Effect of L-NAME on nitric oxide and gastrointestinal motility alterations in cirrhotic rats (original) (raw)

2000

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Abstract

AIM: To investigate the effect of L-NAME on nitric oxide and gastrointestinal motility alterations in cirrhotic rats. METHODS: Rats with cirrhosis induced by carbon tetrachloride were randomly divided into two groups, one(n=13) receiving 0.5mg·kg -1 per day of N-G-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, for 10 days, whereas the other group (n=13) and control (n=10) rats were

Chronic low-dose L-NAME treatment increases nitric oxide production and vasorelaxation in normotensive rats

Physiological research / Academia Scientiarum Bohemoslovaca, 2007

N(G)-nitro-L-arginine methyl ester (L-NAME) is a non-specific nitric oxide (NO) synthase inhibitor, commonly used for the induction of NO-deficient hypertension. The aim of this study was to investigate the effect of chronic low-dose administration of L-NAME on NO production, vascular function and structure of the heart and selected arteries of rats. Adult male Wistar rats were treated with L-NAME in the dose of approximately 1.5 mg/kg/day in drinking water for 8 weeks. Basal blood pressure (BP) of rats (determined by tail-cuff) was 112+/-3 mm Hg. The low-dose administration of L-NAME significantly elevated BP measured on the third and sixth week of treatment vs. controls by approximately 9 % and 12 %, respectively. After this period, BP of L-NAME-treated rats returned to the control values. The relative left ventricular mass, heart fibrosis and collagen III/collagen I ratio were not affected by L-NAME. Similarly, there were no alterations in the cross-sectional area and wall thickn...

Mesenteric vasodilator responses in cirrhotic rats: A role for nitric oxide

Hepatology, 1996

mesenteric endothelial NO is unchanged or possibly di-The contribution of nitric oxide to mesenteric arterial minished. (HEPATOLOGY 1996;23:130-136.) vasodilator responses was investigated in the isolated perfused mesenteric arterial bed of cirrhotic rats (carbon tetrachloride/phenobarbitone; n Å 6). Age-matched (n Å 9) and phenobarbitone-treated rats (n Å 9)

Prolonged bleeding time in experimental cirrhosis: role of nitric oxide

Journal of Hepatology, 1999

Background~Aims: Nitric oxide is a powerful in vitro inhibitor of platelet adhesion and aggregation. Our aim was to investigate whether the in vivo inhibition of nitric oxide release shortens bleeding time, in rats with cirrhosis induced by chronic bile duct ligation. Methods: Mean arterial pressure and bleeding time were measured under basal conditions and 5, 15 and 30 min after administration of vehicle (0.9% saline) or an inhibitor of nitric oxide synthesis, Nw-nitro-Larginine (5 mg/kg, iv). Mean arterial pressure was measured with an intra-arterial catheter and bleeding time with a standardized Simplate device. Results: Cirrhotic rats showed a lower mean arterial pressure (116-+4 mmHg) and a prolonged bleeding time (177-+40 s) compared to control animals (133-+6 mmHg and 95-+12 S, respectively, p<0.01). In cirrhotic rats, Nw-nitro-L-arginine significantly in-creased mean arterial pressure (from 116_+5 to 141_+ 11 mmHg, p<0.05) and completely normalized bleeding time (from 170-+39 to 103-+21 S, p<0.05) 15 min after administration. Pretreatment with L-arginine (300 mg/kg, iv) prevented the hemodynamic and hemostatic changes induced by Nw-nitro-L-arginine. A trend to normalize platelet adhesion was observed in cirrhotic rats after the inhibition of nitric oxide production. In control animals, Nw-nitro-L-arginine increased mean arterial pressure, while no effect on bleeding time was observed. Conclusions: These findings support the concept that nitric oxide may be a mediator in the bleeding time abnormalities associated with experimental cirrhosis.

