pituitrin and Endotoxemia

Angiotensin-(1-7) [Ang-(1-7)]/Mas receptor is a counter-regulatory axis that counteracts detrimental renin-angiotensin system (RAS) effects, especially regarding systemic inflammation, vasopressin (AVP) release, and hypothalamic-pituitary-adrenal (HPA) activation. However, it is not completely understood whether this system may control centrally or systemically the late phase of systemic inflammation. Thus, the aim of this study was to determine whether intracerebroventricular (i.c.v.) administration of Ang-(1-7) can modulate systemic inflammation through the activation of humoral pathways in late phase of endotoxemia. Endotoxemia was induced by systemic injection of lipopolysaccharide (LPS) (1.5 mg/kg, i.v.) in Wistar rats. Ang-(1-7) (0.3 nmol in 2 µL) promoted the release of AVP and attenuated interleukin-6 (IL-6) and nitric oxide (NO) levels but increased interleukin-10 (IL-10) in the serum of the endotoxemic rats. The central administration of Mas receptor antagonist A779 (3 nmol in 2 µL, i.c.v.) abolished these anti-inflammatory effects in endotoxemic rats. Furthermore, Ang-(1-7) applied centrally restored mean arterial blood pressure (MABP) without affecting heart rate (HR) and prevented vascular hyporesponsiveness to norepinephrine (NE) and AVP in animals that received LPS. Together, our results indicate that Ang-(1-7) applied centrally promotes a systemic anti-inflammatory effect through the central Mas receptor and activation of the humoral pathway mediated by AVP.

Topics: Angiotensin I; Animals; Endotoxemia; Gene Expression Regulation; Hypotension; Inflammation; Lactic Acid; Lipopolysaccharides; Male; Osmolar Concentration; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats, Wistar; Receptors, G-Protein-Coupled; Sodium; Vasopressins

Animal models of endotoxemia are frequently used to understand the pathophysiology of sepsis and test new therapies. However, important differences exist between commonly used experimental models of endotoxemia and clinical sepsis. Animal models of endotoxemia frequently produce hypodynamic shock in contrast to clinical hyperdynamic shock. This difference may exaggerate the importance of hypoperfusion as a causative factor in organ dysfunction. This study sought to develop an ovine model of hyperdynamic endotoxemia and assess if there is evidence of impaired oxidative metabolism in the vital organs.. Eight sheep had microdialysis catheters implanted into the brain, heart, liver, kidney, and arterial circulation. Shock was induced with a 4 h escalating dose infusion of endotoxin. After 3 h vasopressor support was initiated with noradrenaline and vasopressin. Animals were monitored for 12 h after endotoxemia. Blood samples were recovered for hemoglobin, white blood cell count, creatinine, and proinflammatory cytokines (IL-1Beta, IL-6, and IL-8).. The endotoxin infusion was successful in producing distributive shock with the mean arterial pressure decreasing from 84.5 ± 12.8 mm Hg to 49 ± 8.03 mm Hg (P < 0.001). Cardiac index remained within the normal range decreasing from 3.33 ± 0.56 L/min/m to 2.89l ± 0.36 L/min/m (P = 0.0845). Lactate/pyruvate ratios were not significantly abnormal in the heart, brain, kidney, or arterial circulation. Liver microdialysis samples demonstrated persistently high lactate/pyruvate ratios (mean 37.9 ± 3.3).. An escalating dose endotoxin infusion was successful in producing hyperdynamic shock. There was evidence of impaired oxidative metabolism in the liver suggesting impaired splanchnic perfusion. This may be a modifiable factor in the progression to multiple organ dysfunction and death.

Topics: Animals; Blood Pressure; Disease Models, Animal; Endotoxemia; Endotoxins; Female; Hemodynamics; Interleukin-1beta; Interleukin-6; Interleukin-8; Sheep; Vasoconstrictor Agents; Vasopressins

