Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Low-dose ('renal-dose') dopamine (i.e. 1-3 micrograms/kg per min) is used widely for the treatment of acute renal failure induced by ischaemia, toxins and/or sepsis. Here we review the scientific rationale, experimental studies and clinical trials evaluating its use in these settings. 2. Renal-dose dopamine augments renal blood flow, sodium excretion and probably glomerular filtration rate in healthy humans and experimental animals and limits ATP utilization and oxygen requirements in nephron segments at risk of ischaemic injury. Renal-dose dopamine is renoprotective in several ischaemic and nephrotoxic models of acute renal failure. 3. However, most studies in humans have not demonstrated prevention of acute renal failure in high-risk patients or improved outcome in those with established acute renal failure. While the safety profile of dopamine in these settings has not been extensively defined, it is known the drug may precipitate serious cardiovascular and metabolic complications in the critically ill. Therefore, we suggest that renal-dose dopamine should not be used for selective renal vasodilatory and natriuretic actions in those patients with acute renal failure until its efficacy is established in randomized control trials. 4. Renal-dose dopamine may be most valuable when combined with agents targeting other events in acute renal failure, such as cast formation, epithelial cell injury and tubule regeneration. These recommendations should not preclude the use of dopamine for its systemic effects in heart failure and septic shock.
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PMID:Renal-dose (low-dose) dopamine for the treatment of sepsis-related and other forms of acute renal failure: ineffective and probably dangerous. 1038 50

High blood lactate concentration (hyperlactacidaemia) in trauma or sepsis is thought to indicate tissue hypoxia and anaerobic glycolysis even when blood pressure, cardiac output, and urine output are within clinically acceptable ranges. However, mechanisms of lactate generation by well-oxygenated tissues have received little attention. Within cells, oxidative and glycolytic energy production can proceed in separate, independent compartments. In skeletal muscle and other tissues, aerobic glycolysis is linked to ATP provision for the Na+-K+ pump, the activity of which is stimulated by epinephrine. In injured patients, hypokalaemia may reflect increased Na+,K+-ATPase activity. We propose that increased blood lactate often reflects increased aerobic glycolysis in skeletal muscle secondary to epinephrine-stimulated Na+,K+-ATPase activity and not anaerobic glycolysis due to hypoperfusion. The hypothesis explains why hyperlactacidaemia often neither correlates with traditional indicators of perfusion nor diminishes with increased oxygen delivery. When other variables have returned to normal, continued attempts at resuscitation based on elevated blood lactate may lead to unnecessary use of blood transfusion and inotropic agents in an effort to increase oxygen delivery and lactate clearance.
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PMID:Lactate is an unreliable indicator of tissue hypoxia in injury or sepsis. 1046 91

Changes in protein kinase A (PKA, or cAMP-dependent protein kinase) activity in the rat liver during different metabolic phases of sepsis were investigated. Sepsis was induced by cecal ligation and puncture (CLP). Experiments were divided into 3 groups: control, early sepsis, and late sepsis. Early and late sepsis refer to those animals killed at 9 and 18 h, respectively, after CLP. Hepatic PKA was extracted and partially purified by acid precipitation, ammonium sulfate fractionation, and diethylaminoethyl (DEAE)-cellulose chromatography. PKA was eluted from DEAE-cellulose column with a linear NaCl gradient. Two peaks of PKA, type I (eluted at low ionic strength) and type II (eluted at high ionic strength), were collected and their activities were determined on the basis of the rate of incorporation of [gamma-32-P]ATP into histone. The results show that during early sepsis, both type I and type II PKA activities remained unchanged. During late sepsis, type I PKA activity was decreased by 40.7-53.6%, whereas type II PKA activity was unaffected. Kinetic analysis of the data on type I PKA during the late phase of sepsis reveals that the Vmax (maximal velocity) values for ATP, cAMP, and histone were decreased by 40.7, 53.6, and 47.3%, respectively whereas the Km (substrate concentration required for half-maximal enzymatic activity) values for ATP, cAMP, and histone were unaltered. These data indicate that type I PKA was inactivated during the late hypoglycemic phase of sepsis in the rat liver. Because PKA-mediated phosphorylation plays an important role in the regulation of hepatic glucose metabolism, an inactivation of PKA may contribute to the development of hypoglycemia during the late phase of sepsis.
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PMID:Liver protein kinase A activity is decreased during the late hypoglycemic phase of sepsis. 1050 29

