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Biomedical subjects

K P Moore

Publications and source records attributed to K P Moore.

At least 37 records · Page 2Linked to original sources
PubMed1993

Effect of supernatants from Kupffer cells stimulated with galactosamine and endotoxin on the function of isolated rat hepatocytes.

Activated Kupffer cells may release substances that are involved in liver injury induced by galactosamine and endotoxin. In the present study Kupffer cells were isolated from rat livers, cultured for 24 hours and incubated with galactosamine, endotoxin (LPS) or tumor necrosis factor-alpha for 4 or 24 hours. The Kupffer cell-conditioned media were than added in separate experiments to freshly prepared isolated rat hepatocytes to determine their cytotoxic effect. No significant effects on the rate of protein synthesis, as assessed by the incorporation of 14C-leucine on lactate dehydrogenase enzyme release from hepatocytes during 1 h incubation was found as compared with conditioned media from control Kupffer cells. In further experiments, Kupffer cells incubated for 4 hours with LPS and galactosamine were shown to produce thromboxane B2 and also the potentially cytoprotective prostaglandins PGE2 and small amounts of prostacyclin measured as 6-keto-PGF1 alpha. It is concluded that under the conditions of the present experiments, factors secreted by cultured Kupffer cells have no cytotoxic effects on isolated rat hepatocytes during short-term incubation.

Animals↗
PubMed1992

Synthesis and metabolism of cysteinyl leukotrienes by the isolated pig kidney.

The metabolism and synthesis of cysteinyl leukotrienes by the isolated perfused pig kidney has been investigated. Kidneys were maintained for up to six hours in a recirculating perfusion system by using an oxygenated Krebs-Henseleit buffer containing albumin and the perfluorinated oxygen carrier, FC-43. Perfusion pressure was maintained at 12-13.5 kPa, with perfusion flow rates of 150-250 ml/min resulting in a urine output of between 20-180 ml/hr. Infusion of 3H-LTC4 into the renal artery resulted in rapid and complete metabolism, with the major urinary metabolites comprising LTE4, omega-hydroxy-LTE4, omega-carboxy-LTE4 and N-acetyl-omega-hydroxy-LTE4. The capacity of the isolated kidney to synthesize cysteinyl leukotrienes was monitored by measuring urinary LTE4 excretion; there was a basal urinary excretion of LTE4 (median 43 pg/min, range 8-470 pg/min). Neither lipopolysaccharide or human recombinant tumor necrosis factor alpha had any effect on basal excretion. Treatment with the calcium ionophore A23187, however, resulted in a 38.1 +/- 9.6-fold increase in urinary LTE4 excretion. We conclude that the isolated pig kidney, in the absence of circulating cells, can synthesize cysteinyl leukotrienes in the absence of circulating cells, which can then undergo extensive oxidative metabolism.

Animals↗
PubMed1992

Response to atrial natriuretic peptide, endopeptidase 24.11 inhibitor and C-ANP receptor ligand in the rat.