Besides their well-established endocrine roles, vasopressin and oxytocin are also important regulators of immune function, participating in a complex neuroendocrine-immune network. In the present study, we investigated whether and how vasopressin and oxytocin could modulate lipopolysaccharide (LPS)-induced nitric oxide (NO) production in a well-established model of experimental endotoxaemia. Male Wistar rats were previously treated i.v. with vasopressin V1 or oxytocin receptor antagonists and then received either an i.v. LPS injection to induce endotoxaemia or a saline imjection as a control. The animals were divided into two groups: in the first group, blood was collected at 2, 4 and 6 h after LPS injection; in the second group, mean arterial blood pressure (MABP) and heart rate (HR) were recorded over 6 h. Plasma vasopressin and oxytocin values were higher in LPS- compared to saline-injected animals at 2 and 4 h but returned to basal levels at 6 h. NO levels exhibited an opposite pattern, showing a progressive increase over the entire period. The previous administration of a vasopressin V1 receptor antagonist significantly reduced NO plasma concentrations at 2 and 4 h but not at 6 h. By contrast, oxytocin receptor agonist pre-treatment had no effect on the NO plasma concentration. In relation to MABP, previous treatment with vasopressin V1 receptor antagonist reversed the LPS-induced hypotension at 4 h, although this was not the case for oxytocin antagonist-treated animals. None of the antagonists affected HR. Our findings indicate that vasopressin (but not oxytocin) has effects on NO production during endotoxaemia in rats, although they do not lend support to the proposed anti-inflammatory actions of vasopressin during endotoxaemia.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Blood Pressure; Endotoxemia; Heart Rate; Hypotension; Lipopolysaccharides; Male; Nitric Oxide; Oxytocin; Pituitary Gland, Posterior; Rats; Receptors, Oxytocin; Time Factors; Vasopressins

We evaluated the role of the renal vascular system and the Rho-A/Rho-kinase pathway in the maintenance of the pressor effects of vasopressin in endotoxemic rats.. In vitro and in vivo animal study.. University research laboratory.. Male Wistar rats (200-300 g).. Rats received either saline or lipopolysaccharide (10 mg/kg, intraperitoneal) 6 or 24 hours before the experiments. The effects of vasopressin on isolated aortic rings, cardiac function, mean arterial pressure, and both the renal vascular perfusion pressure of perfused kidneys in vitro and renal blood flow in situ were evaluated. The role of Rho-kinase in the renal and systemic effects of vasopressin was investigated through administration of the selective inhibitor Y-27632 and Western blot analysis.. The effect of vasopressin on mean arterial pressure was unaltered and that on renal vascular perfusion pressure enhanced in endotoxemic rats at both 6 and 24 hours after lipopolysaccharide, despite reduced contractile responses in aortic rings and the lack of effect on cardiac function. Vasopressin (3, 10, and 30 pmol/kg, IV) produced increased reduction in renal blood flow in endotoxemic rats. In perfused kidneys from lipopolysaccharide groups, administration of Y-27632 reverted the hyperreactivity to vasopressin. Treatment with Y-27632 partially inhibited the effects of vasopressin on mean arterial pressure and significantly reduced the effects of vasopressin on renal blood flow in control but not in endotoxemic rats. Although the protein levels of Rho-A and Rho-kinase I and II had not been impaired, the levels of phosphorylated myosin phosphatase-targeting subunit 1, the regulatory subunit of myosin phosphatase that is inhibited by Rho-kinase, were increased in both the renal cortex and the renal medulla of endotoxemic rats.. Our data suggest that activation of Rho-kinase potentiates the vascular effects of vasopressin in the kidneys, contributing to the maintenance of the hypertensive effects of this agent during septic shock.

Topics: Amides; Analysis of Variance; Animals; Arterial Pressure; Endotoxemia; Enzyme Inhibitors; Heart; Kidney; Male; Myosin-Light-Chain Phosphatase; Perfusion; Phenylephrine; Pyridines; Rats; Rats, Wistar; Renal Circulation; rho-Associated Kinases; Vasoconstrictor Agents; Vasopressins

Topics: Animals; Endotoxemia; Kidney; Male; Phenylephrine; Renal Circulation; rho-Associated Kinases; Vasoconstrictor Agents; Vasopressins

