The classical Guyton view that mean systemic pressure, right atrial pressure, and venous resistance govern venous return is/is not correct.
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Atrial Function, Right↗
Biomedical subjects
S Magder
Publications and source records attributed to S Magder.
Lipopolysaccharide and TNF-alpha produce very similar changes in gene expression in human endothelial cells.
Intracellular signaling pathways regulated by Toll-like receptor 4 (TLR4) and tumor necrosis factor-alpha (TNF-alpha) both activate NFkappaB. This suggests that lipopolysaccharide (LPS) and TNF-alpha should alter transcription of a common set of genes. We tested this hypothesis by treating first passage human umbilical endothelial cells (HUVEC) for 6 h with LPS (50 ng/ml+1 microg/ml CD14) or TNF-alpha (10 ng/ml) and analyzing changes in gene expression by microarray analysis (Affymetrix GeneChips). LPS and TNF-alpha increased expression of 191 common genes and decreased expression of 102 genes. Regulated transcripts encoded for a large number of chemokines, adhesion molecules, procoagulant factors, and molecules that affect cell integrity. Based on the microarray analysis and subsequent confirmation of specific genes by Northern analysis, all 203 genes altered by LPS were altered by TNF-alpha. An additional 17 genes were induced only by TNF-alpha and the expression of 46 was reduced. There were, however, some differences in the kinetics of changes. We also showed that endogenous CD14 was present on these early passage cells and exogenous CD14 was not necessary for most of the LPS response. An autocrine effect from LPS induced expression of TNF-alpha also was ruled out by blocking TNF-alpha with monoclonal antibodies. In conclusion, LPS induces a robust alteration in gene expression in HUVEC that is very similar to that induced by TNF-a. This LPS effect on endothelium could play an important role in the innate immune response.
Antigens, CD↗
Point: the classical Guyton view that mean systemic pressure, right atrial pressure, and venous resistance govern venous return is/is not correct.
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Atrial Function, Right↗
Predicting volume responsiveness in spontaneously breathing patients: still a challenging problem.
The prediction of which patients respond to fluid infusion and which patients do not is an important issue in the intensive care setting. Assessment of this response by monitoring changes in some hemodynamic characteristics in relation to spontaneous breathing efforts would be very helpful for the management of the critically ill. This unfortunately remains a difficult clinical problem, as discussed in the previous issue of the journal. Technical factors and physiological factors limit the usefulness of current techniques.
Blood Volume Determination↗
Muscle contractions increase exercise hyperemia by being permissive for high flows.
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Animals↗
Role of endothelins in septic, cardiogenic, and hemorrhagic shock.
Shock is a condition where blood flow is inadequate for tissue needs. In all forms of shock, the concentrations of endothelins (ETs) are elevated, and they are especially high in septic shock. The rise in ETs plasma levels may initially have some positive homeostatic effects, for ETs can help restore normal vascular tone. However, high levels of ETs compromise the appropriate matching of flow to tissue needs and contribute to the pathophysiology of shock. Attempts at regulating the effects of ETs by the use of pharmacological blockers is made complicated by important interactions between the ETA and ETB receptors and potentially different effects on different tissues. We conclude that antagonism of ET receptors is unlikely to be helpful for cardiogenic or hemorrhagic shock. Furthermore, selective blockade is unlikely to be helpful. However, moderate doses of a mixed ET receptor antagonist may be of use for the management of septic patients.
Animals↗
Theoretical analysis of the noncardiac limits to maximum exercise.
