In-vitro and Ex-vivo Inhibition of Blood Platelet Aggregation by Naftazone

Because of the considerable interest in the role of platelets and antiplatelet therapy in cardiovascular disease, including the aggregation of platelets to each other during arterial thrombosis and atherogenesis, we have studied the effect of naftazone (Etioven), an original vasculotropic drug on platelet aggregation. Rat and human platelets were prepared and incubated in-vitro with different concentrations of naftazone. We found that naftazone inhibited both platelet secretion and aggregation in platelet-rich plasma (PRP) and washed platelets after stimulation with thrombin or ADP. Rats were also treated intraperitoneally for five days with various naftazone doses (0.125-10 mg kg^?1) and ex-vivo platelet aggregation compared, at various times after the last injection, with that of control animals. Inhibition by naftazone was dose-dependent in both PRP and isolated platelets. The inhibition was transient, a maximum value (～ 50%) being obtained about 3–6 h after the last injection, with a return to near-control values after 24 h. Naftazone also facilitated platelet deaggregation after in-vitro stimulation with thrombin or ADP. In another series of experiments, rats were treated intraperitoneally for five days with 10 mg kg^?1 of aspirin, ticlopidine, dipyridamole or naftazone. Platelets were prepared and tested for aggregation 90 min after the last injection. Thrombin-induced aggregation in PRP and washed platelets was significantly reduced after in-vivo treatment with ticlopidine and naftazone. Except for dipyridamole, all the drugs inhibited ex-vivo ADP-induced aggregation in PRP. In isolated platelet preparation, only naftazone induced a significant inhibition of ADP-or thrombin-stimulated aggregation. We conclude that naftazone inhibits platelet aggregation in-vitro and ex-vivo.     

Nitric Oxide Synthase Inhibition by Pentacycloundecane Conjugates of Aminoguanidine and Tryptamine

This paper describes the synthesis and in‐vitro activity of pentacycloundecane‐conjugated aminoguanidine and tryptamine analogues on nitric oxide synthase (NOS) using rat brain homogenate. Both aminoguanidine and tryptamine‐derived NOS inhibitors show selectivity towards the inducible and neuronal isoforms of the NOS enzyme, but are weak inhibitors and complete inhibition of the enzyme occurs only at high millimolar concentrations. In view of the increased NOS inactivation observed with alkyl substitution of these structures, the present study aimed to evaluate the effect of the pentacycloundecane cage moiety as an alkyl substituent on the in vitro NOS inhibition of aminoguanidine and tryptamine compounds. Comparison of the IC₅₀ values of aminoguanidine (IC₅₀ = 2.306×10^–3 M) and 8‐imino‐N‐guanidino‐pentacyclo‐undecane 2 (IC₅₀ = 8.803×10^–5 M) revealed a more than 26‐fold increase in potency. The ability of tryptamine to inhibit NOS activity was also markedly improved by the various pentacycloundecane substituents. The compounds, 3‐hydroxy‐4‐[3‐(2‐aminoethyl)indole]‐azahexacyclo[5.4.1.0^2,6.0^3,10.0^5,9.0^8,11]dodecane 4 and 8‐[3‐(2‐aminoethyl) indole]‐pentacyclo[5.4.0^2,6.0^3,10.0^5,9]undecane 7 showed the best activity of the tryptamine analogues with a more than 3‐fold increase in nitric oxide synthase inhibition. The results confirmed that the pentacycloundecane structure substantially enhanced the NOS inhibitory potency as observed for the six new NOS inhibitors.     

Effect of Hypolaetin-8-Glucoside on Human Platelet Aggregation induced by ADP

Hypolaetin-8-glucoside, a flavonoid isolated from SIDERITIS MUGRONENSIS possessing anti-inflammatory activity inhibited dose-dependently the human PRP aggregation induced by ADP with a IC (50) = 2.4 x 10 (-4) M. This action does not seem to be related to cyclo-oxygenase, as this flavonoid is not an inhibitor and even is able to act as a cofactor for this enzyme.     

