none have yet reached the market because of their low therapeutic efficacy. Our study was aimed to evaluate the anti-inflammatory and anti-arthritic effect of an established phosphodiesterase inhibitor, theophylline, and to investigate the effect of the nitric oxide (NO) donor, sodium nitroprusside (SNP) or NO synthase inhibitor, L-N^G-monomethyl arginine (L-NMMA) on its actions.

Experimental approach:

The effects of theophylline alone and combined with SNP or L-NMMA on the pathogenesis of adjuvant-induced arthritis in rats were evaluated.

Key results:

Prophylactic or therapeutic doses of theophylline significantly ameliorated the pathogenesis of adjuvant arthritis in rats as evidenced by a significant decrease in the arthritis index, hind paws volume, ankle joint diameter, fever, body weight loss and hyperalgesia in a dose-dependent manner. Inflammatory cellular infiltrate in synovium of ankle joint and pannus formation were also markedly inhibited. Interleukin-10 (IL-10) levels were significantly increased in arthritic rats given theophylline alone or in combination with either SNP or L-NMMA. Co-administration of a low dose of SNP or L-NMMA enhanced significantly the anti-inflammatory and anti-arthritic effect of theophylline. In contrast, a high dose of SNP counteracted the anti-inflammatory and anti-arthritic effects of theophylline.

Conclusions and Implication:

These findings confirm the anti-inflammatory and anti-arthritic activities of theophylline and suggest a new approach to enhance the anti-inflammatory and anti-arthritic effects of theophylline would be to administer it in combination with a low dose of a NO donor or a non-specific NO synthase inhibitor.     

子痫前期与血肉碱关系的研究

目的探讨孕妇血浆中肉碱水平与子痫前期的关系,及该疾病血脂代谢的改变。方法①利用串联质谱检测337例健康妊娠孕妇及84例子痫前期孕妇的血干滤纸片,测定血清总肉碱、游离肉碱、中长链肉碱、短链肉碱。②常规测定血总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白(HDL)、低密度脂蛋白(LDL)、载脂蛋白A(apoA)-1及载脂蛋白B(apoB)。结果①子痫前期病例组中除中链脂酰肉碱外,其他所有肉碱血浆浓度均明显高于对照组(团体t检验),以孕32周后更为显著(P<0.01)。游离肉碱和短链、长链脂酰肉碱的检测值和对照组相比约增加50%(P<0.01)。②子痫前期病例组中血TC,TG,LDL,apoB较对照组显著升高(P<0.01),HDL,apoA-1较对照组显著降低(P<0.01)。结论①子痫前期疾病的发生、发展,可能与肉碱水平有关,随孕龄增加更为显著,故检测肉碱浓度可有助子痫前期的病情评估。②子痫前期病程中可能存在血脂代谢异常。