Effects of l-arginine pretreatment on nitric oxide metabolism and hepatosplanchnic perfusion during porcine endotoxemia

Poeze, Martijn; Bruins, Maaike J.; Kessels, Fons; Luiking, Yvette C.; Lamers, Wouter H.; Deutz, N.E.P.

doi:10.3945/ajcn.110.007237

Cited by 30 publications

(28 citation statements)

References 52 publications

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“…Whole body rate of appearance of de novo arginine was determined with the flux of plasma L-citrulline to L-argininestable isotopes as described previously (32).…”

Section: Methodsmentioning

confidence: 99%

Nitric oxide and l-arginine metabolism in a devascularized porcine model of acute liver failure

Sharma

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Ytrebø

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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In acute liver failure (ALF), the hyperdynamic circulation is believed to be the result of overproduction of nitric oxide (NO) in the splanchnic circulation. However, it has been suggested that arginine concentrations (the substrate for NO) are believed to be decreased, limiting substrate availability for NO production. To characterize the metabolic fate of arginine in early-phase ALF, we systematically assessed its interorgan transport and metabolism and measured the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) in a porcine model of ALF. Female adult pigs (23-30 kg) were randomized to sham (N ϭ 8) or hepatic devascularization ALF (N ϭ 8) procedure for 6 h. We measured plasma arginine, citrulline, ornithine levels; arginase activity, NO, and ADMA. Whole body metabolic rates and interorgan flux measurements were calculated using stable isotope-labeled amino acids. Plasma arginine decreased Ͼ85% of the basal level at t ϭ 6 h (P Ͻ 0.001), whereas citrulline and ornithine progressively increased in ALF (P Ͻ 0.001 and P Ͻ 0.001, vs. sham respectively). No difference was found between the groups in the whole body rate of appearance of arginine or NO. However, ALF showed a significant increase in de novo arginine synthesis (P Ͻ 0.05). Interorgan data showed citrulline net intestinal production and renal consumption that was related to net renal production of arginine and ornithine. Both plasma arginase activity and plasma ADMA levels significantly increased in ALF (P Ͻ 0.001). In this model of early-phase ALF, arginine deficiency or higher ADMA levels do not limit whole body NO production. Arginine deficiency is caused by arginase-related arginine clearance in which arginine production is stimulated de novo.arginine; asymmetric dimethylarginine; arginase ACUTE LIVER FAILURE (ALF) is characterized by sudden and severe liver dysfunction with rapid progression to coagulopathy, encephalopathy, and multiorgan failure. Without liver transplantation, mortality from ALF is about 50% (4). A hallmark of ALF is the presentation of systemic hypotension and a hyperdynamic circulation (39). This is associated with increased guanylate cyclase (GC) activation by nitric oxide (NO) (33), which converts guanidine triphosphate to cyclic guanidine monophosphate and is thought to cause the vasodilatation seen in ALF (34). Previously, we have reported the characteristics of the same devascularized porcine liver model of ALF, which was shown to have a hyperdynamic circulation as evidenced by a high cardiac output and low mean arterial pressure and systemic vascular resistance (50). However, in this hyperacute model of ALF, no significant changes in the metabolites of NO were observed. Indeed, the kinetics of NO in this model and whether it is involved in the initiation of the vasodilation of ALF remain unknown.L-Arginine has several important biological functions (2, 3, 5), one of which is to be the nitrogen-donating substrate for endothelial NO synthase (eNOS) to produce NO and citrulline in stoichiometric quantities (...

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“…Whole body rate of appearance of de novo arginine was determined with the flux of plasma L-citrulline to L-argininestable isotopes as described previously (32).…”

Section: Methodsmentioning

confidence: 99%

Nitric oxide and l-arginine metabolism in a devascularized porcine model of acute liver failure

Sharma

Have

Ytrebø

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…There are two different isotypes of arginase; arginase-I and arginase-II. The cytosolic arginase-I is highly expressed constitutively in the liver, which accounts for 20% of the whole body conversion of arginine into ornithine [ 74 , 75 ]. Furthermore, arginase-I is also expressed in macrophages [ 65 , 76 , 77 ] and endothelial cells [ 76 , 78 , 79 , 80 , 81 ].…”