Pharmacology: Effects of Copper-aspirin Complex on Platelet Aggregation and Thrombosis in Rabbits and Mice

The effects of intragastric and intraduodenal copper-aspirin complex on rabbit platelet aggregation were observed by Born's method. Myers's method was used to evaluate the antithrombotic effect of copper-aspirin complex in mice. In-vitro copper-aspirin complex selectively inhibited arachidonic acid-induced platelet aggregation with an IC50 value (concentration resulting in 50% inhibition) of 13.2 μM (95% confidence limits 9.1–16.8 μM). Copper-aspirin complex (10 mg kg^?1 given intragastrically or intraduodenally) was more potent than aspirin in inhibiting arachidonic acid-induced platelet aggregation. Copper-aspirin complex (10 mg kg^?1) had a stronger inhibitory effect and a longer duration of action when given intragastrically than when given intraduodenally. It was shown by radioimmunoassay that copper-aspirin complex significantly reduced the level of thromboxane B₂ in plasma while markedly increasing that of 6-ketoprostaglandin F_1α (6keto-PGF_1α). Copper-aspirin complex (10 mg kg^?1 given intragastrically for 7 days) significantly reduced mouse mortality caused by intravenous injection of arachidonic acid. The results suggest that both in-vitro and in-vivo copper-aspirin complex is more potent in selectively inhibiting arachidonic acid-induced platelet aggregation than aspirin. When given intragastrically the complex has a more potent antiplatelet effect and a longer duration of action than when given intraduodenally. The antithrombotic effect of the complex was more potent than that of aspirin.     

Endothelium-Derived Nitric Oxide: Pharmacology and Relationship to the Actions of Organic Nitrate Esters

Vascular smooth muscle relaxation elicited by various endogenous substances results from their interaction with vascular endothelial cells to trigger the formation of endothelium-derived relaxing factor (EDRF). EDRF from pulmonary and peripheral arteries and veins and from cultured and freshly harvested aortic endothelial cells has been identified pharmacologically and chemically as nitric oxide (NO) or a labile nitroso compound. Endothelium-derived NO (EDNO) and authentic NO activate the cytoplasmic form of guanylate cyclase by heme-dependent mechanisms and thereby stimulate intra-cellular cyclic GMP accumulation in cells including vascular smooth muscle and platelets. Cyclic GMP functions as a second messenger to cause vascular smooth muscle relaxation and inhibition of platelet aggregation and adhesion to vascular endothelial surfaces. EDNO is synthesized from L-arginine and perhaps arginine-containing peptides by an unidentified calcium-requiring process coupled to the occupation of extracellular endothelial receptors. The biological actions of EDNO are terminated by spontaneous oxidation to NO₂ ^– and NO₃ ^–. The biological half-life of the very lipophilic EDNO is only 3–5 sec and this allows EDNO to function locally as an autacoid. Nitroglycerin and other organic nitrate esters elicit endothelium-independent relaxation after entering vascular smooth muscle cells and undergoing denitration and formation of NO. The pharmacological actions of nitroglycerin are therefore essentially the same as those of EDNO, and the endogenous NO receptor is the heme group bound to soluble guanylate cyclase. EDNO may serve a biological role to modulate local blood flow and platelet function.     

Stretch-Induced Stimulation of Lower Airway Nitric Oxide Formation in the Guinea-Pig: Inhibition by Gadolinium Chloride

Abstract: The effect of stretch on lower airway nitric oxide formation was studied in normoxic tracheostomized anaesthetized guinea-pigs. Increase of level of positive end-expiratory pressure caused increased lower airway nitric oxide formation, as measured by its presence in exhaled tracheal air. The L-type calcium channel blocker, verapamil, did not decrease lower airway nitric oxide formation. Neither the local anaesthetic xylocaine nor the ganglion blocker trimetaphan affected exhaled nitric oxide, excluding local and centrally-mediated neuronal reflexes. Intravenous administration of gadolinium chloride (GdCl₃, 50 mg/kg) induced a rapid and pronounced decrease (75%) in the basal level of exhaled nitric oxide. GdCl₃ completely abolished lower airway nitric oxide formation induced by ventilation with positive end-expiratory pressure (7 cm H₂O). GdCl₃ induced hypoxaemia, but there was no indication for the development of lung oedema. The results indicate that positive end-expiratory pressure stimulates lower airway nitric oxide formation in the guinea-pig. GdCl₃ inhibits lower airway nitric oxide formation in the guinea-pig in vivo, perhaps by interference with stretch-induced cellular calcium-influx.     