{"__content__"=>"The Protective Effect of L. in Visceral Hypersensitivity in Rat Using 2 Models of Acid-induced Colitis and Stress-induced Irritable Bowel Syndrome: A Possible Role of Nitric Oxide Pathway.", "i"=>{"__content__"=>"Melissa officinalis"}}

Journal of neurogastroenterology and motility, 2018

The aim of present study is to estimate the effects of L. (MO) on visceral hypersensitivity (VH), defecation pattern and biochemical factors in 2 experimental models of irritable bowel syndrome (IBS) and the possible role of nitric oxide. Two individual models of IBS were induced in male Wistar-albino rats. In the acetic acid model, the animals were exposed to rectal distension and abdominal withdrawal reflex, and the defecation patterns were determined. In the restraint stress model, the colons of rats were removed and the levels of TNF-α, myeloperoxidase, lipid peroxidation, and antioxidant powers were determined. Rats had been treated with MO, L-NG-nitroarginine methyl ester (L-NAME), aminoguanidine (AG), MO + AG, or MO + L-NAME in the mentioned experimental models. Hypersensitive response to rectal distension and more stool defecation in control rats have been observed in comparison to shams. MO-300 significantly reduced VH and defecation frequency in comparison to controls. VH ...

Nitric oxide production in arterial vessels of cirrhotic rats

Hepatology, 1995

Indirect evidence exists implicating vascular nitric oxide in the pathogenesis of arterial vasodilation in cirrhosis. In the current study, a coincubation assay to estimate the vascular nitric oxide production was developed and the nitric oxide production by arterial segments of cirrhotic and control rats was assessed. In the assay, measurement of reporter monolayer cell-associated cGMP levels allows the influence of nitric oxide released by arterial segments to be determined. RFL-6 cells served as reporter cells. Nitric oxide production was determined in thoracic aorta and mesenteric arteries of 22 control rats, 10 cirrhotic rats without ascites, and 12 cirrhotic rats with ascites. Basal and bradykinin-stimulated (10 moYL) intracellular content of nitric oxidedependent cGMF' was significantly higher in RFL-6 cells coincubated with aortic segments of cirrhotic rats with (21.3 -c 3.6 pm01/105 cells, P < .05 and 44.7 2 7 . 0 pmol/105 cells, P < .025) and without ascites (15.3 5 3.0 pmoY105 cells, P < .05 and 43.2 i 7.6 pmol/105 cells, P < .05) than in those incubated with aortic segments of control rats (9.7 i 1.3 and 19.5 I 2.5 pmol/105 cells). RFLS cells exposed to bradykinin-stimulated mesenteric arterial segments of cirrhotic rats also showed increased cGMP content (ascitic: 2.73 ? 0.31 pmol/105 cells, P < .005; nonascitic: 2.58 ? 0.51 pmoY105 cells, P < .025) compared with cells exposed to control mesenteric arterial segments (1.28 t-0.15 pmol/105 cells). No differences between cirrhotic and control vessels were observed after endothelium denudation. These results indicate that basal and bradykinin-stimulated vascular nitric oxide production is higher in cirrhotic rats with and without ascites than in control rats in and that the endothelial lining is the site where vascular L-arginine nitric oxide pathway activation takes place in experimental cirrhosis. (HEPA-TOLOGY 1995; 21:554-560.) Patients and experimental animals with cirrhosis present a circulatory dysfunction characterized by arterial hypotension, marked decrease in peripheral vascular resistance, hypervolemia, and high cardiac output.'" The mechanism of these circulatory abnormalities is an arterial vasodilation, which predominantly takes place in the splanchnic circulation. Splanchnic arterial vasodilation is an important event in cirrhosis. By increasing portal venous inflow, it aggravates portal hypertension., On the other hand, arterial vasodilation is the most likely mechanism of the effective arterial hypovolemia, the activation of the renin-aldosterone and sympathetic nervous systems and antidiuretic hormone, and the impaired renal sodium and water excretion that characterize patients with advanced cirrhosis and ascites.5

