T. Teerlink

Organ blood flow and distribution of cardiac output in dopexamine- or dobutamine-treated endotoxemic rats.

Endotoxemia causes a decrease of blood flow to most organs. If this could be prevented, chances of survival might improve. In endotoxemic rats, we studied the effect of a therapeutic infusion of dopexamine (dopaminergic, beta 2-adrenergic) on blood flow and percentage of the cardiac output distributed to heart, brain, hepatic artery, stomach, intestines, spleen, pancreas, kidneys, adrenals, diaphragm, skeletal muscle, and skin. Dopexamine action was compared with that of dobutamine (beta 1-adrenergic). Endotoxin shock was induced in 28 rats with infusion of 8 mg/kg Escherichia coli O127:B8 endotoxin from 0 to 60 minutes; the rats were then divided into 3 groups, which received from 60 to 135 minutes of an infusion of saline (ES; n = 10), dopexamine hydrochloride (DX, 3 x 10(-8) mol/kg.min; n = 10) or dobutamine (DB, 10(-7) mol/kg.min; n = 8). A fourth group served as time-matched controls (C, saline from 0 to 135 minutes; n = 8). In the untreated endotexemic rats, cardiac output decreased and organ blood flow decreased except in the diaphragm, heart, and brain; the percentage of the cardiac output to those organs increased. Dopexamine and dobutamine similarly improved cardiac output in endotoxemic rats. All organs benefitted to the same extent from the increased cardiac output. Therapeutic infusion of dopexamine during endotoxemia did not favor flow to any particular organ; redistribution of cardiac output changed little after administration of dopexamine, and its effects were not significantly different from those of dobutamine.

Dietary glutamine supplementation reduces plasma nitrate levels in rats

It was recently shown that L-glutamine inhibits vascular nitric oxide (NO) production in vitro. The present study investigated the effect of glutamine enriched enteral diets on in vivo NO production in the rat. Nitrate, the stable end-product of NO production, was measured in plasma and 24 h urine collections in glutamine supplemented rats (6.25%, 12.5% and 25% w/w) and compared to the effect of isocaloric, nitrogenous control diets. Glutamine supplementation increased plasma levels of glutamine (up to 91%), arginine (up to 17%) and citrulline (up to 54%). After 1 week of glutamine supplementation plasma nitrate levels were significantly reduced by 50% compared to control (P < 0. 0001); irrespective of the amount of supplementation. No further decrease was observed after 2 weeks of feeding. No differences in daily urinary losses were found between the groups. These results point to an in vivo inhibitory effect of glutamine supplemented enteral feeding on NO production.

Alzheimer's disease is not associated with altered concentrations of the nitric oxide synthase inhibitor asymmetric dimethylarginine in cerebrospinal fluid

Summary. Nitric oxide (NO) may play a role in the pathophysiology of Alzheimers disease (AD). Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, is involved in regulation of NO production. Recently it has been reported that dimethylarginine dimethylaminohydrolase, an enzyme that hydrolyses ADMA into citrulline and dimethylamine, is specifically elevated in neurons displaying cytoskeletal abnormalities and oxidative stress in AD. We hypothesized that this could lead to altered CSF concentrations of ADMA in AD. Measurement of ADMA and dimethylamine in CSF revealed no significant differences between AD patients (n = 20) and age-matched control subjects (n = 20). Our results suggest that in early stages of AD overall regulation of NO production by ADMA is not aberrant.

Low arginine plasma levels in patients after thoracoabdominal aortic surgery

Objective: Thoracoabdominal aortic surgery is a high-risk procedure and associated with a significant morbidity and mortality. Ischemia reperfusion of visceral organs and lower extremities is one of the most important determinants of this morbidity. Arginine is the precursor of nitric oxide and arginine plasma levels are important in maintaining organ blood flow. Furthermore, arginine is important in wound healing and the immune system. Because of increased utilization of arginine, low arginine plasma levels could be expected after thoracoabdominal aortic surgery. We therefore measured arginine plasma levels in these patients.Design: Six patients with thoracoabdominal aortic aneurysm were included in this study.Setting: University Hospital Vrije Universiteit, Department of Surgery, Amsterdam, The Netherlands.Subjects: Six patients undergoing thoracoabdominal aortic surgery.Intervention: Plasma levels of arginine were measured by high-performance liquid chromatography.Results: Very low arginine plasma levels were seen on the first postoperative day. From day 1 arginine slowly increased, but did not reach normal plasma levels on day 6.Conclusions: A significant decrease of arginine plasma levels was found and because of the fact that arginine has multiple functions, it may be important to keep these arginine plasma levels at normal or even higher levels in patients undergoing major vascular surgery.European Journal of Clinical Nutrition (2000) 54, 615–617.

Gut endotoxin restriction prevents catabolic changes in glutamine metabolism after surgery in the bile duct-ligated rat.