Cholecystokinin (CCK) was first described as a gastrointestinal hormone, but its receptors have been located in cardiac and vascular tissues, as well as in immune cells. Our aims were to investigate the role of CCK on lipopolysaccharide (LPS)-induced hypotension and its ability to modulate previously reported inflammatory mediators, therefore affecting cardiovascular function. To conduct these experiments, rats had their jugular vein cannulated for drug administration, and also, the femoral artery cannulated for mean arterial pressure (MAP) and heart rate records. Endotoxemia induced by LPS from Escherichia coli (1.5 mg/kg; i.v.) stimulated the release of CCK, a progressive drop in MAP, and increase in heart rate. Plasma tumor necrosis factor α (TNF-α), interleukin 10 (IL-10), nitrate, vasopressin, and lactate levels were elevated in the endotoxemic rats. The pretreatment with proglumide (nonselective CCK antagonist; 30 mg/kg; i.p.) aggravated the hypotension and also increased plasma TNF-α and lactate levels. On the other hand, CCK (0.4 μg/kg; i.v.) administered before LPS significantly restored MAP, reduced aortic and hepatic inducible nitric oxide synthase (iNOS) production, and elevated plasma vasopressin and IL-10 concentrations; it did not affect TNF-α. Physiological CCK concentration reduced nitrite and iNOS synthesis by peritoneal macrophages, possibly through a self-regulatory IL-10-dependent mechanism. Together, these data suggest a new role for the peptide CCK in modulating MAP, possibly controlling the inflammatory response, stimulating the anti-inflammatory cytokine, IL-10, and reducing vascular and macrophage iNOS-derived nitric oxide production. Based on these findings, CCK could be used as an adjuvant therapeutic agent to improve cardiovascular function.

Topics: Animals; Aorta; Blood Pressure; Cholecystokinin; Drug Evaluation, Preclinical; Endotoxemia; Heart Rate; Hypotension; Inflammation Mediators; Interleukin-10; Lactic Acid; Lipopolysaccharides; Liver; Macrophages, Peritoneal; Male; Nitric Oxide Synthase Type II; Proglumide; Rats; Rats, Wistar; Shock, Septic; Tumor Necrosis Factor-alpha; Vasopressins

Although plasmid DNA encoding an antigen from pathogens or tumor cells has been widely studied as vaccine, the use of plasmid vector (without insert) as therapeutic agent requires further investigation.. Here, we showed that plasmid DNA (pcDNA3) at low doses inhibits the production of IL-6 and TNF-α by lipopolysaccharide (LPS)-stimulated macrophage cell line J774. These findings led us to evaluate whether plasmid DNA could act as an anti-inflammatory agent in a Wistar rat endotoxemia model. Rats injected simultaneously with 1.5 mg/kg of LPS and 10 or 20 μg of plasmid DNA had a remarkable attenuation of mean arterial blood pressure (MAP) drop at 2 hours after treatment when compared with rats injected with LPS only. The beneficial effect of the plasmid DNA on MAP was associated with decreased expression of IL-6 in liver and increased concentration of plasma vasopressin (AVP), a known vasoconstrictor that has been investigated in hemorrhagic shock management. No difference was observed in relation to nitric oxide (NO) production.. Our results demonstrate for the first time that plasmid DNA vector at low doses presents anti-inflammatory property and constitutes a novel approach with therapeutic potential in inflammatory diseases.

Topics: Animals; Blood Pressure; Body Temperature; Cell Line; DNA; Endotoxemia; Heart Rate; Interleukin-6; Lipopolysaccharides; Liver; Macrophages; Mice; Nitrates; Plasmids; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha; Vasopressins

Acute renal failure during human sepsis is often nonoliguric. To study the underlying mechanisms, renal function was assessed in endotoxic and control male Wistar rats during and after saline loading and treatment with the selective V2 receptor agonist desmopressin. Escherichia coli endotoxin (dose, 8 mg/kg) was administered from time (t)=0 to t=60 min; saline loading (rate, 5 mL/100 g per hour) was administered from t=0 to t=120 min. Thereafter, half of each group received desmopressin (dose, 10 microg) for 1 h. The inner medullary (IM) osmolality, hematocrit, plasma, and urinary concentrations of sodium, potassium, urea, and osmolality were measured; then, aquaporin 2 (AQP2) immunohistochemistry was performed. Plasma vasopressin concentrations were measured at t=180 min. Saline loading increased urine volume in all rats. In the endotoxic group, mean arterial pressure decreased when saline loading was stopped. Despite increased hematocrit and vasopressin levels (>16 pg/mL), the endotoxin group had a low IM osmolality (mean +/- SEM, 412+/-0.04 mOsm/kg H2O) in comparison with the control group (mean +/- SEM, 1,094+/-0.17 mOsm/kg H2O) and was not able to either decrease urine volume or raise urine osmolality. Desmopressin treatment in endotoxin-treated rats maintained mean arterial pressure, increased sodium reabsorption, IM osmolality, and urine osmolality, and decreased urine flow. The AQP2 intensity decreased in the endotoxin group, and the apical localization disappeared; both were not affected by desmopressin. Our results indicate that endotoxemia in rats acutely diminishes renal urinary concentration capacity and is associated with a decreased IM osmolality and diminished apical AQP2 localization. These findings may help to explain nonoliguric acute renal failure in human septic shock.