When right atrial pressure (Pra) is greater than zero (atmospheric pressure), cardiac output is determined by the intersection of two functions, cardiac function and return function, which is used here to mean the determinants of venous return. When Pra < or = 0, flow is only determined by circuit function. The objective of this analysis was to determine the potential changes in return function that need to occur to allow the maximum cardiac output during exercise when Pra < or = 0 or is constant. The analysis expands on the model of Green and Jackman and includes the effects of changes in circuit parameters, including venous resistance, changes in capacitance, and muscle contractions. The analysis is based on the model of the circulation proposed by Permutt and co-workers, which assumes that the systemic circulation has two lumped compliant regions in parallel with independent inflow and outflow resistances. Changes in total flow in this model can come about by changes in the distribution of flow between the regions, recruitment of unstressed vascular volume, and changes in the regional venous resistances. The data for the analysis are from previous animal studies and are normalized to a 70-kg man. The major conclusions are that, to achieve the high cardiac output that occurs at peak exercise, there need to be marked changes in the distribution of blood flow, recruitment of unstressed volume, and the venous resistance draining vascular beds. A consequence of the increase in peripheral flow is a marked increase in pressure in the veins of the working muscle. Muscle contractions are potentially a very important mechanism for transiently decreasing this pressure and preventing excessive filtration of plasma during exercise.
Animals↗
The use of respiratory variations in right atrial pressure to predict the cardiac output response to PEEP.
PURPOSE: The purpose of this study was to determine whether the pattern of respiratory variation in right atrial pressure (Pra) predicts the cardiac output response to positive end-expiratory pressure (PEEP). MATERIALS AND METHODS: We studied 18 patients with a variety of cardiac and pulmonary disorders requiring ventilatory support. A pulmonary artery flotation catheter was in place as part of their routine management. Changes in PEEP were made from 0 to 14 cm H2O to determine the level of PEEP, which increased PO(2) without decreasing cardiac output (ie, assessment of best PEEP). Static lung compliance and auto-PEEP were obtained from the pressure signal on the ventilator. The change in Pra with a spontaneous inspiratory effort (ie, triggered breath) was used to determine whether patients had a restrictive (ie, operating on the flat part of the Starling curve), or nonrestrictive pattern (acting on the ascending part of the Starling curve) as previously described. RESULTS: Cardiac output decreased 0.7 +/- 0.8 L/min (change from baseline P <.05) in the group with an inspiratory decrease in Pra and -0.04 +/- 1.50 L/min (P = NS) in the group without an inspiratory decrease in Pra. The groups were not significantly different. However, the variance in cardiac output was large and, in contrast to our hypothesis, two patients in the group with an inspiratory decrease in Pra did not have a decrease in cardiac output. Pra and pulmonary artery occlusion pressure after the PEEP trial were greater than before, indicating that reflex circulatory adjustments occurred in response to the PEEP. CONCLUSIONS: The inspiratory pattern in Pra does not predict the response to cardiac output to PEEP in individual patients. This is most likely because of reflex adaptations in the circuit that occur with the application of PEEP. The response of a patient to PEEP is affected by the patient's volume reserves, filling status of the right atrium, and neurosympathetic activity.
Adult↗
Regional changes in constitutive nitric oxide synthase and the hemodynamic consequences of its inhibition in lipopolysaccharide-treated pigs.
The role of constitutive nitric oxide synthases (cNOS) in sepsis remains controversial. Part of the problem is that many of the studies have been performed in rats, which respond differently than larger animals. Our objective, therefore, was to determine whether cNOS, i.e. ecNOS (NOS-3) and nNOS (NOS-1) are still active in vessels of pigs treated with lipopolysaccharide (LPS) from Escherichia coli. We also characterized the dose-response relationship of the NOS inhibitor N(G)-nitro-L-arginine-methyl-ester (L-NAME) in the arterial, venous, and pulmonary circuits as a reflection of NO production. We anesthetized and ventilated 14 pigs, which were instrumented for hemodynamic measurements. We measured mean circulatory filling pressure and resistance to venous return by transiently arresting the circulation with a balloon in the right atrium. Animals were given 20 microg/kg of LPS (n = 8) or saline (n = 6) over 2 h. They were then given progressively increasing doses of L-NAME (0.5 to 16 microg/kg). We injected 20 microg boluses of norepinephrine at baseline, after 2 h, and after 0.5, 4, and 16 microg of L-NAME to test the pressor response. Tissue was obtained from six control animals followed for 2 h, eight animals treated with LPS for 2 h and then sacrificed, and four animals treated for 2 h and sacrificed after 2 more h. Cardiac output did not change, and the systemic vascular resistance fell in LPS animals. By Western analysis, ecNOS was increased in LPS animals at 2 and 4 h in the aorta and vena cava, and this was paralleled by changes in nNOS in the vena cava. In contrast, ecNOS decreased in the pulmonary artery and nNOS did not change. Calcium-dependent NOS activity increased with LPS in the aorta and vena cava but decreased in pulmonary artery at 4 h. The dose-response relationships to L-NAME for systemic vascular resistance, resistance to venous return, and cardiac output were shifted to the left after LPS in support of increased sensitivity supporting increased NO. The pressor response to norepinephrine was depressed after LPS and was partially restored with 4 mg/kg of L-NAME, but this dose produced 90% of the fall in cardiac output. In conclusion, in contrast to rats, cNOS activity is present in the systemic vessels of LPS-treated pigs and could play a role in the pathophysiology of sepsis.
