atrial-natriuretic-factor and Endotoxemia

WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Natriuretic peptides are used, based on empirical observations, in intensive care units as antioliguric treatments. We hypothesized that natriuretic peptides prevent lipopolysaccharide-induced oliguria by activating guanylyl cyclase A, a receptor for natriuretic peptides, in proximal tubules and endothelial cells.. Normal Sprague-Dawley rats and mice lacking guanylyl cyclase A in either endothelial cells or proximal tubular cells were challenged with lipopolysaccharide and assessed for oliguria and intratubular flow rate by intravital imaging with multiphoton microscopy.. Recombinant atrial natriuretic peptide efficiently improved urine volume without changing blood pressure after lipopolysaccharide challenge in rats (urine volume at 4 h, lipopolysaccharide: 0.6 ± 0.3 ml · kg · h; lipopolysaccharide + fluid resuscitation: 4.6 ± 2.0 ml · kg · h; lipopolysaccharide + fluid resuscitation + atrial natriuretic peptide: 9.0 ± 4.8 ml · kg · h; mean ± SD; n = 5 per group). Lipopolysaccharide decreased glomerular filtration rate and slowed intraproximal tubular flow rate, as measured by in vivo imaging. Fluid resuscitation restored glomerular filtration rate but not tubular flow rate. Adding atrial natriuretic peptide to fluid resuscitation improved both glomerular filtration rate and tubular flow rate. Mice lacking guanylyl cyclase A in either proximal tubules or endothelium demonstrated less improvement of tubular flow rate when treated with atrial natriuretic peptide, compared with control mice. Deletion of endothelial, but not proximal tubular, guanylyl cyclase A augmented the reduction of glomerular filtration rate by lipopolysaccharide.. Both endogenous and exogenous natriuretic peptides prevent lipopolysaccharide-induced oliguria by activating guanylyl cyclase A in proximal tubules and endothelial cells.

Topics: Acute Kidney Injury; Animals; Atrial Natriuretic Factor; Disease Models, Animal; Endothelial Cells; Endotoxemia; Enzyme Activation; Humans; Infusions, Intravenous; Kidney Tubules, Proximal; Lipopolysaccharides; Mice; Mice, Knockout; Rats; Rats, Sprague-Dawley; Receptors, Atrial Natriuretic Factor

Pharmacological blockade of the renin-angiotensin system is thought to maintain gut perfusion during circulatory stress and thereby avoid later failure of distant organs. In this controlled experimental study, we investigated the effects of carperitide, a synthetic atrial natriuretic peptide that inhibits the renin-angiotensin system, on the systemic and splanchnic circulation during fluid-resuscitated endotoxemia in pigs.. Sixteen domestic pigs of both sexes were randomly divided into 2 groups. The pigs were anesthetized and their lungs ventilated before receiving either saline (Group A: n = 8) or carperitide (Group B: n = 8). After a baseline measurement was taken, the pigs from both groups received a continuous infusion (1.7 microg x kg(-1) x h(-1)) of endotoxin for 240 min. Group B received a continuous infusion of carperitide (0.05 microg x kg(-1) x min(-1)) starting 30 min before the endotoxin infusion and lasting until the end of the study, whereas Group A received the same volume of saline. Fluid resuscitation was titrated to maintain pulmonary artery wedge pressure between 10 and 12 mm Hg. Systemic and regional hemodynamics, oxygenation variables, and the arterial-to-intestinal PCO(2) gap were measured at baseline and after endotoxin infusion for 240 min. The primary end points were cardiac index, superior mesenteric artery flow index, and PCO(2) gap at the end of this study (T240).. Cardiac index and superior mesenteric artery flow index in Group B were significantly higher than those in Group A at T240 (83 +/- 15 vs 135 +/- 23 mL x kg(-1) x min(-1), P < 0.001; 2.6 +/- 1.4 vs 7.9 +/- 4.8, P = 0.01), respectively. Carperitide administration resulted in a significantly better maintenance of intestinal mucosal perfusion assessed by the PCO(2) gap at T240 (33.0 +/- 14.5 vs 11.6 +/- 10.0 mm Hg, P = 0.004). The PaO(2)/FIO(2) ratio in Group B was significantly greater than that in Group A from T60 to T240.. In this porcine fluid-resuscitated endotoxemia model, a low dose of carperitide administered before endotoxemia maintained systemic and splanchnic circulation, and prevented the deterioration of oxygenation. Atrial natriuretic peptide infusion is a potentially beneficial therapy with respect to systemic and splanchnic circulation as well as the respiratory system during sepsis.