OBJECTIVE The objective of this study was to investigate the role of gut-derived endotoxemia in postoperative glutamine (GLN) metabolism of bile duct-ligated rats. SUMMARY BACKGROUND DATA Postoperative complications in patients with obstructive jaundice are associated with gut-derived endotoxemia. In experimental endotoxemia, catabolic changes in GLN metabolism have been reported. Glutamine balance is considered important in preventing postsurgical complications. METHODS Male Wistar rats were treated orally with the endotoxin binder cholestyramine (n = 24, 150 mg/day) or saline (n = 24). On day 7, groups received a SHAM operation or a bile duct ligation (BDL). On day 21, all rats were subjected to a laparotomy followed 24 hours later by blood flow measurements and blood sampling. Glutamine organ handling was determined for the gut, liver, and one hindlimb. Intracellular GLN muscle concentrations were determined. RESULTS Compared to the SHAM groups, BDL rats showed lower gut uptake of GLN (28%, p < 0.05); a reversal of liver GLN release to an uptake (p < 0.05); higher GLN release from the hindlimb (p < 0.05); and lower intracellular muscle GLN concentration (32%, p < 0.05). Cholestyramine treatment in BDL rats maintained GLN organ handling and muscle GLN concentrations at SHAM levels. CONCLUSIONS Disturbances in postoperative GLN metabolism in BDL rats can be prevented by gut endotoxin restriction. Gut-derived endotoxemia after surgery in obstructive jaundice dictates GLN metabolism.

Development of Renal Failure in Endotoxemic Rats: Can It Be Explained by Early Changes in Renal Energy Metabolism?

Endotoxin shock not only causes renal failure, endotoxemia also leads to metabolic impairment, resulting in energy shortage and loss of cellular integrity; therefore, we tested the hypothesis that early changes in renal metabolism contribute to the development of acute renal failure during endotoxin shock. Endotoxin (Escherichia coli 127B8; 8 mg/kg from t = 0 to 60 min) was infused in three groups of 8 rats, in which renal biopsies were taken at t = 30, 50 and 90 min, respectively; a fourth group (n = 8) served as control. In the biopsies, glucose, lactate, ATP, ADP, AMP and creatine phosphate concentrations were determined. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured from the clearances of 131I-hippurate and 125I-thalamate, respectively. We also assayed urine flow (V; catheter in the bladder), cardiac output (CO), blood pressure (MAP), heart rate (HR) and arterial lactate, glucose and creatinine concentrations. During the first 30 min of endotoxemia, we found no systemic hemodynamic or biochemical changes. From t = 30 to t = 90, CO and MAP decreased to 59 and 70%, respectively, while HR and serum levels rose to 110 and 800%, respectively (p < 0.05), indicating progression of shock. Renal function clearly deteriorated from t = 30; at t = 90 RPF, GFR and V had decreased by 86, 84 and 86%, respectively, plasma creatinine being 193% of the baseline value (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of mild endotoxemia during low arginine plasma levels on organ blood flow in rats

Objective Arginine is the sole precursor in the generation of the vasodilating agent nitric oxide. Arginine plasma levels are low in situations associated with endotoxemia such as major trauma, sepsis, and experimental obstructive jaundice. The aim of the study was to evaluate hemodynamics at low arginine plasma levels during a low-grade endotoxemia. Design Randomized, placebo-controlled animal laboratory investigation. Subjects Male Wistar rats (n = 29), anesthetized. Interventions Rats were randomly assigned to receive (at t = 0 mins) an intravenous infusion of 1.5 mL of 0.9% NaCl (SAL, n = 12) or 1.5 mL of an arginase (3200 IU) solution (ASE, n = 17) over a 20-min period. After the SAL or ASE infusion, rats were randomly assigned to receive an intravenous endotoxin (lipopolysaccharide [LPS], 150 &mgr;g/kg in 1.0 mL of 0.9% NaCl; ASE/LPS, n = 10 and SAL/LPS, n = 6) challenge or a control infusion (1.0 mL of 0.9% NaCl; ASE/SAL, n = 7 and SAL/SAL, n = 6) at t = 30 mins. Measurements and Main Results Organ blood flow was measured at t = 270 mins, using radiolabeled microspheres. At this time point, arginine plasma levels were lower in the ASE-treated rats (ASE/SAL vs. SAL/SAL and ASE/LPS vs. SAL/LPS, both p < .005, respectively). Cardiac output, mean arterial pressure, and therefore total peripheral resistance were similar for all groups. In the LPS-treated animals (SAL/LPS and ASE/LPS), cardiac output was maintained by a higher heart rate compensating the lower stroke volume. Organ blood flow to the small intestine and splanchnic blood flow was lower in the ASE/LPS-treated rats (both p < .05 when compared with other groups). Total liver blood flow was similar for all groups; the lower splanchnic blood flow was compensated for by a higher hepatic arterial blood flow. Conclusion The present study shows that low arginine plasma levels do not influence organ blood flow, whereas, during a low-grade endotoxemia, low arginine plasma levels result in reduced blood flow to the small intestine.