Animals↗
Presence of nitrotyrosine with minimal inducible nitric oxide synthase induction in lipopolysaccharide-treated pigs.
The production of large amounts of nitric oxide (NO) by the inducible form of nitric oxide synthase (iNOS) and the subsequent production of peroxynitrite (OONO-) are believed to be major factors in the hemodynamic abnormalities of sepsis. This finding is based on data from rats and mice but has not been established in other species. Therefore, we examined the role of iNOS in lipopolysaccharide (LPS)-treated pigs, which have a hemodynamic pattern with sepsis that is more similar to humans than rats. Pigs were anesthetized, ventilated, and given LPS (n = 12), 20 microg/kg over 2 h, or saline (n = 7). They were killed after 2 (n = 8 LPS, 7 control) or 4 h (4 LPS). We measured cardiac output (CO), mean arterial (Part), and pulmonary and central venous pressures. We evaluated NO production by measuring expired NO, and plasma nitrate/nitrite concentration, NOS activity (in lung tissue), and iNOS protein by Western analysis, and immunohistochemistry (lung and liver), as well as iNOS mRNA by Northern analysis (liver and lung). We also measured nitrotyrosine as evidence of OONO- production by slot blot, Western analysis, and immunohistochemistry. By 2 h, Part fell and CO did not change so that systemic vascular resistance decreased from 21.5+/-2.9 to 12.7+/-3.1 mmHg x L(-1) x min (P < 0.05) and remained at 11.3+/-1.7 mmHg x L(-1) x min in the animals observed for 4 h. Plasma nitrate/nitrite, expired NO, and NOS activity did not change. We found no iNOS in tissues by Western analysis with 5 different antibodies but detected a small amount of iNOS by immunohistochemistry in inflammatory cells and small vessels. There was a small increase in iNOS mRNA in liver and lung. Despite the minimal increase in iNOS, nitrotyrosine was increased in small vessels and in inflammatory cells. In conclusion, caution should be used when extrapolating the septic response in rodents to other species, for the pattern of iNOS induction is very different.
Animals↗
Regional distribution of endothelin-1 and endothelin converting enzyme-1 in porcine endotoxemia.
Endothelin-1 (ET-1) levels are markedly increased in sepsis. Since ET-1 is primarily transcriptionally regulated, there should be a corresponding increase in pre-pro-endothelin-1 (ppET-1). Our objective was to determine whether ppET-1 is increased in pigs with a low systemic vascular resistance. We also examined the distribution of ET-1 and the regulation of endothelin-converting enzyme 1 (ECE-1), the rate limiting enzyme in ET-1 production. We anesthetized and ventilated 16 pigs. We measured arterial, pulmonary, and central venous pressures, as well as cardiac output. ET-1 was measured by radioimmunoassay in plasma and in multiple tissues. We infused 20 microg/kg of endotoxin over 2 h and then sacrificed the animals. ppET-1 and ECE-1 mRNA were assessed by Northern analysis. We performed immunohistochemistry for the assessment of tissue ET-1 and ECE-1. The systemic vascular resistance rose at 30 min, but fell by 120 min. Plasma ET-1 more than doubled by 2 h. However, there was no change in the concentration of ET-1 in any tissue except in the pulmonary artery. By immunohistochemistry, there was also no change in ET-1 in aorta, vena cava, heart, lung, liver, and kidney. Distribution of ECE-1 followed that of ET-1 on immunohistochemistry. There was a significant increase in ppET-1 mRNA in liver, kidney papillae, and vena cava, and a tendency for an increase in other tissues. This was paralleled by an increase in ECE-1 mRNA. In conclusion, the amount of ECE-1 mRNA and protein parallel those of ET-1. Endotoxemia is associated with a marked increase in plasma ET-1 and an increase in ppET-1 and ECE-1 mRNA in multiple tissues; however, there was no significant change in tissue ET-1 except in the pulmonary artery. The rise in plasma levels without a change in tissue levels suggests a greater release into the vasculature in sepsis than under normal conditions.