Role of Nitric Oxide in Neurodegeneration: Function,Regulation, and Inhibition

Reactive nitrogen species (RNS) and reactive oxygen species (ROS), collectively known as reactive oxygen and nitrogen species (RONS), are the products of normal cellular metabolism and interact with several vital biomolecules including nucleic acid, proteins, and membrane lipids and alter their function in an irreversible manner which can lead to cell death. There is an imperative role for oxidative stress in the pathogenesis of cognitive impairments and the development and progression of neural injury. Elevated production of higher amounts of nitric oxide (NO) takes place in numerous pathological conditions, such as neurodegenerative diseases, inflammation, and ischemia, which occur concurrently with elevated nitrosative/oxidative stress. The enzyme nitric oxide synthase (NOS) is responsible for the generation of NO in different cells by conversion of L-arginine (Arg) to L-citrulline. Therefore, the NO signaling pathway represents a viable therapeutic target. Naturally occurring polyphenols targeting the NO signaling pathway can be of major importance in the field of neurodegeneration and related complications. Here, we comprehensively review the importance of NO and its production in the human body and afterwards highlight the importance of various natural products along with their mechanisms against various neurodegenerative diseases involving their effect on NO production.     

Arginase Inhibition by Ethylacetate Extract of Caesalpinia sappan Lignum Contributes to Activation of Endothelial Nitric Oxide Synthase

Caesalpinia sappan (C. sappan) is a medicinal plant used for promoting blood circulation and removing stasis. During a screening procedure on medicinal plants, the ethylacetate extract of the lignum of C. sappan (CLE) showed inhibitory activity on arginase which has recently been reported as a novel therapeutic target for the treatment of cardiovascular diseases such as atherosclerosis. CLE inhibited arginase II activity prepared from kidney lysate in a dose-dependent manner. In HUVECs, inhibition of arginase activity by CLE reciprocally increased NOx production through enhancement of eNOS dimer stability without any significant changes in the protein levels of eNOS and arginase II expression. Furthermore, CLE-dependent arginase inhibition resulted in increase of NO generation and decrease of superoxide production on endothelium of isolated mice aorta. These results indicate that CLE augments NO production on endothelium through inhibition of arginase activity, and may imply their usefulness for the treatment of cardiovascular diseases associated with endothelial dysfunction.     

Different Contributions of the Endothelin ETA Receptor to Hypertension Induced by Acute or Chronic Inhibition of Nitric Oxide Synthesis

The effects of FR139317(R)2-[(R)-2-[S)-2-[[1-(hexahydro-1H-azepinyl)]carbonyl] amino-4-methyl-pentanoyl] amino-3-[3-(1-methyl-1H-indoyl)]propionyl]-amino-3-(2-pyridyl)propionic acid), an endothelin ET_A receptor antagonist, on systemic and renal haemodynamic responses and excretory responses to chronic or acute nitric oxide (NO) synthase inhibition with N^G-nitro-L-arginine (NOARG) have been examined. An intravenous bolus injection of FR139317 (10 mg kg^?1) to chronic NO-deficient hypertensive rats (2.74 mM NOARG in drinking water for 4 weeks) elicited only a slight decrease in mean arterial pressure (MAP), to the same extent as seen in normotensive control rats. Injection of this drug induced no alteration of the renal haemodynamics of this chronic hypertensive model. Urine formation in control rats was significantly reduced by administration of FR139317. No significant decrease in urine formation was observed in the chronic NO-deficient rats. Acute intravenous injection of NOARG (5 mg kg^?1) induced a gradual and significant increase in MAP, with a significant decrease in renal blood flow. A slight but insignificant diuretic effect was observed. In animals pretreated with FR139317 (10 mg kg^?1 i.v.) NOARG induced a significantly less potent increase in MAP, whereas similar renal haemodynamic responses to NOARG were observed. In contrast to the FR139317-untreated group, urine formation tended to decrease after administration of NOARG. These results suggest that endothelin, via the ET_A receptor, contributes to the systemic pressor response to acute NO synthase inhibition, although renal vasoconstriction and functional changes induced by acute NO synthase inhibition are independent of ET_A receptor-related effects. These results imply that action of endothelin via the ET_A receptor is not involved in the maintenance of sustained hypertension induced by chronic NO synthase inhibition.     