Effect of L-NAME on decreased ileal muscle contractility induced by peritonitis in rats

Journal of Pediatric Surgery, 2002

Background/Purpose: It is now well established that intestinal inflammation is associated with disturbed contractility. The aim of this study was to determine the effects of peritonitis on longitudinal ileum smooth muscle responses to KCl, carbachol and substance P (SP) and to examine the role of nitric oxide (NO) and N omega-nitro-L-arginine methylester (L-NAME) on ileal contractility in this peritonitis model. Methods: Peritonitis was induced by cecal ligation and puncture (CLP) in 20 rats. While 10 of these received 1 mL distilled water as placebo, the other 10 received 5 mg/kg (subcutaneously) L-NAME before the operation. Another group of 10 rats underwent a sham operation. Twenty-four hours after the operation, the rats were killed, and their ileum was excised. Ileum segments were placed in longitudinal direction in a 10-mL organ bath; concentration-response relationship for KCl, carbachol, and SP were obtained by adding the reagent cumulatively to the bath. Results: The KCl-, carbachol-, and SP-induced contractions were decreased markedly, with no change in the pD 2 values in the peritonitis group compared with controls. Peritonitisinduced changes in the contractile responses were restored significantly by in vivo L-NAME pretreatment. Conclusions: The model of CLP-induced peritonitis in rats showed that KCl-induced nonreceptor-mediated, carbacholand SP-induced receptor-mediated contractions are significantly decreased by inflammation in the longitudinal ileum muscle. Increased synthesis of NO may be responsible for these decreases in contractile responses because they were restored significantly by in vivo L-NAME injection. Inhibition of NOS with L-NAME injection may afford a new therapeutic approach to the treatment of gastrointestinal stasis in septic patients.

New Issues about Nitric Oxide and its Effects on the Gastrointestinal Tract

Current Pharmaceutical Design, 2001

Over the last years the important role of nitric oxide (NO) as endogenous modulator of numerous physiological functions has been shown. NO is involved in the regulation of blood flow, maintenance of vascular tone, control of platelet aggregation, and modulation of the activity of the mastocytes. It also plays a key role as neurotransmitter in the central and peripheric nervous system (non adrenergic non colinergic, NANC, neurons), in the nervous control of the cerebral blood flow and in the neuroendocrine regulation or synaptic plasticity. However, NO shows a dual behavior: at physiological concentrations, released through the constitutive synthase (cNOS), it regulates house-keeping functions, whereas its overproduction by the inducible isoenzyme (iNOS) exhibits cytotoxic activity because interacting with reactive species producing peroxinitrites (ONOO • ) and other compounds, which are highly damaging for the tissues.

Increased aortic cyclic guanosine monophosphate concentration in experimental cirrhosis in rats: Evidence for a role of nitric oxide in the pathogenesis of arterial vasodilation in cirrhosis

Hepatology, 1995

Arterial vasodilation is considered to be the key factor in the development of sodium and water retention leading to ascites formation in cirrhosis. To determine if nitric oxide (NO) is involved in the pathogenesis of arterial vasodilation in cirrhosis, we measured the concentration of cyclic guanosine monophosphate (cGMP), the second messenger of NO, in arterial tissue from rats with carbon tetrachloride-induced cirrhosis. Aortic cGMP concentration was markedly increased in cirrhotic rats, particularly in those with ascites (ascites, 826 _+ 70; no ascites, 597 _+ 48; controls, 331 _+ 25 filaol/mg, ANOVA F = 23.1, P < .0001), and correlated inversely with arterial pressure (r = -.56, P < .0001) and systemic vascular resistance (r = -.69, P = .014) and directly with cardiac index (r = .74, P < .01). The chronic administration of the NO synthesis inhibitor Na-nitro-L-arginine-methylester (L-NAME) (10 mg/kg/day for 7 days) induced a marked reduction in aortic cGMP concentration in cirrhotic rats with ascites to similar values obtained in L-NAME-treated control rats (86 _+ 14 vs. 89 _+ 8 fmol/mg, respectively, NS), indicating that the high-aortic cGMP content in cirrhotic rats was caused by an increased NO synthesis. Mean arterial pressure after L-NAME treatment increased to similar values in both groups of animals. These results suggest that in cirrhosis there is an increased vascular production of NO that may play a role in the pathogenesis of arterial vasodilation. (HEPA-TOLOGY 1995;21:1625-1631.)