1. Although hepatic function is well known to deteriorate following bacterial infection, the underlying mechanisms remain poorly understood. We have previously reported that nitric oxide (NO) radical leads to a decrease in the ketone body ratio (KBR) and in ATP content due to the inhibition of mitochondrial electron transport in primary cultured rat hepatocytes. 2. To evaluate the effects of NO radical on the liver in patients with postoperative sepsis, we analysed both the stable end-product of nitric oxide radical (NOx) as well as the arterial KBR (AKBR), which reflects liver tissue NAD+/NADH. 3. Twenty patients who had undergone general abdominal surgery and who developed postoperative sepsis were divided into two groups: (i) surviving; and (ii) non-surviving. Blood samples were collected before the development of postoperative sepsis and every 3 days until the patient either died or was discharged from hospital. 4. Plasma NOx levels in seven patients who subsequently died became progressively higher than those in the 13 surviving patients over the clinical course of postoperative sepsis. 5. In the non-surviving group, the AKBR was significantly lower than in surviving patients, indicating impaired hepatic function. In contrast, plasma NOx levels in non-surviving patients were significantly higher than in surviving patients. 6. Decreases in AKBR to levels below 0.7 in non-surviving patients followed high NOx levels. Moreover, plasma NOx levels were closely correlated with the AKBR, indicating that NO radical is associated with mitochondrial dysfunction in the liver. 7. It is likely that the overproduction of NO radical plays an important role in causing fatal metabolic disorders in patients with postoperative sepsis.
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PMID:Nitric oxide production and hepatic dysfunction in patients with postoperative sepsis. 1074 47

The healthy term, and particularly the premature infant, is born with a very low glomerular filtration rate (GFR), controlled by a delicate balance of intrarenal vasoconstrictor and vasodilator forces. Vasoactive disturbances can easily further reduce the already low GFR. The newborn infant is thus prone to develop vasomotor nephropathy (VMNP) or acute renal failure (ARF). The main causes for ARF at this young age are prerenal mechanisms, and include hypotension, hypovolemia, hypoxemia perinatal asphyxia, and neonatal septicemia. Other causes include the administration of angiotensin converting enzyme inhibitors, indomethacin and tolazoline. The most-important factors governing the ultimate renal prognosis are the severity of the underlying disorder, the rapidity of an accurate diagnosis, prompt treatment, and avoidance of severe iatrogenic complications. The immediate treatment is of particular importance in VMNP, i.e., prerenal ischemic ARF, and consists of correcting abnormalities in fluid homeostasis and reduction of the complications of the acute azotemic state (uremia, hyperkalemia, acidosis, and hypertension). In severe and prolonged (established) ARF, temporary dialysis therapy may be indicated. Prerenal ARF with oliguria or anuria warrants immediate volume resuscitation. Special attention should be given to infants with congestive heart failure (CHF). The sick neonate with persistent oliguria and CHF should be treated with intravenous dopamine. Furosemide (FM) is the second line of therapy for babies with indomethacin-induced ARF. In most other conditions, the therapeutic effect of FM is limited to a transient increase in urine flow, without improving basic renal function. The special conditions of the maturing kidney have to be appreciated in order to protect babies from undue renal injury. With the increasing knowledge of the mechanisms governing the development of ARF, progress has been made in the development of new treatment modalities. For example theophylline, calcium antagonists, ATP-MgCl2, thyroxine, and a variety of cytokines may in the near future be used to prevent or ameliorate VMNP and/or recently established ARF. With a combination of time-honored and new therapeutic strategies, there may well be a brighter future for neonates with vasomotor, prerenal, ischemic ARF.
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PMID:The stressed neonatal kidney: from pathophysiology to clinical management of neonatal vasomotor nephropathy. 1075 64