1. The present studies compared the renal and hypotensive response to (a) exogenous atrial natriuretic peptide (ANP) (99-126), (b) an endopeptidase-24.11 inhibitor (candoxatrilat) and (c) an antagonist of ANP clearance receptors (SC 46542) in conscious rats. 2. Infusion of low-dose-ANP (100 ng kg-1 min-1) produced a gradual increase in urinary sodium and guanosine 3':5'-cyclic monophosphate (cyclic GMP) excretion without significant change in glomerular filtration rate (GFR) or fractional lithium clearance (FeLi). There was a significant fall in blood pressure. 3. Infusion of high-dose ANP (300 ng kg-1 min-1) produced a brisk, 3 fold increase in urinary sodium and cyclic GMP excretion along with a rise in GFR, but had no significant effect on FeLi compared to the control group. The renal response was accompanied by a pronounced fall in blood pressure. 4. Candoxatrilat or SC 46542, alone, had no significant effect on sodium excretion compared to control animals. Both compounds enhanced the natriuretic and cyclic GMP responses to a low-dose ANP infusion (100 ng kg-1 min-1) to levels similar to, or greater than, those observed with the high-dose ANP (300 ng kg-1 min-1). However, unlike high-dose ANP, these renal effects were not accompanied by a significant change in GFR and neither compound potentiated the hypotensive effect of the low-dose ANP infusion. Only candoxatrilat when given with ANP produced a marked rise in FeLi.5. Similarly, combined administration of candoxatrilat and SC 46542 (without exogenous ANP) induced an increase in sodium and cyclic GMP excretion comparable to high-dose ANP but did so without a significant increase in GFR and with a significantly smaller fall in blood pressure. Interestingly, there was no increase in FeLi with the combination of the two compounds, suggesting that the major contribution to sodium excretion came from SC 46542.6. Both candoxatrilat and SC 46542 increased sodium and cyclic GMP excretion in the rat A-V fistula model of heart failure, a model hyporesponsive to infusions of ANP, without significant change in blood pressure.7. These data show that candoxatrilat and SC 46542 do not simply reproduce the effects of an ANP infusion but preferentially enhance the natriuretic response to ANP. Inhibition of E-24.11 may potentiate a tubule action of ANP while the renal mechanism of action of the C-ANP receptor ligand needs further study. Both manipulations are of potential value in the management of heart failure.

Animals↗
PubMed1991

Leukotriene and prostaglandin production after infusion of tumour necrosis factor in man.

Tumor necrosis factor-alpha is believed to be an important mediator of endotoxaemia and septic shock, the effects of which are thought to be mediated through the generation of cysteinyl-leukotrienes, thromboxane A2 and other prostanoids. We have investigated the production of these eicosanoids and also that of prostacyclin in vivo after infusion of tumor necrosis factor-alpha into 4 subjects with a chronic hepatitis B virus infection. This resulted in plasma TNF levels considerably greater than those observed in septic shock. Urinary excretion rate of leukotriene E4 increased by 2 to 3-fold in all subjects by 8 h following TNF infusion. Urinary excretion of thromboxane B2 and 6-oxo-prostaglandin F1 alpha, however, increased in the first 4 h in 3/4 subjects by 2 to 40-fold and returned towards baseline by 8 h. Excretion of the hepatic metabolite, 2,3-dinor 6-oxo-prostaglandin F1 alpha, increased in all subjects (2 to 4-fold at 4h). We conclude that there is increased production of cysteinyl leukotrienes, thromboxane A2 and prostacyclin after infusion of tumour necrosis factor into man.

Adult↗
PubMed1990

Metabolism of cysteinyl leukotrienes in monkey and man.

The proinflammatory cysteinyl leukotrienes are inactivated in primates by (a) intravascular degradation, (b) hepatic and renal uptake from the blood circulation, (c) intracellular metabolism of leukotriene E4 (LTE4), and (d) biliary and renal excretion of LTC4 degradation products. We have analyzed cysteinyl leukotriene metabolites excreted into bile and urine of the monkey Macaca fascicularis and of man. In both species, hepatobiliary leukotriene elimination predominated over renal excretion. In a representative healthy human subject at least 25% of the administered radioactivity were recovered from bile and 20% from urine within 24 h. In monkey and man intravenous administration of 14,15-3H2-labeled LTC4 resulted in the biliary and urinary excretion of labeled LTE4, omega-hydroxy-LTE4, omega-carboxy-LTE4, omega-carboxy-dinor-LTE4, and omega-carboxy-tetranor-dihydro-LTE4. Small amounts of N-acetyl-LTE4 were detected in human urine only. Oxidative metabolism of LTE4 proceeded more rapidly in the monkey resulting in the formation of higher relative amounts of omega-oxidized leukotrienes in this species as compared to man. [3H]H2O amounted to less than 2% of the administered dose in monkey and human bile and urine samples. Incubation of isolated human hepatocytes with [3H2]LTC4, [3H2]LTD4, and [3H2]LTE4 showed that only [3H2]LTE4 underwent intracellular oxidative metabolism resulting in the formation of omega- and beta-oxidation products. N-Acetylated LTE4 derivatives were not detected as products formed by human hepatocytes. By a combination of reversed-phase high-performance liquid chromatography and radioimmunoassay, endogenous LTE4 and N-acetyl-LTE4 were detected in human urine in concentrations of 220 +/- 40 and 24 +/- 3 pM, corresponding to 12 +/- 1 and 1.5 +/- 0.2 nmol/mol creatinine, respectively (mean +/- SEM; n = 10). Endogenous LTD4 and LTE4 were detected in human bile (n = 3) in concentrations between 0.2-0.9 nM. Our results demonstrate that LTD4 and LTE4 are major LTC4 metabolites in human bile and/or urine and may serve as index metabolites for the measurement of endogenously generated cysteinyl leukotrienes. Moreover, omega-oxidation and subsequent beta-oxidation from the omega-end contribute to the metabolic degradation of LTE4 not only in monkey but also in man.