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Effects of L-Arginine and L-NAME on Duodenal Histologic Parameters in Female Wistar Rats

Introduction: Nitric oxide (NO), as a free radical, involves in several physiologic functions in GI tract such as nerve impulse transmission and vascular tonicity regulation. Nitric oxide synthase (NOS) is the enzyme for the production of NO from L-Arginine which in turn inhibits by L-NGNitroarginine Methyl Ester (L-NAME). In the current work, we aimed to evaluate morphometric analysis of duodenum under exposure of L-Arginine and L-NAME in female Wistar rats. Methods: In this study, 5 groups (N=8) of 40 female rats (200-250 g, 8 weeks age) were chosen. Normal saline (2 mL/kg), L-Arginine (200 mg/kg), L-NAME (20 mg/kg) and L-Arginine+LNAME (with the same doses) were administered intraperitoneal — for 3 days. After 2 weeks, samples were collected, stained with hematoxylin and eosin (H&E) and observed under light microscopy. Duodenal epithelial cell height and number, gland diameter, and submucosal and muscular thicknesses were measured using optical software and analyzed by one-way ANOVA followed by Tukey’s post hoc test using SPSS-16. P≤ 0.05 was considered statistically significant. Results: There were no significant changes in mean variables compared to the control group. Conclusion: The results attested no noticeable changes in regard with the effects of L-arginine and L-NAME on duodenum parameters despite the major roles of NO in GI tract.

Modulation of the hyperdynamic circulation of cirrhotic rats by nitric oxide inhibition

Gastroenterology, 1992

The effects of A7c-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide (NO) biosynthesis on the splanchnic and systemic circulation, were investigated in rats with cirrhosis induced by carbon tetrachloride. Portal hypertension in these rats was accompanied by decreased arterial blood pressure and peripheral vascular resistance as well as by splanchnic vasodilation with increased portal venous inflow and decreased splanchnic resistance. Intravenous bolus administration of L-NMMA (25 mg/kg) significantly increased systemic blood pressure and decreased cardiac output. L-NMMA also significantly increased systemic and splanchnic vascular resistance; whereas blood flow to the stomach, small intestine, colon, pancreas, mesentery, spleen, and kidney was decreased significantly. L-NMMA did not alter the portal pressure or portosystemic shunting in these cirrhotic rats, yet portal vascular resistance increased, suggesting effects on the intrahepatic and collateral circulation. Pretreatment with L-arginine (300 mg/kg) prevented the hemodynamic changes induced by L-NMMA. These findings support the concept that local excess formation of NO contributes to changes in splanchnic circulation associated with portal hypertension in cirrhosis.

Upregulation of muscarinic receptors by long‐term nitric oxide inhibition in the rat ileum