Effects of Nickel Chloride on Human Platelets: Enhancement of Lipid Peroxidation,Inhibition of Aggregation and Interaction with Ascorbic Acid

In order to elucidate whether urinary levels of inorganic and organic arsenic metabolites are associated with previous exposure to high-arsenic artesian well water, a total of 302 residents of age 30 yr or older were recruited from three arseniasis-hyperendemic villages in Taiwan. Most study subjects had stopped consuming high-arsenic artesian well water for more than 20 yr. The mean total arsenic (Ast) determined by inductively cout pled plasma mass spectrometer (ICPMS) was 267.05 +/- 20.95 mug/L, and the mean level of inorganic arsenic and its metabolites (Ast) was 86.08 +/- 3.43 mug/L. In the multivariate analysis, urinary dimethylarsinic acid (DMA) levels were significantly inversely associated with age, with women exhibiting significantly lower urinary amounts of arsenite [As(III)], arsenate [As(V)], monomethylarsonic acid (MMA), organic arsenic (Aso), and Ast compared to men. After adjustment for age and sex, previous cumulative arsenic exposure through consumption of artesian well water was significantly associated with elevated urinary levels of MMA and DMA, but not As(III) + As(V), Asot, and Ast. In the multivariate analysis, the percentage of As in As was significantly higher in men than women, but this was not significantly associated with age. The percentage of As(III) + As(V) in As increased significantly with age, while the reverse was noted with DMA in Asi. Women had a significantly higher DMA percentage but lower As(III) + As(V) and MMA percentages in Asi than men. After adjustment for age and sex, the percentages of As(III) + As(V) in Asi were significantly inversely associated with previous arsenic exposure through consumption of artesian well water. Data suggested that women seem to possess a more efficient arsenic methylation capability than men, and aging diminishes this methylation capability; furthermore, the higher the cumulative arsenic exposure, the greater is the body burden of inorganic arsenic, mainly in the form of MMA and DMA.     

Nephroprotective Mechanism(s) of Pentoxifylline: Reduction of Erythrocyte-Mediated Vascular Congestion and Inhibition of Nitric Oxide Release *