Topics: Animals; Aquaporin 2; Deamino Arginine Vasopressin; Endotoxemia; Endotoxins; Hemodynamics; Immunohistochemistry; Kidney Medulla; Kidney Tubules, Collecting; Male; Osmolar Concentration; Potassium; Rats; Rats, Wistar; Sodium; Vasopressins

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

Tachyphylaxis against catecholamines often complicates hemodynamic support in patients with septic shock. Recent experimental and clinical research suggests that the hemodynamic response to exogenous arginine vasopressin (AVP) infusion may also be blunted. The purpose of the present study was therefore to clarify whether the efficacy of a continuous AVP infusion (0.04 U x min(-1)) decreases over time in ovine endotoxemia. An additional objective was to determine whether the anticipated hyporesponsiveness can be counteracted by corticosteroids. Fourteen adult ewes (37 +/- 1 kg) were instrumented for chronic hemodynamic monitoring. All ewes received a continuous endotoxin infusion that contributed to a hypotensive-hyperdynamic circulation. After 16 h of endotoxemia, the sheep were randomized to receive either AVP (0.04 U x min(-1)) or the vehicle (normal saline; n = 7 each). After 6 h of AVP or placebo infusion, respectively, methylprednisolone (30 mg x kg(-1)) was injected. Arginine vasopressin infusion increased mean arterial pressure and systemic vascular resistance index at the expense of a reduced cardiac index (P < 0.05 each). Supraphysiologic AVP plasma levels in the treatment group (298 +/- 15 pg x mL(-1)) were associated with increased surrogate parameters of liver, mesenterial, and myocardial dysfunction. After 6 h of continuous AVP infusion, the vasopressor effect was significantly reduced. Interestingly, a bolus infusion of methylprednisolone (30 mg x kg(-1)) reestablished mean arterial pressure by increasing both cardiac index and systemic vascular resistance index. The present study demonstrates that in endotoxemia, (a) the vasopressor effect of AVP infusion may be reduced, (b) corticosteroids may potentially be useful to increase the efficacy of AVP infusion, and (c) even moderate AVP doses may potentially impair myocardial and hepatic function.

Topics: Adrenal Cortex Hormones; Animals; Arginine Vasopressin; Blood Pressure; Endotoxemia; Endotoxins; Female; Methylprednisolone; Oxygen; Pressure; Sepsis; Sheep; Shock; Time Factors; Vasopressins

Volatile anesthetics such as isoflurane have been shown to offer anti-inflammatory effects during experimental endotoxemia whereas the alpha-adrenergic vasopressor norepinephrine exhibits proinflammatory properties on systemic cytokine release under the same conditions. However, during major surgery and in patients with systemic inflammatory response syndrome or sepsis both agents are frequently administered concurrently. We therefore aimed to investigate the influence of preexisting i.v. administration of noradrenaline or vasopressin on the anti-inflammatory effects of isoflurane during experimental endotoxemia. Anesthetized, ventilated Sprague-Dawley rats (n=7 per group) were randomly treated. In the LPS-only group, animals received lipopolysaccharide (LPS, 5 mg/kg, i.v.) with no further specific treatment. In the LPS-isoflurane group, isoflurane inhalation at 1 MAC was initiated simultaneously with induction of endotoxemia (LPS 5 mg/kg, i.v.). Animals in the LPS-isoflurane-norepinephrine group received norepinephrine infusion at 50 microg/kg/h 10 min prior to injection of LPS and inhalation of isoflurane. In the LPS-isoflurane-vasopressin group, vasopressin was administered at 0.5 IE/kg/h 10 min prior to LPS and isoflurane. In the LPS-norepinephrine and the LPS-vasopressin groups the infusion of each vasopressor was started prior to LPS injection without any application of isoflurane. A Sham group served as the control. After 4 h of endotoxemia, plasma levels of TNFalpha, IL-1beta and IL-10 were measured. Alveolar macrophages (AM) were cultured ex vivo for nitrite assay. Induction of endotoxemia resulted in a significant rise in measured plasma cytokines and nitrite production from cultured AM. Inhalation of isoflurane significantly attenuated plasma levels of TNFalpha (-65%) and IL-1beta (-53%) compared to the LPS-only group whereas it had no effect on nitrite production from cultured AM. Preexisting infusions of norepinephrine or vasopressin abolished the anti-inflammatory effects of isoflurane. The data demonstrate that the administration of norepinephrine or vasopressin both counteracted the anti-inflammatory effects of inhaled isoflurane on proinflammatory cytokine release during experimental endotoxemia in rats.