The effect of sepsis on the ubiquitously expressed ATP-sensitive potassium (uK(ATP)-1) channel expression was measured in Sprague-Dawley rat diaphragms. Rats were treated with either 0.5 ml saline or 20 mg/Kg E. coli lipopolysaccharides and sacrificed at 3, 6, 12, 24, or 48 h later. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis showed that channel mRNA expression was increased at 3 h and continued to rise up to 48 h. Western blotting analysis showed a approximately 9-fold increase in channel protein expression 24 h after sepsis. Our results demonstrate that sepsis upregulates the uK(ATP)-1 channel.
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PMID:Induction of the ATP-sensitive potassium (uK(ATP)-1) channel by endotoxemia. 1084 76

A 22-year-old man developed unconsciousness, severe quadriplegia and muscle atrophy, and had markedly elevated serum creatine kinase levels after using the high-dose steroid and nondepolarizing neuromuscular blocking agents during the course of sepsis and DIC. On neurological examination, he was lethargic. The patient had generalized muscle weakness and wasting, and diminished deep tendon reflexes. He weakly responsed to painful stimuli on the legs. The motor nerve conduction study demonstrated decreased CMAP (compound muscle action potential) amplitudes. Motor and sensory nerve conduction velocities and their distal latencies were normal. Muscle biopsy revealed marked muscle fiber atrophy predominantly in type 2 fibers and numerous basophilic and a few necrotic fibers. Some atrophic fibers had decreased to absent myosin adenosine triphosphatase activity in their center. Accordingly, he was diagnosed as having acute quadriplegic myopathy (AQM), which has been reported mainly in Western countries. The mechanism of muscle fiber degradation in this myopathy is still unknown. On immunohistochemical analysis to our patient, enzyme activities of various proteases such as calpain, cathepsin B, and proteasomes were increased in the sarcoplasm, especially in the atrophic fibers. We suggest that lysosomal cathepsin, nonlysosomal calpain, and ATP-ubiquitin-proteasome proteolytic pathways participate in muscle fiber degradation in AQM.
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PMID:[A case of acute quadriplegic myopathy]. 1108 98

Alterations of the ATP-dependent Ca2+ uptake in the cardiac sarcoplasmic reticulum (SR) during the 2 hemodynamically distinct phases of sepsis were investigated. Sepsis was induced by cecal ligation and puncture (CLP). Control rats were sham-operated. The SR vesicles were isolated by sucrose gradient centrifugation. The results show that the rates of ATP-dependent Ca2+ uptake in the cardiac SR were unaffected during the early hyperdynamic phase, whereas they were decreased by 41-46% (P < 0.01) during the late hypodynamic phase of sepsis. Analysis of the kinetics of Ca2+ transport indicates that during the late phase of sepsis, the Vmax values of Ca2+ pump for ATP and Ca2+ were decreased, whereas the affinities of Ca2+ pump for ATP and Ca2+ were unaffected. Magnesium stimulated, whereas vanadate inhibited the ATP-dependent Ca2+ uptake, but the Mg2+-stimulated and the vanadate-inhibited Ca2+ uptake activities were significantly lower during the late sepsis. Phosphorylation of SR by the cAMP-dependent and the calmodulin-dependent protein kinases stimulated the ATP-dependent Ca2+ uptake in the control and the early septic experiments, whereas it failed to stimulate Ca2+ uptake in the late sepsis. The extent of the phosphorylation-stimulated Ca2+ uptake activities was reduced by 65-69% (P < 0.01) during the early sepsis, and they were completely abolished during the late sepsis. These data indicate that the ATP-dependent Ca2+ uptake in cardiac SR was impaired during the late hypodynamic phase of sepsis. The impaired Ca2+ uptake during late sepsis was associated with a defective phosphorylation of SR proteins. Because the ATP-dependent Ca2+ uptake by cardiac SR plays an important role in the regulation of contraction-relaxation coupling, our findings may contribute to the understanding of the pathogenesis of altered cardiac function during the progression of sepsis.
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PMID:Calcium uptake by sarcoplasmic reticulum is impaired during the hypodynamic phase of sepsis in the rat heart. 1119 57