Abstract: The present study attempted to evaluate pentoxifylline's mechanism(s) of action in the prevention of acute renal failure by examining its vascular decongestant activity in a rat model for acute renal failure and inhibitory activity of nitric oxide release from activated macrophage-like (RAW 264.7 cells) and murine mammary adenocarcinoma (EMT-6 cells) cell lines. Radiolabeled chronium-erythrocytes were injected intravenously into all rats. Following occlusion of the left kidney for 45 minutes, rats were treated with pentoxifylline or normal saline. The medulla of the left (ischaemic) kidney had significantly higher radioactive counts than the right (control kidney) following an intravenous dose of normal saline. The medulla to whole blood radioactivity ratio of the left kidney was significantly greater than for the right (control) kidney. Animals administered intravenous pentoxifylline (5 mg/kg) had significantly lower radioactive counts in the medulla of the left (ischaemic) kidney than animals administered intravenous normal saline. No differences in radioactivity counts in the medulla of the left (ischaemic) kidney were observed when animals received intraperitoneal pentoxifylline (45 mg/kg) versus normal saline. In a second set of experiments the nitrite synthesis and percent cytotoxicity of pentoxifylline- and dexamethasone-treated cells were determined. Pentoxifylline at concentrations of 4 mM and 8 mM significantly decreased nitrite synthesis in RAW 264.7 cells, and at pentoxifylline concentrations of 2 mM, 4 mM, and 8 mM in EMT-6 cells compared to untreated cells. Dexamethasone at a concentration of 1 μM decreased nitrite synthesis in RAW 264.7 and EMT-6 cells compared to untreated cells. Pentoxifylline at concentrations of 0.5 mM through 8 mM significantly decreased cytotoxicity in RAW 264.7 and EMT-6 cells compared to untreated cells. Dexamethasone at a concentration of 1 μM decreased cytotoxicity in RAW 264.7 and EMT-6 cells compared to untreated cells. These finding suggest that pentoxifylline's ability to prevent acute renal failure may be a consequence of reduced vascular congestion and inhibition of nitric oxide release from activated macrophages.     

齐墩果酸对氧化损伤人脐静脉内皮细胞线粒体中一氧化氮合酶的调控作用

目的:研究齐墩果酸对氧化损伤人脐静脉内皮细胞(HUVECs)线粒体中一氧化氮合酶(mtNOS)的调控作用。方法:将对数生长期HUVECs细胞分为正常组、模型组和齐墩果酸低、中、高浓度(5、20、35μmol/L)组,药物作用24h后,除正常组外均加入含100μg/ml氧化低密度脂蛋白(ox-LDL)的培养液复制氧化损伤,CCK-8法检测细胞存活率。提取细胞线粒体,酶化学法检测mtNOS的活性和线粒体一氧化氮(mtNO)的含量,荧光酶标仪法检测活性氧(ROS)荧光强度,Westernblot法检测细胞色素C(Cyto-C)的表达。结果:与正常组比较,模型组细胞存活率降低,mtNOS活性、mtNO含量、ROS荧光强度和Cyto-C蛋白表达均增加,差异具有统计学意义(P<0.05);与模型组比较,齐墩果酸低、中、高浓度组细胞存活率增加,mtNOS活性、mtNO含量、ROS荧光强度和Cyto-C蛋白表达均降低,差异具有统计学意义(P<0.05),且与浓度呈正相关。结论:齐墩果酸能降低HUVECs细胞mtNOS活性,减少mtNO和Cyto-C的产生,其机制可能与下调ROS表达有关。     

H2 Receptor-Mediated Relaxation of Circular Smooth Muscle in Human Gastric Corpus: the Role of Nitric Oxide (NO)

This study was designed to examine the effects of histamine on gastric motility and its specific receptor in the circular smooth muscle of the human gastric corpus. Histamine mainly produced tonic relaxation in a concentration-dependent and reversible manner, although histamine enhanced contractility in a minor portion of tissues tested. Histamine-induced tonic relaxation was nerve-insensitive because pretreatment with nerve blockers cocktail (NBC) did not inhibit relaxation. Additionally, K⁺ channel blockers, such as tetraethylammonium (TEA), apamin (APA), and glibenclamide (Glib), had no effect. However, N^G-nitro-L-arginine methyl ester (L-NAME) and 1H-(1,2,4)oxadiazolo (4,3-A) quinoxalin-1-one (ODQ), an inhibitor of soluble guanylate cyclase (sGC), did inhibit histamine-induced tonic relaxation. In particular, histamine-induced tonic relaxation was converted to tonic contraction by pretreatment with L-NAME. Ranitidine, the H₂ receptor blocker, inhibited histamine-induced tonic relaxation. These findings suggest that histamine produced relaxation in circular smooth muscle of human gastric smooth muscle through H₂ receptor and NO/sGC pathways.     