Topics: Animals; Anti-Inflammatory Agents; Blood Pressure; Cells, Cultured; Cytokines; Drug Interactions; Endotoxemia; Heart Rate; Humans; Isoflurane; Lipopolysaccharides; Macrophages, Alveolar; Male; Nitrites; Norepinephrine; Oxygen; Rats; Rats, Sprague-Dawley; Subcellular Fractions; Vasopressins

The effects of vasopressin, norepinephrine, and L-arginine alone or combined on intestinal microcirculation were evaluated in the septic mouse by intravital microscopy, with which we measured the erythrocyte flux and velocity in villus tip arterioles and the density of perfused villi.. Controlled animal study.. University research laboratory.. Female BALB/c mice weighing between 18 and 21 g.. Anesthetized and ventilated mice received at t0 an intravenous injection of Escherichia coli endotoxin (2 mg/kg bolus intravenously), inducing after 1 hr (t60) a decrease in mean arterial blood pressure to 40-50 mm Hg associated with a significant decrease in erythrocyte flux and velocity in villus tip arterioles and in the density of perfused villi. The mice then received a randomly different treatment for endotoxin-induced shock. Treatments consisted in continuous intravenous infusion for 1 hr with either saline (control group), norepinephrine, vasopressin, L-arginine, vasopressin+L-arginine, or norepinephrine+L-arginine. The doses of vasopressors (used alone or combined with L-arginine) were titrated to restore mean arterial pressure to the baseline level.. At the end of the treatment (t120), we observed in the control group further decreases in arteriolar flux and velocity and in the density of perfused villi. In the groups treated by a vasopressor alone, mean arterial pressure returned to baseline and there were no additional decreases in arteriolar flux and velocity or in the density of perfused villi. However, these latter three variables did not return to their preshock baseline values. Even though L-arginine did not restore mean arterial pressure, the infusion of L-arginine alone prevented the decrease in flux or erythrocyte velocity occurring between t60 and t120 and conserved to some extent the density of perfused villi compared with that in the control groups. In addition, we found that simultaneous administration of norepinephrine or vasopressin with L-arginine improved all microcirculation variables more efficiently than either vasopressor alone.. From these data, we conclude that a) restoring mean arterial pressure after 1 hr of endotoxemia was not sufficient to restore ad integrum intestinal mucosa microvascular perfusion; b) L-arginine could have a beneficial effect at the microcirculatory level, which was independent of mean arterial pressure; and c) administration of L-arginine combined with the maintenance of perfusion pressure by vasopressive drugs allowed a better preservation of intestinal microcirculation at an early stage of endotoxemia.

Topics: Animals; Arginine; Blood Pressure; Disease Models, Animal; Drug Therapy, Combination; Endotoxemia; Escherichia coli Infections; Female; Ileum; Mice; Mice, Inbred BALB C; Microcirculation; Norepinephrine; Vasoconstrictor Agents; Vasopressins

Topics: Animals; Arginine; Blood Pressure; Drug Synergism; Drug Therapy, Combination; Endotoxemia; Escherichia coli Infections; Humans; Ileum; Microcirculation; Norepinephrine; Vasoconstrictor Agents; Vasopressins