Acetylation↗
PubMed1990

Increased production of cysteinyl leukotrienes in hepatorenal syndrome.

The cysteinyl leukotrienes C4 and D4 are potent renal vasoconstrictors which may modulate glomerular function in vivo, and may therefore be important in the pathogenesis of hepatorenal syndrome. Urinary leukotriene E4, the major metabolite of leukotrienes C4 and D4, was elevated in patients with hepatorenal syndrome (17.8 ng/h) when compared with normal controls (5.1 ng/h) or subjects with renal failure alone (1.9 ng/h). Urinary leukotriene E4 was also elevated in subjects with decompensated liver disease (cirrhosis with ascites 28.6 ng/h, severe hepatocellular dysfunction 57.5 ng/h), but normal in compensated liver disease (6.7 ng/h). In the early stages of hepatorenal syndrome, leukotriene E4 excretion rate was up to 100-fold higher (560 ng/h) than in normals, and fell in parallel with creatinine clearance, indicative of the glomerular filtration rate-dependent renal excretion. Following correction for creatinine clearance, leukotriene E4, excretion was considerably higher in hepatorenal syndrome (54.1 pg/ml creatinine clearance) compared with normals (1.0 pg/ml creatinine clearance), chronic renal failure (3.2 pg/ml creatinine clearance), decompensated liver disease (ascites 7.7 pg/ml creatinine clearance, and severe hepatocellular dysfunction 11.0 pg/ml creatinine clearance), and compensated liver disease (1.9 pg/ml creatinine clearance). To interpret the significance of these findings, we determined renal clearance and endogenous metabolism of the cysteinyl leukotrienes by infusion of [3H]leukotriene C4 into a single subject with hepato-renal syndrome and two control subjects. Renal clearance of leukotriene E4, was reduced in hepatorenal syndrome (2.4 ml/min) compared with controls (greater than 17 ml/min) which together with the increased excretion rate of leukotriene E4 demonstrates that there is increased cysteinyl leukotriene production in hepatorenal syndrome. This may be one of the factors involved in its pathogenesis.

Adolescent↗
PubMed1988

Frequency of pancreatitis in fulminant hepatic failure using isoenzyme markers.

Evidence of acute pancreatitis was sought in 35 patients with fulminant hepatic failure. Total amylase was raised in 22 patients and isoenzyme separation showed a distinct P3 isoenzyme (indicative of pancreatitis) in 14. In four patients with marked hyperamylasaemia (greater than 1000 U/l) the predominant isoenzyme was the salivary fraction. Pancreatic lipase was abnormally raised (greater than 200 U/l) in 34 patients but exceeded 1000 U/l in 12 of the 14 with a distinct P3 isoenzyme. Thus on the basis of a distinct P3 isoenzyme of amylase and an increased pancreatic lipase activity evidence of pancreatitis was found in 34% of patients in this series.

Acute Disease↗
PubMed1987

Anaesthesia for congenital hypertrophic pyloric stenosis. A review of 350 patients.

The anaesthetic management of 350 consecutive patients with congenital hypertrophic pyloric stenosis over an 8-year period is reviewed. The anaesthetic technique is discussed and the complications encountered reviewed. The morbidity rate was 15.9%. The anaesthetic related morbidity rate was 3.7%. One patient in the series died (0.27%) 8 weeks after pyloromyotomy, as a result of an underlying myopathy.

Anesthesia, Inhalation↗