Clinical and …, 2003

1. The aim of the present study was to examine the effects of long-term nitric oxide (NO) blockade on contractions of the rat ileum induced by muscarinic agonists. 2. Male Wistar rats received the NO synthesis inhibitor N G-nitro-L-arginine methyl ester (L-NAME; 20 mg/rat per day) in drinking water for 7, 15, 30 and 60 days. Concentrationresponses curves to methacholine and carbachol were obtained and pEC 50 values were calculated. Saturation binding assays were performed in membranes prepared from rat ileum after 60 days of L-NAME treatment and the dissociation constant (K D) and maximal number of binding sites (B max) were determined by Scatchard analysis. 3. The NO synthase activity of the ileum was markedly reduced in all L-NAME-treated groups. At 60 days after L-NAME treatment, a significant increase in the potency of methacholine (fourfold) and carbachol (threefold) was observed. In binding studies, we found a significant increase in B max for [ 3 H]-quinuclidinyl benzilate of approximately 57% in the L-NAME treated group without any significant change in K D values. The contractile response to methacholine was not modified by the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (3 mol/L). No morphological alterations in the rat ileum were observed in L-NAME-treated rats. 4. Our findings suggest that treatment with L-NAME for 60 days induces a marked increase in the potency of methacholine and carbachol, as well as an increase in receptor number in the rat ileum. Key words: contractile response, nitric oxide synthase, N G-nitro-L-arginine methyl ester, non-adrenergic noncholinergic fibres. Tissue preparation Rats were anaesthetized with halothane and exsanguinated. Ileal segments were taken 10 cm from the ileocaecal junction and washed with Krebs'-Henseleit solution (pH 7.3-7.5) with the following composition (in mmol/ L): NaCl 117; KCl 4.7; CaCl 2 2.5; MgCl 2 1.2; NaH 2 PO 4 1.2; NaHCO 3 25; glucose 11.

NG-nitro-L-arginine methyl ester modulates intestinal secretion and motility produced by carbachol

European journal of pharmacology, 1994

The effects of the nitric oxide (NO) synthesis inhibitor, NG-nitro-L-arginine methyl ester, on carbachol-induced diarrhoea, fluid accumulation and motility changes were studied. Pretreatment of mice with NG-nitro-L-arginine methyl ester (1-25 mg/kg i.p.) and NG-nitro-L-arginine (2.5-50 mg/kg i.p.) but not NG-nitro-D-arginine methyl ester (25 mg/kg i.p.) prevented in a dose-related manner the carbachol (0.5 mg/kg i.p.)-induced diarrhoea in mice. L-Arginine (150-1500 mg/kg i.p.) administered to mice pretreated with NG-nitro-L-arginine methyl ester counteracted the antidiarrhoeal activity of NG-nitro-L-arginine methyl ester in a dose-related manner. Pretreatment of rats with NG-nitro-L-arginine methyl ester (2.5-25 mg/kg i.p.) decreased the intestinal fluid accumulation induced by carbachol in rats. NG-Nitro-D-arginine methyl ester was without effect. Intraperitoneal pretreatment of rats with NG-nitro-L-arginine methyl ester (2.5-25 mg/kg) reduced the increase in small intestinal trans...

Nitric Oxide Synthase 3Dependent Vascular Remodeling and Circulatory Dysfunction in Cirrhosis

American Journal of Pathology, 2003

Vascular remodeling is an active process that consists in important modifications in the vessel wall. Endothelium-derived nitric oxide (NO) plays a major role in this phenomenon. We assessed wall thickness (WT), total wall area (TWA), lumen diameter, and total nuclei number/cross-section (TN) in cirrhotic rats with ascites and in control rats. A second group of cirrhotic rats received the NO synthesis inhibitor, L-NAME, or vehicle daily for 11 weeks and systemic hemodynamics, arterial compliance, aortic NO synthase 3 (NOS3) protein expression, and vascular morphology were analyzed. Cirrhotic vessels showed a significant reduction in WT, TWA, and TN as compared to control vessels. Long-term inhibition of NOS activity in cirrhotic rats resulted in a significant increase in WT, TWA, and TN as compared to cirrhotic rats receiving vehicle. NOS3 protein abundance was higher in aortic vessels of nontreated cirrhotic animals than in controls. This difference was abolished by chronic treatment with L-NAME. NOS inhibition in cirrhotic rats resulted in higher arterial pressure and peripheral resistance and lower arterial compliance than cirrhotic rats receiving vehicle. Therefore, vascular remodeling in cirrhosis with ascites is a generalized process with significant functional consequences that can be negatively modulated by long-term inhibition of NOS activity.