Endotoxemia can lead to fluid metabolism alterations despite unchanged or elevated plasma vasopressin (VP) levels, suggesting a refractoriness of the kidney to the effect of the peptide. To test this hypothesis, we examined the effect of lipopolysaccharide (LPS) injection on the expression of V2 receptors and aquaporin-2 in the kidney.. Plasma VP and urine osmolality, and binding of [3H]VP to kidney membranes, Western blot, and immunohistochemical analysis of aquaporin-2, in situ hybridization for V2 VP receptors and cytokines mRNAs were measured in the kidney 3 to 24 hours after LPS injection, 250 microg/100 g, intraperitoneally.. LPS injection caused prolonged decreases in urine osmolality (up to 24 hours) without significant changes in plasma levels of sodium or VP. This was associated with marked decreases in V2 VP receptor mRNA and VP receptor number in the kidney, which were evident for up to 12 hours after LPS injection. Aquaporin-2 in kidney inner medulla was also reduced by about 50%. LPS induced interleukin (IL)-1beta in the kidney medulla by 3 hours, reached maximum at 6 hours, and started to decline by 12 hours, while it increased IL-6 mRNA significantly only at 3 hours. Interleukin mRNA expression was absent in kidneys of control rats. In vitro incubation of kidney medulla slices with IL-1beta reduced VP binding.. The inflammatory response to acute endotoxemia down regulates V2 VP receptors and aquaporin-2 of the kidney inner medulla resulting in prolonged impairment of the renal capacity to concentrate urine.

Topics: Acute Disease; Animals; Aquaporin 2; Aquaporins; Down-Regulation; Endotoxemia; Interleukin-1; Interleukin-6; Kidney Concentrating Ability; Kidney Medulla; Lipopolysaccharides; Male; Osmolar Concentration; Rats; Rats, Wistar; Receptors, Vasopressin; RNA, Messenger; Sodium; Tritium; Urine; Vasopressins

Reduced pressor responsiveness to norepinephrine (NE) in sepsis is well documented but the associated regional haemodynamic changes are less well characterized, and there are varying reports of changes in haemodynamic responses to arginine vasopressin (AVP). We compared changes in regional haemodynamic responsiveness to AVP and NE during a 24 h continuous infusion of lipopolysaccharide (LPS) in conscious rats.. Conscious, male Sprague-Dawley rats were infused with saline (0.4 ml h(-1)) or LPS (150 micro g kg(-1) h(-1)). Renal, mesenteric, and hindquarter haemodynamic responses to 3 min infusions of AVP (0.25, 0.625, and 1.25 ng kg(-1) min(-1)) or NE (75, 250, and 750 ng kg(-1) min(-1)) were assessed 2, 6, and 24 h after the onset of LPS or saline.. Two and six hours after the onset of LPS, all haemodynamic effects of NE were markedly reduced, but by 24 h, there was some recovery in the vasoconstrictor actions of NE although the pressor and bradycardic effects were still depressed. Two hours after the onset of LPS, the cardiovascular effects of AVP were depressed but there was some recovery in vascular responsiveness at 6 h. By 24 h, only the mesenteric vasoconstrictor effect of AVP was consistently reduced.. During low dose LPS infusion, there are differential changes in haemodynamic responsiveness to AVP and NE, which show different temporal and regional profiles of recovery with time. Furthermore, reduced pressor responsiveness to NE is not necessarily accompanied by a reduced capacity of vessels for vasoconstriction.

Topics: Animals; Blood Pressure; Endotoxemia; Heart Rate; Hemodynamics; Lipopolysaccharides; Male; Norepinephrine; Rats; Rats, Sprague-Dawley; Vascular Resistance; Vasoconstrictor Agents; Vasopressins

We sought to determine the role of oxidative stress in the development of vascular dysfunction in inflammation.. Hyporeactivity to catecholamines and other vasoconstrictors is present in acute inflammation. Because oxidative stress plays a significant role in inflammation, impaired responsiveness may be overcome by anti-oxidants.. In randomized, double-blind, cross-over studies, forearm blood flow (FBF) responses to norepinephrine (NE), angiotensin II (ANG II), and vasopressin (VP) were assessed before and 4 h after induction of systemic inflammation by low doses of Escherichia coli endotoxin (lipopolysaccharide [LPS], 20 IU/kg intravenously) or after placebo in healthy volunteers. Furthermore, the effect of intra-arterial vitamin C (24 mg/min) or placebo on NE-induced or ANG II-induced vasoconstriction was studied after LPS.. Administration of LPS caused systemic and forearm vasodilation, increased white blood cell count, elevated body temperature, and reduced vitamin C plasma concentrations. Lipopolysaccharide decreased the responses of FBF to NE by 59%, to ANG II by 25%, and to VP by 51% (n = 9, p < 0.05, all effects). Co-administration of vitamin C completely restored the response to NE and to ANG II, which was comparable to that observed under baseline conditions (n = 8).. E. coli-endotoxemia reduces FBF responsiveness to vasoconstrictors. The hyporeactivity can be corrected by high doses of vitamin C, suggesting that oxidative stress may represent an important target for inflammation-induced impaired vascular function.