Section: Arginine During Physiological Conditionsmentioning

confidence: 99%

“…l -arginine supplementation exhibited beneficial effects on the arginine concentrations without deleterious side effects in an endotoxemia model in pigs. Furthermore, in this model, pre-treatment with arginine prior to endotoxemia induction resulted in an increased hepatosplanchnic perfusion and enhanced NO production compared to untreated endotoxemic animals [ 75 ]. In addition, l -arginine supplementation not only enhances the immune response, but also the protein turnover in endotoxemic pigs [ 205 ] and resulted in elevated whole-body NO synthesis without adverse effects [ 286 ].…”

Section: Enhancement Of Arginine and Citrulline Availability In Sementioning

confidence: 99%

Arginine and Citrulline and the Immune Response in Sepsis

et al. 2015

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Arginine, a semi-essential amino acid is an important initiator of the immune response. Arginine serves as a precursor in several metabolic pathways in different organs. In the immune response, arginine metabolism and availability is determined by the nitric oxide synthases and the arginase enzymes, which convert arginine into nitric oxide (NO) and ornithine, respectively. Limitations in arginine availability during inflammatory conditions regulate macrophages and T-lymfocyte activation. Furthermore, over the past years more evidence has been gathered which showed that arginine and citrulline deficiencies may underlie the detrimental outcome of inflammatory conditions, such as sepsis and endotoxemia. Not only does the immune response contribute to the arginine deficiency, also the impaired arginine de novo synthesis in the kidney has a key role in the eventual observed arginine deficiency. The complex interplay between the immune response and the arginine-NO metabolism is further underscored by recent data of our group. In this review we give an overview of physiological arginine and citrulline metabolism and we address the experimental and clinical studies in which the arginine-citrulline NO pathway plays an essential role in the immune response, as initiator and therapeutic target.

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“…Several animal studies supplementing arginine prior to the onset of sepsis and/or predominantly using enteral or low-dose intravenous supplementation, show favorable effects on markers of immunological function ( 58 , 59 ), bacterial invasion ( 60 ), gut bacterial translocation ( 61 , 62 ), and physiological parameters ( 63 ). Notably, the differential effects on mucosal immune parameters and macrophage phagocytic activity of enteral arginine supplementation before caecal ligation and puncture vs. intravenous arginine administration after caecal ligation and puncture, were shown in a model of rat sepsis ( 64 , 65 ).…”

Section: Does An Arginine Deficiency State Contribute To Clinical Sepmentioning

confidence: 99%

Arginine depletion increases susceptibility to serious infections in preterm newborns

2014

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Preterm newborns are highly susceptible to bacterial infections. This susceptibility is regarded as being due to immaturity of multiple pathways of the immune system. However, it is unclear whether a mechanism that unifies these different, suppressed pathways exists. Here, we argue that the immune vulnerability of the preterm neonate is critically related to arginine depletion. Arginine, a “conditionally essential” amino acid, is depleted in acute catabolic states, including sepsis. Its metabolism is highly compartmentalized and regulated, including by arginase-mediated hydrolysis. Recent data suggest that arginase II-mediated arginine depletion is essential for the innate immune suppression that occurs in newborn models of bacterial challenge, impairing pathways critical for the immune response. Evidence that arginine depletion mediates protection from immune activation during first gut colonization suggests a regulatory role in controlling gut-derived pathogens. Clinical studies show that plasma arginine is depleted during sepsis. In keeping with animal studies, small clinical trials of L-arginine supplementation have shown benefit in reducing necrotizing enterocolitis in premature neonates. We propose a novel, broader hypothesis that arginine depletion during bacterial challenge is a key factor limiting the neonate's ability to mount an adequate immune response, contributing to the increased susceptibility to infections, particularly with respect to gut-derived sepsis.

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Effects of l-arginine pretreatment on nitric oxide metabolism and hepatosplanchnic perfusion during porcine endotoxemia

Abstract: Arginine treatment starting before endotoxemia appears to be beneficial because it improves hepatosplanchnic perfusion and oxygenation during prolonged endotoxemia, probably through an enhancement in NO synthesis, without causing deleterious systemic side effects.

Cited by 30 publications

References 52 publications

Nitric oxide and l-arginine metabolism in a devascularized porcine model of acute liver failure

Nitric oxide and l-arginine metabolism in a devascularized porcine model of acute liver failure

Arginine and Citrulline and the Immune Response in Sepsis

Arginine depletion increases susceptibility to serious infections in preterm newborns

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