Topics: Anesthesia; Animals; Atrial Natriuretic Factor; Blood Circulation; Blood Gas Analysis; Endotoxemia; Endotoxins; Female; Hemodynamics; Lipopolysaccharides; Lung Diseases; Male; Mesenteric Arteries; Oxygen Consumption; Splanchnic Circulation; Swine

Atrial natriuretic peptide (ANP) plays important roles in the regulation of cardiovascular and renal homeostasis. Furthermore, several studies have shown that ANP may have anti-inflammatory activities. We hypothesized that ANP may alleviate cardiovascular and/or metabolic disorders in rats with lipopolysaccharide (LPS)-induced endotoxemia.. In rats anesthetized with pentobarbital, LPS was injected and ANP was continuously infused at 0.15 µg/kg/min. Mean arterial pressure and pulse rate were monitored hourly, and arterial blood gases were analyzed before LPS injection and at 1, 4, and 6 hours after LPS injection. The expression in the rat left ventricle of mRNAs encoding nitric oxide synthase 2 and 3 (iNOS, eNOS), heme oxygenase 1 and 2 (HO-1, 2), tumor necrosis factor α (TNFα), and interleukin (IL)-1β was measured with the real-time reverse transcriptase-polymerase chain reaction.. LPS increased the expression of TNFα, IL-1β, iNOS, and HO-1, which was inhibited by infusion of ANP. Furthermore, the LPS-induced decrease in mean arterial pressure was attenuated, and the acid-base imbalance caused by increased lactate production was improved 6 hours after the administration of ANP.. Our results suggest that continuous infusion of ANP counteracts the cardiovascular and metabolic disorders associated with endotoxemia, possibly via anti-inflammatory mechanisms.

Topics: Acidosis; Animals; Anti-Inflammatory Agents; Atrial Natriuretic Factor; Blood Pressure; Cardiovascular Diseases; Endotoxemia; Lipopolysaccharides; Male; Rats; Rats, Wistar

Topics: Adrenomedullin; Atrial Natriuretic Factor; Biomarkers; Endotoxemia; Glucocorticoids; Hormones; Humans; Inflammation Mediators; Neurophysins; Prednisolone; Protein Precursors; Shock, Septic; Vasopressins

Sepsis intervention studies need better patient stratification methods, and one way to realize this is the introduction of stable biomarkers. A set of recently developed novel biomarkers, based upon precursor-fragments of short-lived hormones, was previously shown to be increased during sepsis. However, it is not known whether these biomarkers are influenced by sepsis intervention strategies. Therefore we investigated the markers in a model of human endotoxemia intervened by increasing doses of prednisolone.. Prospective, open-label study in a specialized clinical research unit of a university hospital.. Thirty-two healthy male volunteers.. Subjects received prednisolone orally at doses of 0, 3, 10 or 30 mg (n=8 per group) at 2 h before intravenous injection of Escherichia coli lipopolysaccharide (LPS) (4 ng/kg). Blood samples were drawn during 24 h after LPS injection.. LPS injection caused an increase in levels of midregional pro-adrenomedullin (MR-proADM), midregional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-arginine-vasopressin (CT-proAVP) and procalcitonin (PCT). Prednisolone caused a dose dependent inhibition of MR-proADM, MR-proANP and CT-proAVP levels.. These results show that a set of novel, highly stable sepsis biomarkers was increased during human endotoxemia and was dose-dependently inhibited by corticosteroid pre-treatment.