Platelet Aggregation Inhibiting and Anticoagulant Effects of Oligoamines,XXVII Inhibition of Leucocyte Adherence to Endothelium by the Oligoamine RE 1492C and the NO-Donor RE 2047

The oligoamine RE 1492C (N,N′,N″ -4-phenylbutyl-1,3,5-benzene-trimethanamine-N,N′,N″ -triethylcarbamate) inhibited the electrically provoked leucocyte adhesion to the endothelium of rat mesenteric venoles. An oral dose of 60 mg/kg gave a significant inhibition of 65–78%. This is comparable to effects seen after i.v. administration of iloprost or PGE₁, respectively. In the same dosage the NO-donor RE 2047 (3-methyl-N-nitroso-sydnone-5-imine) produced an inhibition of 21–27%.     

Platelet Aggregation Inhibiting and Anticoagulant Effects of Oligoamines,XXV: Interactions of the Oligoamine RE 1492 with Biomembranes

The absorption of D-glucose by rat thymocytes is reduced to half of control by 30 μmol/L and decreased to 10 % by 100 μmol/L of RE 1492. This is backed by the fact that the absorption of 2-deoxy-D -glucose is inhibited in the same extent. The more hydrophilic oligoamine RE 1888 had an analogous but smaller effect while spermine was ineffective. In a lipid peroxidation model RE 1492 or spermine in a concentration of 100 μmol/L nearly completely inhibited for formation of Fe³⁺ ions when the phospholipid was mimicked by adenosine monophosphate. This suggests an interaction with negatively charged membrane phospholipids. RE 1888 had an equal but smaller effect. The effect of RE 1492 on lipid order and lipid motility was checked on ovine lymphocyte membranes by fluorescence polarization measurements. The steady state as well as the limiting anisotropy as an expression for lipid order is decreased by rising concentrations of RE 1492. The use of several anthroyloxy stearic acids as fluorescent probes also shows an increased lipid motility in several areas of the membrane bilayer. The use of fluorescent parinaric acids suggests that areas of high regularity, i.e. liquid crystal formation are involved, too.     

Potentiation of Carrageenan-Induced Rat Paw Edema by Natural Honey: Possible Role of Nitric Oxide and its Clinical Implication

The effect of subplanter injection of honey alone or in combination with carrageenan in the rat paw was investigated. Paw volume was measured at different time intervals (0.5, 1, 2, 3 or 6 h) by using a plethysmometer. Injection of 0.1 ml of (10 or 20%) honey dose-dependently caused edema formation and maximum effects were observed at 1 h after injection. Similarly, injection of 0.1 ml of 1% carrageenan caused gradual increase in paw volume and maximum value was obtained at 6 h. Co-administration of either 10 or 20% honey with carrageenan resulted in significantly greater edema formation as compared to the values obtained with carrageenan alone for a period up to 2 h. Pre-treatment of rats with intraperitoneal injection of a nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (12.5 mg/kg) significantly reduced the paw edema that was obtained with honey alone or in combination with carrageenan for up to the period of 2 h only, whereas a dose of 6.25 mg/kg or enantiomer NG-nitro-D-arginine methyl ester (12.5 mg/kg) did not cause significant inhibition of edema formation. These results suggest that endogenous nitric oxide may be involved in the edematogenic response of honey. It is suggested that honey may activate nitric oxide system and this property of honey may be relevant for its effectiveness in healing of superficial open wounds.     

Platelet Aggregation Inhibiting and Anticoagulant Effects of Oligoamines,XXVIII: Oligoamines with Fluorescent Properties. Part C: Fluorescent Oligoamines with Enhanced Hydrophilic Properties

Fifteen fluorescent oligoamines with one or two fluorescent groups and two or three basic N-functions were prepared and tested for antiplatelet activity (Born-test). Five compounds involving three different fluorophores, i.e. 2-fluorenyl, 1-pyrenyl, and 9-phenanthryl, show an IC₅₀ of 7–11 μmol/L. They are suitable to serve as probes in the field of oligoamine-biopolymere interactions.     