Myocardial function is impaired 24 h after the induction of sepsis, however, recovery of left ventricular (LV) function after 35 min of global ischemia is complete. The mechanisms by which this protection occurs are unknown. Ischemic preconditioning, another form of myocardial protection from ischemia/reperfusion (I/R) injury, has been shown to be modulated by ATP-sensitive potassium (K+ATP) channels. To investigate the role of K+ATP channels in the regulation of coronary flow (CF) and protection from I/R injury in septic rat hearts, we assessed the effects of the K+ATP channel antagonist glibenclamide (GLIB) and the agonist cromakalim (CROM) on pre- and post-ischemic CF and left ventricular developed pressure (LVDP). Although GLIB decreased pre-ischemic CF in both control and septic rat hearts, LVDP was unaffected. After I/R, CF was decreased in GLIB-treated control and septic rat hearts and LVDP was more severely depressed in control rat hearts than in septic rat hearts. CROM increased pre-ischemic CF in the septic group although LVDP was unaltered in both groups. After I/R, control rat heart CF was depressed but LVDP completely recovered. Post-ischemic CF in septic rat hearts was elevated compared with vehicle-treated septic rat hearts, but the recovery of LVDP was not improved. These results suggest that K+ATP channels modulate CF in septic rat hearts, but do not mediate cardioprotection as observed in control rat hearts.
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PMID:The role of K+ATP channels in the control of pre- and post-ischemic left ventricular developed pressure in septic rat hearts. 1129 97

Changes in Ca2+-induced Ca2+ release in cardiac sarcoplasmic reticulum (SR) during different phases of sepsis were studied. Sepsis was induced by cecal ligation and puncture (CLP). The 45Ca2+ release studies show that the amount of Ca2+ released from the passively and the actively loaded SR vesicles was unaffected during the early sepsis (9 h after CLP), but it was significantly decreased during the late phase (18 h after CLP) of sepsis. The [3H]ryanodine binding assays reveal that the Bmax for ryanodine binding was unaffected during the early phase, but was decreased by 32.1% during the late phase of sepsis. The affinity of ryanodine receptor for Ca2+ remained unchanged during sepsis. ATP, AMP-PCP, and caffeine stimulated binding, while MgCl2 and ruthenium red inhibited [3H]ryanodine binding in control, early sepsis, and late sepsis groups. The EC50 and IC50 values for these regulators were unaffected during the progression of sepsis. Digestion of control SR with phospholipase A2 decreased [3H]ryanodine binding and the decrease was reversible by the addition of phosphatidylcholine (PC), phosphatidylethanolamine (PE), or phosphatidylserine (PS). Addition of PC, PE, or PS to the SR isolated from septic rats stimulated [3H]ryanodine binding. These data demonstrate that Ca2+-induced Ca2+ release from cardiac SR remained relatively unaffected during the early phase, but was significantly impaired during the late phase of sepsis. The sepsis-induced impairment in SR Ca2+ release is a result of a quantitative reduction in the number of Ca2+ release channels. Furthermore, the reduction is associated with a mechanism involving a modification of membrane lipid profile in response to certain stimuli such as activation of phospholipase A2.
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PMID:Impairment of the ryanodine-sensitive calcium release channels in the cardiac sarcoplasmic reticulum and its underlying mechanism during the hypodynamic phase of sepsis. 1144 13


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