Topics: Adult; Angiotensin II; Antioxidants; Ascorbic Acid; Endotoxemia; Escherichia coli Infections; Humans; Inflammation; Male; Oxidative Stress; Regional Blood Flow; Vasoconstriction; Vasoconstrictor Agents; Vasopressins

Topics: Angiotensin II; Antioxidants; Endotoxemia; Humans; Inflammation; Oxidative Stress; Regional Blood Flow; Vasoconstriction; Vasoconstrictor Agents; Vasopressins

The primary aim of this study was to define the secretory dynamics of oxytocin and vasopressin in pituitary venous effluent from ambulatory horses during acute endotoxaemia, a stimulus that may release both hormones. Our secondary aim was to investigate the role of oxytocin in regulating adrenocorticotropic hormone (ACTH) secretion by comparing oxytocin, vasopressin, corticotropin-releasing hormone (CRH) and ACTH secretory profiles during endotoxaemia and by monitoring the ACTH response to oxytocin administration. Pituitary venous blood was collected nonsurgically continuously and divided into 1-min segments from eight follicular phase mares. Four mares were sampled for 30 min before and 3.5 h after receiving an i.v. infusion of bacterial endotoxin (TOX). Four control mares were sampled for 2.5 h without infusion of TOX. Another three follicular phase mares were given 5 U of oxytocin to replicate the peak response to TOX and pituitary blood collected every 1 min for 10 min before and 15 min after injection. Endotoxin raised the secretion rates of all hormones measured. All hormones were released episodically throughout the experiment, with TOX increasing the amplitude of peaks in each hormone. Peaks in oxytocin and vasopressin were coincident in each treated mare. Similarly, ACTH peaks were coincident with peaks of oxytocin and vasopressin in each treated mare, and with peaks of CRH in three mares. However, oxytocin administration did not affect ACTH secretion. We conclude that during endotoxaemia in horses: (i) oxytocin and vasopressin are secreted synchronously; (ii) oxytocin is unlikely to be acting as an ACTH secretagogue since inducing peak oxytocin concentrations observed during TOX does not raise ACTH; and therefore (iii) the close relationship between oxytocin and ACTH secretion is circumstantial and due to the fact that oxytocin secretion is concurrent with that of vasopressin, a proven ACTH secretagogue in horses.

Topics: Adrenocorticotropic Hormone; Animals; Body Temperature; Corticotropin-Releasing Hormone; Endotoxemia; Endotoxins; Female; Follicular Phase; Heart Rate; Horses; Jugular Veins; Oxytocin; Stress, Physiological; Vasopressins

The gastric acid hyposecretory state associated with endotoxemia is mediated by a nervous reflex involving the central nervous system. The aim of the present study was to analyse the central effects of different peptides on distension-stimulated gastric acid secretion and the endogenous role of such peptides on the hyposecretory effects of endotoxin. The effect of an intracisternal (i.c.) administration of oxytocin, vasopressin, corticotropin releasing factor (CRF), bombesin, somatostatin and the opioid receptor agonist BW443C or an intravenous (i.v.) injection of a small dose of endotoxin on distension-stimulated gastric acid secretion was studied in the continuously perfused stomach of anaesthetised rats. In some animals, specific receptor antagonists for oxytocin (Compound VI [d(CH2)5, Tyr(Me)2, Thr4, Tyr-NH2(9)]-OVT, 0.01-1 microg/rat), vasopressin (des-Gly9-[beta-Mercapto-beta,beta-cyclopentamethylene-propiony l1, O-Et-Tyr2, Val4, Arg8]-VP, 20 microg/rat), CRF (alpha-helical CRF [9-41], 50 microg/rat) or bombesin (D-Phe12-Bombesin, 20 microg/rat) were administered i.c. before endotoxin. Distension-stimulated acid secretion was significantly inhibited by central oxytocin (0.2, 2 or 4 nmol/rat, 45+/-16%, 69+/-10% and 79+/-5% reduction, respectively), CRF (0.5, 1 or 2 nmol/rat, 52.2+/-15.6%, 74.3+/-9.1% and 93.2+/-1.6% reduction, respectively) and bombesin (2 nmol/rat, 79.1+/-5.8% reduction). The hyposecretory effect induced by endotoxin (5 microg/kg, 60.2+/-2.3% reduction) was reversed in a dose-dependent manner by pretreatment with the oxytocin receptor antagonist (0.01, 0.1 and 1 microg/rat, 65.2+/-14.4%, 88.0+/-22.5% and 112.4+/-25.2% of control response, respectively) while the vasopressin (20 microg/rat), CRF (50 microg/rat) or bombesin (20 microg/rat) receptor antagonists had no effect. The present results support a role for the endogenous release and action in the central nervous system of oxytocin in the inhibitory effect of endotoxin on gastric acid secretion.