The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough

Hepatology (Baltimore, Md.), 2002

C hronic liver diseases are often characterized by portal hypertension, an important component of which is increased intrahepatic vascular resistance (IHVR). We have long understood that structural changes, viewed by light microscopy, are largely irreversible with our current therapeutic tools. In supplementing liver histology with liver and vascular physiology, we have encountered the existence of dynamic, nonstructural components that are in fact, reversible.

Nitric oxide synthases inhibition results in renal failure improvement in cirrhotic rats

Abstract: Nitric oxide (NO) has been implicated in cirrhosis and might be implicated in renal failure end-stage cirrhosis. Aim: Our aim was to evaluate NO role in renal failure induced during decompensated cirrhosis, using the following inhibitors: aminoguanidine (AG), a specific inducible nitric oxide synthase (iNOS) inhibitor and NG-nitro-L-arginine methyl ester (L-NAME), a nonselective blocker of NOS isoforms. Methods: Endothelial (eNOS) and iNOS gene expression was analyzed by reverse transcriptase-polymerase chain reaction. Cirrhotic rats received a single intragastric dose of CCl4 to induce acute liver damage (ALD). Results: After ALD, aspartate aminotransferase highest levels were observed in rats treated with AG and ALT in rats treated with L-NAME. Inhibitors decreased creatinine serum levels to normal values and serum sodium levels re-established after the third day of ALD. L-NAME diminished (Po0.05) eNOS RNA renal expression. Renal iNOS with no inhibitor was overexpressed but was down-regulated by AG treatment. Liver eNOS RNA expression had a decreased expression before ALD in cirrhotic rats, but L-NAME treatment down-regulated eNOS after ALD. AG induced an important iNOS liver decrease. Conclusion: Both inhibitors improved renal function, although AG displayed a better effect and did not aggravate liver function. We concluded that NOS isoforms are implicated in the renal pathophysiologic events induced by ALD.

Inhibitors of nitric oxide synthase enhance rat ileum contractions induced by ricinoleic acid in vitro

European Journal of Pharmacology, 1993

The effects of N~-nitro-L-arglnine methyl ester (L-NAME) and N°-monomethyl-L-argmine (L-NMMA), inhibitors of mtrlc oxide (NO) synthase, were studied on ricinoleic acid-evoked contractions in rat isolated ileum. Rlcinoleic acid (10 -5 to 10 -4 M) caused a concentration-dependent contraction. Addition of L-NAME (30-300/zM) or L-NMMA (30-300/xM) to the Tyrode's solution increased in a concentration-dependent fashion the amplitude of the ricinolelc acid-evoked responses. L-Arginine (900 /zM), a natural substrate of NO synthase, but not D-arginine (900 /zM), counteracted the effect of L-NAME (300 /xM). The potentiating effect of L-NAME was also prevented by sodium nitroprusside (0.1-1 /zM), a generator of NO. These results provide evidence that endogenous NO may modulate the contraction of rat deum induced by ricinolelc acid. As the contraction induced by ncinoleic acid is not blocked by tetrodotoxin (0.6 and 6.0/zM) the contractile effect of ricinoleic acid results mainly from a direct action on the smooth muscle.

The role of nitric oxide in the pathogenesis of systemic and splanchnic vasodilation in cirrhotic rats before and after the onset of ascites

Liver International, 2005

Angeli P, Ferna´ndez-Varo G, Dalla Libera V, Fasolato S, Galioto A, Arroyo V, Sticca A, Guarda S, Gatta A, Jime´nez W. The role of nitric oxide in the pathogenesis of systemic and splanchnic vasodilation in cirrhotic rats before and after the onset of ascites. Liver International 2005: 25: 429-437. r Blackwell Munksgaard 2005