Topics: Administration, Oral; Adrenomedullin; Adult; Arginine Vasopressin; Atrial Natriuretic Factor; Biomarkers; Calcitonin; Calcitonin Gene-Related Peptide; Dose-Response Relationship, Drug; Endotoxemia; Humans; Inflammation Mediators; Injections, Intravenous; Lipopolysaccharides; Male; Peptide Hormones; Prednisolone; Prospective Studies; Protein Precursors; Sepsis; Severity of Illness Index

To investigate the effects of atrial natriuretic peptide(ANP) on constriction and relaxation of pulmonary artery and aorta in endotoxemia rat in vitro.. 24 male SD rats were randomly divided into 3 groups, control group, LPS group, ANP therapy group. These groups were injected physiologic salt water, lipopolysaccharide (LPS 2 mg/kg) and LPS + ANP(LPS 2 mg/kg, ANP 2 microg/kg) into vein respectively. After 4 hours, rats were exsanguinated to kill and aorta and pulmonary artery were separated from heart-lung for experiment of blood vessel rings. Constriction effects of aorta and pulmonary artery by norepinephrine (NE), relaxation of aorta and pulmonary artery by acetylcholine (ACh) and sodium nitroprusside SNP) observed by perfusion system in vitro.. Sensitiveness of NE-induced (10(-9)-10(-7) mol/L) constriction of aorta in LPS group was attenuated and EC50 was increased, but its strength (3 x 10(-7)-10(-6) mol/L) was greater comparing with control group (P < 0.01). In ANP group, the NE-induced contractility of aorta was similar to LPS group (P > 0.05). Comparing with control group, NE-induced constriction of pulmonary artery exposure to LPS was reinforced especially in 3 x 10(-7)-10(-6) mol/L of NE (P < 0.01), but its EC50 was obviously higher (P <0.05). There was no significant difference between ANP group and control group in constriction of pulmonary artery (P > 0.05). Relaxation and sensitiveness of aorta and pulmonary artery exposure to LPS were evidently improved in ANP therapy group induced by ACh and SNP respectively (P < 0.01, P < 0.05) and their EC50 markedly decreased comparing with LPS group (P < 0.01, P < 0.05) respectively.. ANP can suppress the reinforcing of NE-induced constriction of pulmonary artery exposure to LPS and partly or entirely reverse the attenuated relaxation of pulmonary artery and aorta induced by ACh and SNP in endotoxemia rats.

Topics: Acetylcholine; Animals; Aorta; Atrial Natriuretic Factor; Endotoxemia; Male; Nitroprusside; Norepinephrine; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Vasoconstriction; Vasodilation

1. We studied endotoxin (lipopolysaccharide, LPS)-induced platelet-activating factor (PAF) production in various visceral organs, and the effect of PAF antagonists or splenectomy on LPS-induced changes. 2. PAF production in response to LPS was highest in the spleen, followed by ileum, heart, lung and kidneys. None was found in the liver. The splenic response was rapid, reaching 10 times the basal level at 30 min. The increased PAF content in each organ was unrelated to the enzyme activity of either macrophages or neutrophils. 3. LPS-induced hypotension and haemoconcentration were largely prevented by PAF antagonists and splenectomy. 4. Plasma volume fell, and plasma atrial natriuretic peptide (ANP) rose, after LPS administration. Splenectomy or pretreatment with PAF antagonists almost completely prevented these LPS-induced changes at 30 min, but only partially reversed them at 90 min. 5. These results suggest that during endotoxaemia: (a) the spleen is the site of the highest endogenous PAF production; (b) the initial release of ANP is dependent on the production of endogenous PAF, and a PAF-ANP interaction mediates the early plasma volume reduction; (c) plasma volume reduction as well as ANP release depend on the spleen; (d) PAF mediated the hypotensive response and its action in the spleen; and (e) sequestered neutrophils are probably not the main source of PAF in the spleen.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Endotoxemia; Endotoxins; Homeostasis; Lipopolysaccharides; Male; Organ Specificity; Plasma Volume; Platelet Activating Factor; Rats; Rats, Sprague-Dawley; Spleen; Time Factors