Animals↗
Differential expression of Tie-2 receptors and angiopoietins in response to in vivo hypoxia in rats.
In this study, we assessed the effects of in vivo hypoxia on the expression of Tie-2 receptors and angiopoietins in various organs of conscious rats and correlated these effects with the expression of hypoxia-inducible factor-1 (HIF-1). RT-PCR and Southern blotting were used to amplify mRNA expression of angiopoietin-1, -2, and -3, Tie-2, and HIF-1 alpha in tissues of normoxic and hypoxic (fraction of inspired oxygen of 9--10% for either 12 or 48 h) rats. Hypoxia provoked a decline in angiopoietin-1 mRNA and Tie-2 mRNA, protein, and phosphorylation levels in the lung, liver, cerebellum, and heart but not in the kidney and diaphragm. In comparison, hypoxia raised the levels of angiopoietin-2 mRNA in the cerebellum and angiopoietin-3 mRNA in the lung, kidney, and diaphragm. HIF-1 alpha mRNA was abundant in most organs of normoxic rats but was significantly induced in the kidney and diaphragm of hypoxic rats. We conclude that in vivo hypoxia exerts inhibitory effects on the activity of the angiopoietin-1/Tie-2 receptor pathway through reduction of angiopoietin-1 and upregulation of angiopoietin-2 and -3. Induction of angiopoietin-3 in the kidney and diaphragm of hypoxic rats could be mediated through the HIF-1 transcription factor.
Angiopoietin-1↗
The limitations of evidence from randomized trials.
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Heart Failure↗
Role of poly-(ADP-ribose) synthetase in lipopolysaccharide-induced vascular failure and acute lung injury in pigs.
PURPOSE: To assess the contribution of poly (adenosine 5'-diphosphate ribose) synthetase (PARS) to the development of bacterial lipopolysaccharide (LPS)-induced acute lung injury and vascular failure in pigs. MATERIALS AND METHODS: Four groups of anesthetized, paralyzed, and mechanically ventilated domestic white pigs. Group 1 served as control, whereas Escherichia coli LPS (20 microg/kg/h) was continuously infused in group 2. Group 3 received 20 mg/kg injection of 3-aminobenzamide (a selective inhibitor of PARS activity) 15 minutes before LPS infusion. Only 3-aminobenzamide and not LPS was injected in group 4. All animals were examined for 180 minutes. Systemic and pulmonary hemodynamics and lung mechanics were measured during the experimental period. Lung wet/dry ratio, bronchoalveolar lavage (BAL) protein levels and cell counts and lung nitrotyrosine (footprint of peroxynitrite) immunostaining were also measured in a few animals. RESULTS: LPS infusion evoked a progressive decline in systemic arterial pressure, a small increase in cardiac output, and biphasic elevation of pulmonary arterial pressure. Lung compliance declined progressively, whereas lung and total respiratory resistance rose significantly after LPS infusion. Prominent nitrotyrosine immunostaining was detected around small airways and pulmonary endothelium of LPS-infused animals. No significant changes in lung wet/dry ratio and BAL protein levels and cell counts were produced by LPS infusion. Pretreatment with 3-aminobenzamide did not alter the systemic and pulmonary hemodynamic responses to LPS infusion but eliminated the rise in pulmonary and total respiratory resistance. CONCLUSIONS: We concluded that PARS activation plays an important role in the changes of lung mechanics associated with LPS-induced acute lung injury but had no role in vascular failure.