Minocycline Attenuates Depressive‐Like Behaviour Induced by Rat Model of Testicular Torsion: Involvement of Nitric Oxide Pathway

Testicular torsion/detorsion (T/D) can induce depression in pre‐ and post‐pubertal patients. This study was conducted to investigate the psychological impact of testicular torsion and mechanism underlying its depressive‐like behaviour, as well as antidepressant‐like activity of minocycline and possible involvement of nitric oxide (NO)/cyclic GMP pathway in this paradigm in male rats undergoing testicular T/D. Unilateral T/D was performed in 36 male adult Wistar rats, and different doses of minocycline were injected alone or combined with N^ω‐nitro‐l ‐arginine methyl ester (l ‐NAME), non‐specific NO synthase (NOS) inhibitor; aminoguanidine (AG), specific inducible NOS inhibitor; l ‐arginine, an NO precursor; and selective PDE5I, sildenafil. After assessment of locomotor activity in open‐field test, immobility times were recorded in the forced swimming test (FST). Moreover, 30 days after testicular T/D, testicular venous testosterone and serum nitrite concentrations were measured. A correlation was observed between either a decrease in plasma testosterone or an increase in serum nitrite concentrations with prolongation in immobility time in the testicular T/D‐operated rats FST. Minocycline (160 mg/kg) exerted the highest significant antidepressant‐like effect in the operated rats in the FST (p < 0.001). Furthermore, combination of subeffective doses of minocycline (80 mg/kg) and either l ‐NAME (10 mg/kg) or AG (50 mg/kg) demonstrated a significant robust antidepressant‐like activity in T/D group (p < 0.01). Consequently, NO/cGMP pathway was involved in testicular T/D‐induced depressive‐like behaviour and antidepressant‐like activity of minocycline in the animal model. Moreover, a contribution was observed between either decreased testosterone or elevated serum nitrite levels and depressive‐like behaviour following testicular T/D.     

Nitric Oxide Modulates the Acute Increase of Gastrointestinal Transit Induced by Endotoxin in Rats: a Possible Role for Tachykinins

Because of the evidence that endogenous nitric oxide (NO) plays an essential role in the physiological regulation of gastrointestinal motility we have investigated, by use of the NO synthase inhibitor, N^G-nitro-l -arginine methyl ester (l -NAME), the role of endogenous NO in the acute endotoxin-induced changes of gastrointestinal transit. Pre-treatment with E. coli endotoxin (100 μg kg^?, i.v.) induced a significant increase in the gastrointestinal transit of a charcoal suspension in anaesthetized rats. Previous administration of the NO synthase inhibitor, l -NAME (10 mg kg^?, i.v.) significantly prevented the effects of endotoxin. l -arginine (200 mg kg^?, i.v.) and the substance P antagonist [d -Pro², d -Trp^7,9]-substance P (SPA), significantly reversed the effects of l -NAME on gastrointestinal transit in rats treated with endotoxin. Pre-treatment with dexamethasone (5 mg kg^?, s.c., twice), an inhibitor of the expression of inducible NO synthase, did not affect the increase in the gastrointestinal transit through constitutive NO synthesis. The results suggest that constitutive nitric oxide is involved in the increase of gastrointestinal transit induced by endotoxin and that the reduction in transit induced by l -NAME in endotoxin-treated rats is mediated by endogenous tachykinins.     

Platelet Aggregation Inhibiting and Anticoagulant Effects of Oligoamines,XVIII: Oligoamines with Fluorescent Properties,Part B: Fluorophores in the Molecular Periphery

Seventeen N,N′-benzene-1,3-dimethane and nine N,N′,N″-benzene-1,3,5-trimethane derivatives with fluorescent properties have been synthesized. Three of them show antiplatelet activities (inducer collagen, IC50 Born-test) in concentrations < 10 μmol/L. They are suitable for interaction studies with biological macromolecules and synthetical and biological membranes. Structure activity relationships demonstrate that heteropolycyclic fluorophores i.e. quinoline, dibenzofurane, or carbazole are favorable substituents for this purpose.