Nitric oxide formation lowers norepinephrine-induced intrahepatic resistance without major effects on the metabolism in the perfused rat liver

✍ Scribed by H Weidenbach; A K Nussler; Z Shu; G Adler; K Beckh

• Publisher: John Wiley and Sons
• Year: 1997
• Tongue: English
• Weight: 296 KB
• Volume: 26
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.510260120

✦ Synopsis

shown to function as a cell-signaling molecule in the regula-Nitric oxide (NO) and norepinephrine are potent vasoactive tion of vascular tone. 3,4 agents that are involved in the control of portal blood flow.

The second NOS isoform, the inducible NOS (NOS2) (for We have studied NO and norepinephrine in a non-recirculated review, see Nathan 5 , Nussler 6 ) is expressed after exposing rat liver perfusion to analyze their influence on portal flow cells or mammals to various pathogens, such as bacterial and hepatic metabolism. Animals were either pretreated with products (endotoxin), or inflammatory cytokines. 7,8 Inducendotoxin (4 hours; 10 mg/kg intraperitoneally) to activate tion of the NOS2 in response to inflammatory stimuli has the inducible NO synthase (NOS2), or used without pretreatbeen shown in the liver for all major hepatic cell types. 9,10 ment for the constitutive NO synthase (NOS3). In both This isoform is Ca // -independent and synthesizes NO for groups, portal flow, bile flow, bile secretion, and the sinusoiextended periods and in high concentrations. 11-13 dal bile acid uptake were reduced by norepinephrine with It has been suggested that vascular tone is actively maina simultaneous increase of glucose and lactate output. The tained by a balance of vasoconstrictive and vasodilatory stimaddition of the substrate for NO synthesis, L-arginine (0.5 uli. 13 While NO is probably the most potent vasodilator, mmol/L), to the perfusate markedly inhibited the effect of 0.1 norepinephrine is one of the strongest vasoconstrictors. In mmol/L norepinephrine on portal flow from 02.6 { 0.32 to the liver, norepinephrine is released by sympathetic nerves 0.3 { 0.1 mL/g/10 min in endotoxin-treated animals, and from and has pronounced effects on carbohydrate metabolism and 02.9 { 0.45 to 0.77 { 0.29 mL/g/10 min in the untreated bile secretion. [14][15][16] However, it remains uncertain how norepiones. In contrast, neither NO formation after L-arginine supnephrine interferes with the balance of sinusoidal tonus and plementation nor inhibition of NO synthesis via the structural metabolism. There is controversial evidence for the proposal analogue (N G -monomethyl-L-arginine [L-NMMA]) changed that norepinephrine has direct effects on the hepatic bile cholestatic and glycogenolytic effects caused by norepinephformation, and that the alterations observed are not secondrine. Only the sinusoidal bile acid uptake was reduced followary to the increase of the intrahepatic resistance. 14,17,18 ing increased NO formation. Thus, we conclude that endoge-

The present study investigated whether NO formation or nous NO formation prevents a-catecholaminergic-increased inhibition alters norepinephrine effects in a single-pass liver intrahepatic resistance without a major influence on the metaperfusion model under constant perfusion pressure condibolic effects. (HEPATOLOGY 1997;26:147-154.) tions. We perfused livers of untreated and endotoxin-pretreated animals. Our data indicate that the norepinephrineincreased hepatic resistance was significantly affected by NO, Nitric oxide (NO) has been recognized to play a pivotal role in the homeostatic control of blood pressure and micro-whereas a-catecholaminergic-associated metabolic effects were unaffected with the exception of the sinusoidal bile acid vascular blood flow. NO is only synthesized from its natural substrate, the amino acid, L-arginine, by NO synthase (NOS). transport. In the liver, at least two different isoforms of NOS have been

Methods

identified. One of them, termed endothelial constitutive NOS (NOS3) is constantly present and produces relatively small Materials. Phenol-extracted lipopolysaccharide from Escherichia amounts of NO. 1,2 NOS3 is Ca // /calmodulin-dependent and coli (serotype 026:B6) were used as endotoxin. L-Arginine, N G - accounts for a rapid increase of NO in response to hormonemonomethyl-L-arginine (L-NMMA), and norepinephrine were ob- tained from Sigma Chemical Co. (St. Louis, MO), and 14 C-taurocho-receptor interactions. NO released by this isoform has been late ( 14 C-TC) was obtained from DuPont-New England Nuclear (Boston, MA). All other chemicals and reagents were of the highest purity available and were from a commercial source (Sigma Chemi-Abbreviations: NO, nitric oxide; NOS, nitric oxide synthase; NOS3, constitutive cal). nitric oxide synthase; NOS2, inducible nitric oxide synthase; L-NMMA, N G -mono-Animals and Experimental Protocol. Male Wistar rats (200-250 g methyl-L-arginine; 14 C-TC, 14 C-taurocholate; PBS, phosphate-buffered saline. body weight) from the breeding colony of the University of Ulm From the Departments of