Animals↗
Endothelin receptor blockade attenuates lipopolysaccharide-induced pulmonary nitric oxide production.
Increased nitric oxide (NO) synthesis by the inducible nitric oxide synthase (iNOS) has been shown to contribute to the development of acute lung injury and delayed hypotension in animals injected with bacterial lipopolysaccharides (LPS). Recent evidence indicates that endothelin-1 (ET-1) is also elevated in septic humans and in animals. To assess the contribution of ETs to LPS-induced pulmonary NO production and iNOS expression, we used P1/fl, a 22 amino acid peptide, to selectively antagonize endothelin-A receptors. Anesthetized, mechanically ventilated rats were injected with either saline or LPS (E. coli endotoxin, 20 mg/kg) and studied for 5 h. Two other groups of rats were pretreated 15 min earlier with P1/fl peptide (20 microg/kg). Unlike saline-treated rats, rats injected with LPS showed a progressive decline in arterial pressure and a significant rise in plasma ET concentration and serum nitrite-nitrate level. In the lungs, LPS injection elicited a several-fold rise in lung iNOS activity and exhaled NO concentration and increased lung wet/dry ratio significantly. Pretreatment with P1/fl peptide eliminated the decline in arterial pressure, the rise in lung wet/dry ratio, lung NOS activity, and iNOS protein expression and significantly attenuated the increase in pulmonary exhaled NO production but had no effect on plasma ET concentration. We conclude that activation of ET-A receptors by rising ET-1 concentration enhances NO production and iNOS expression in the respiratory and vascular systems and contributes to both LPS-induced hypotension and acute lung injury.
Animals↗
Regulators of G-protein signaling (RGS) 1 and 16 are induced in response to bacterial lipopolysaccharide and stimulate c-fos promoter expression.
Regulators of G-protein signaling (RGS) are negative regulators of G-protein-coupled receptor (GPCR) signaling. Sepsis is a pathophysiological condition that is induced primarily in response to bacterial infection and is associated with decreased responsiveness to a number of vasoactive GPCR agonists. Using a degenerate RT-PCR screen, we report that RGS1 and RGS16 were amplified from the heart and aorta of septic animals. By Northern blot analysis, RGS1 and RGS16 were upregulated, with their respective levels increasing 6- and 50-fold in septic hearts. Using a yeast-based bioassay, both RGS1 and RGS16 were found to be equipotent in their ability to attenuate GPCR signaling. These results suggest that both RGS1 and RGS16 contribute to the sepsis-mediated decrease in GPCR signaling. Elevated levels of some RGSs may also lead to an increase in Gbetagamma-activated signaling pathways in the absence of GPCR agonists. Using a c-fos luciferase reporter gene that is responsive to Gbetagamma-activated signaling pathways, we observed a respective 8- and 7-fold increase in the basal luciferase in serum-deprived transfected mammalian cells overexpressing RGS1 or RGS16. This suggests that RGSs play a role in promoting the sepsis-mediated increases in the activation of intracellular signal transduction pathways.
Amino Acid Sequence↗
Effectiveness of albumin versus normal saline as a test of volume responsiveness in post-cardiac surgery patients.
