nitroarginine and Ascites

Experiments in vitro were performed to investigate the effects of the nitric oxide donor (SNP), the substratum of NO-synthase (L-arginine), and the inhibitor of NO-synthase (nitroarginine) on the ROS-generating activity of blood plasma polymorphonuclear leucocytes and ascitic fluid macrophages isolated at different times of tumor (Zaidel hepatoma) growth in animal organism. It was found that in the initial period of tumor growth the nitric oxide donor at a concentration of 8 x 10(-5) M reduced the potential ROS-generating activity of macrophages by 38.5 +/- 9.0% and that of polymorphic-nuclear leucocytes of plasma by 27.6 +/- 7.0 %. However, the dynamics of this process during tumor growth was conservative: variations in the production of ROS by phagocytes were 10 +/- 3.0%. L-arginine induced a decrease in the ROS-generating activity of granulocytes and mononucleares by 25-30%. This fact points to an inducible inhibiting effect of NO-synthase on the ROS-generating activity of NADPH-oxidase in the course of tumor growth. The inhibitor of NO-synthase, nitroarginine, produced a monotonous increase in the ROS-generating activity of phagocytes isolated from the tumor at different periods of its growth. The use NO-synthase inhibitors for increasing ROS levels in the region of tumor growth may favor the suppression of tumor cell growth in vivo.

Topics: Animals; Arginine; Ascites; Liver Neoplasms; Liver Neoplasms, Experimental; Macrophages; Male; NADPH Oxidases; Neutrophils; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase Type II; Nitroarginine; Nitroprusside; Rats; Rats, Wistar; Reactive Nitrogen Species; Reactive Oxygen Species; Up-Regulation

Recent work indicates that nitric oxide (NO) plays an important role in the systemic and renal alterations of liver cirrhosis. This study used aminoguanidine (AG), a preferential inhibitor of inducible nitric oxide synthase (iNOS), to evaluate the role of this NOS isoform in the systemic and renal alterations of an experimental model of liver cirrhosis with ascites (carbon tetrachloride/ phenobarbital). Experiments have been performed in anesthetized cirrhotic rats and their respective control rats prepared for clearance studies. Administration of AG (10 to 100 mg/kg, iv) elevated dose-dependent mean arterial pressure (MAP, in mm Hg) in the cirrhotic rats from a basal level of 79.3 +/- 3.6 to 115.0 +/- 4.7, whereas in the control animals, MAP increased only with the highest dose of the inhibitor (from 121.8 +/- 3.6 to 133.3 +/- 1.4). In the cirrhotic group, AG also significantly increased sodium and water excretion, whereas these effects were very modest in the control group. Plasma concentration of nitrates+nitrites, measured as an index of NO production, were significantly increased in the cirrhotic animals in the basal period and decreased with AG to levels not significantly different from the control animals. Similar experiments performed with the nonspecific NOS inhibitor N omega-nitro-L-arginine (NNA) also demonstrated an increased pressor sensitivity of the cirrhotic rats, but the arterial hypotension was completely corrected. These results, in an experimental model of liver cirrhosis with ascites, show that AG exerts a beneficial effect as a result of inhibition of NO production, increasing blood pressure and improving the reduced excretory function. Because NNA, but not AG, completely normalized the arterial hypotension, it is suggested that the constitutive NOS isoform is also contributing in an important degree. It is concluded that the activation of both inducible and constitutive NOS isoforms plays an important role in the lower systemic blood pressure and associated abnormalities that characterize liver cirrhosis.

Topics: Animals; Ascites; Blood Pressure; Enzyme Inhibitors; Guanidines; Kidney; Liver Cirrhosis, Experimental; Male; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Rats; Rats, Sprague-Dawley

To assess whether aortic vessels of rats with cirrhosis and ascites possess an enhanced vascular response to endothelium-derived, nitric oxide-dependent vasodilators, we performed relaxation studies in isolated aortic rings of 21 control rats and 24 rats with carbon tetrachloride-induced cirrhosis and ascites. We carried out studies after contracting the vessels with norepinephrine. We measured endothelium-dependent vasodilator response by administering increasing concentrations of acetylcholine (10(-6) to 10(-2) mol/L) and ADP (10(-7) to 10(-4) mol/L). We evaluated endothelium-independent response by giving increased concentration of sodium nitrite (10(-5) to 10(-2) mol/L). The maximal absolute tension developed in response to norepinephrine was significantly decreased in cirrhotic rings (816 +/- 72 mg, p < 0.025) compared with control (1,425 +/- 75 mg) rings. Dose-response curves for endothelium-dependent vasodilators were shifted to the left in aortic rings of cirrhotic rats, and EC50 for acetylcholine and ADP were significantly decreased in cirrhotic (0.8 +/- 0.15 mmol/L and 0.42 +/- 0.16 mumol/L, p < 0.025 and p < 0.01, respectively) than in control rings (1.91 +/- 0.33 mmol/L and 3.09 +/- 0.82 mumol/L). In both acetylcholine- and ADP-stimulated vessels, differences between cirrhotic and control rings disappeared after nitric oxide synthesis inhibition with N omega-nitro-L-arginine (10(-4) mol/L). No difference in the relaxing effect of sodium nitrite was observed between cirrhotic and control rings. These results therefore demonstrate for the first time enhanced in vitro vascular responsiveness to nitric oxide-dependent vasodilators in rats with cirrhosis and ascites, giving further support to the concept that nitric oxide activity is increased in cirrhosis.

Topics: Acetylcholine; Adenosine Diphosphate; Amino Acid Oxidoreductases; Analysis of Variance; Animals; Aorta; Arginine; Ascites; In Vitro Techniques; Liver Cirrhosis, Experimental; Male; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Norepinephrine; Rats; Rats, Wistar; Regression Analysis; Sodium Nitrite; Vasodilation

Nitric oxide is a vasodilator tonically secreted by endothelial cells that is involved in the regulation of arteriolar tone. This study, which includes two protocols, was performed to investigate whether nitric oxide plays a role in the pathogenesis of arterial hypotension in cirrhosis with ascites. In protocol 1, the administration of increasing doses (25, 50, 250, 500 and 1,000 micrograms.kg-1.min-1) of the nitric oxide biosynthesis inhibitor N omega-nitro-L-arginine to 18 conscious rats with cirrhosis and ascites produced, at each dose tested, a significantly greater increase in arterial pressure than in 17 conscious control rats. At the lowest dose of N omega-nitro-L-arginine, arterial pressure significantly rose in cirrhotic rats but not in controls. In protocol 2, arterial pressure, estimated renal plasma flow, glomerular filtration rate and sodium excretion were measured in 12 cirrhotic rats with ascites and 10 control rats before and during the sequential infusion of previously selected doses of N omega-nitro-L-arginine (25, 50 and 250 micrograms.kg-1.min-1). Changes in arterial pressure reproduced those observed in protocol 1. In control rats, N omega-nitro-L-arginine caused a decrease in estimated renal plasma flow without affecting glomerular filtration rate or sodium excretion. In contrast, N omega-nitro-L-arginine administration to cirrhotic animals did not produce any appreciable renal vasoconstrictor effect, and it increased glomerular filtration rate and sodium excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arginine; Arteries; Arterioles; Ascites; Hemodynamics; Hypotension; Kidney; Liver Cirrhosis, Experimental; Male; Nitric Oxide; Nitroarginine; Rats; Rats, Inbred Strains; Renal Circulation; Sodium; Vasodilation