Topics: Adrenergic Agents; Animals; Antidiuretic Hormone Receptor Antagonists; Bombesin; Corticotropin-Releasing Hormone; Dose-Response Relationship, Drug; Endotoxemia; Endotoxins; Female; Gastric Acid; Gastric Dilatation; Gastric Mucosa; Hormones; Injections, Intraventricular; Male; Narcotic Antagonists; Oligopeptides; Oxytocin; Rats; Rats, Wistar; Receptors, Bombesin; Receptors, Corticotropin-Releasing Hormone; Receptors, Oxytocin; Somatostatin; Vasoconstrictor Agents; Vasopressins

1. Male, Long Evans rats were instrumented chronically with pulsed Doppler probes and intravascular catheters to allow assessment of regional haemodynamic changes during i.v. infusion of lipopolysaccharide (LPS, 150 micrograms kg-1 h-1). 2. In the presence of the AT1-receptor antagonists, losartan (10 mg kg-1 + 10 kg-1 h-1), the initial (1-2 h) hypotensive and renal, mesenteric and hindquarters vasodilator responses to LPS were enhanced significantly. Thereafter these effects waned, but between 8-23 h after the onset of LPS infusion, a further fall in mean atrial blood pressure (MAP) and increases in renal and hindquarters flows and conductances occurred. All these changes were significantly greater than seen with losartan or LPS alone, and exceeded the sum of their effects. 3. In the presence of captopril (2 mg kg-1 + 2 mg kg-1 h-1), the initial hypotensive and renal vasodilator responses to LPS were enhanced, but less so than in the presence of losartan. However, the effects of LPS in the presence of losartan and captopril together were not different from those in the presence of losartan alone. These observations indicate that the ability of captopril to inhibit the degradation of bradykinin had no additional influence, and the differences between the effect of captopril and losartan on the initial effects of LPS were probably due to more effective suppression of the action of angiotensin II by losartan. 4. In the absence of LPS, co-infusion of losartan and the non-selective endothelin antagonist, SB 209670 (600 micrograms kg-1 + 600 micrograms kg-1 h-1), caused a substantial, progressive hypotension (-25 +/- 2 mmHg at 24 h) accompanied by increases in renal, mesenteric and hindquarters vascular conductances (31 +/- 13, 44 +/- 9 and 45 +/- 12%, respectively), indicating an involvement of angiotensin II and endothelin in the maintenance of normal cardiovascular status in conscious, Long Evans rats. 5. In the presence of losartan and SB 209670, the initial, LPS-induced fall in MAP (-42 +/- 2 mmHg) was not different from that in the presence of losartan (-39 +/- 4 mmHg), and the increases in renal, in mesenteric, and in hindquarters vascular conductances were similar in the two conditions. However, there was no recovery in MAP, and there were persistent renal, mesenteric and hindquarter vasodilatations. 6. In all experiments involving LPS, administration of the V1- receptor antagonist, d(CH2)5-O-Me-Tyr-AVP (10 micrograms kg-1), 23 h after the start of LPS

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Arginine Vasopressin; Biphenyl Compounds; Captopril; Endothelins; Endotoxemia; Hemodynamics; Imidazoles; Indans; Lipopolysaccharides; Losartan; Male; Rats; Renal Circulation; Tetrazoles; Vasopressins