PURPOSE: A volume challenge is useful for determining whether cardiac output will respond to further volume loading by the Frank-Starling mechanism. To properly test this mechanism, there must be an increase in right atrial pressure (Pra) but this requires variable amounts of normal saline. The purpose of this study was to determine if 100 mL of 25% albumin would reliably provide a predictable increase in Pra and to compare this with a volume challenge with normal saline. As in a previous study, we also examined the potential for the pattern of respiratory variation of Pra to predict the response to a fluid challenge. MATERIALS AND METHODS: Twenty-eight stable patients following cardiopulmonary bypass surgery were studied in a randomized, nonblinded interventional study in an intensive care unit. All patients had pulmonary artery flotation catheter as part of their routine management and were breathing spontaneously. They were randomized to receive sufficient normal saline to increase Pra by 2 mm Hg (n = 15) or 100 mL of 25% albumin (n = 13). We also tested the ability of the respiratory variation in Pra to predict the response to a fluid challenge. They had to have an inspiratory fall in the pulmonary capillary wedge pressure of more than 2 mm Hg as an indication that they had an adequate inspiratory effort. They were classified as either having or not having an inspiratory fall in Pra. We predicted that patients without an inspiratory fall in Pra should not respond to volume loading. RESULTS: In contrast to our prediction, the increase in Pra with albumin was less than the increase with normal saline. However, the cardiac output increased more with albumin, which suggests that there was an increase in cardiac function with the hypertonic, hyperosmolar albumin solution. In the saline group, a lack of inspiratory fall in Pra successfully predicted that cardiac output would fail to increase with an increase in Pra in 8 out of 10 patients given saline, and 5 of 6 patients given albumin. CONCLUSION: A hyperoncotic albumin solution appears to have an inotropic effect in patients following cardiopulmonary bypass procedures. We also again show that the pattern of respiratory variation in right atrial pressure is a useful guide to predict response to volume loading.
Analysis of Variance↗
Porcine endotoxemic shock is associated with increased expired nitric oxide.
OBJECTIVES: Nitric oxide (NO) is believed to decrease systemic vascular resistance in sepsis, but the data are mainly from studies on rats and mice. We tested this hypothesis in pigs and also whether there is induction of the inducible form of nitric oxide synthase (iNOS). DESIGN: Animal study. SETTING: University center. SUBJECTS: Ten pigs. INTERVENTIONS: The pigs were anesthetized and mechanically ventilated. MEASUREMENTS AND MAIN RESULTS: Pulmonary and systemic hemodynamics were monitored and mixed expired NO was measured by chemiluminescence. Animals received 20 microg/kg of endotoxin over 2 hrs. We then infused 25 mg/kg of N(omega)-nitro-L-arginine methyl ester (L-NAME) over 10 mins, followed by 0.5 g/kg of L-arginine, the precursor of NO, for 30 mins more to reverse the effects of L-NAME. Five additional pigs were treated with 20 microg/kg of endotoxin for 2 hrs and followed for another hour. Plasma nitrite/nitrate was measured by Greiss reaction. The animals were then killed and tissues were sampled for iNOS by Western blot, and iNOS messenger RNA by reverse transcriptase polymerase chain reaction. After endotoxin infusion, arterial pressure (BP) initially increased, then decreased to 62+/-1 mm Hg from the baseline of 115+/-4 mm Hg (p<.001). Cardiac output initially decreased, then increased slightly from the baseline of 3.7+/-0.2 to 4.2 +/-0.3 L/min (p<.05). The BP pattern was mirrored by an increase in expired NO concentration from 6.4+/-0.8 to 10.4+/-1.4 parts per billion (p<.05) and increased rate of pulmonary NO excretion in expired gas (VeNO) from 71+/-10 to 146+/-24 pmol/kg/min (p<.05). Inhibition of NOS with L-NAME decreased expired NO concentration and VeNO and increased BP; however, cardiac output decreased. The vasoconstriction produced by L-NAME was partially reversed by L-arginine, and this also increased VeNO from 80+/-18 after L-NAME to 132+/-31 pmol/kg/min (p<.05). Plasma nitrite (n = 5) did not change and there was no iNOS by Western blot analysis in multiple tissues. However, there was a small increase in messenger RNA by reverse transcriptase polymerase chain reaction. CONCLUSIONS: The time course and pattern of changes in expired NO during endotoxemia followed the change in systemic hemodynamics, which supports a causal role for NO in sepsis. However, this is not due to a large production of NO by iNOS induction. The hemodynamic pattern, nitrite in blood, and changes in expired NO also differed markedly from those findings in rodent models and caution should be used in extrapolating from rodents to higher order animals.
Analysis of Variance↗