The Journal of clinical investigation
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During caloric deprivation, the septic host may fail to develop ketonemia as an adaptation to starvation. Because the plasma ketone body concentration is a function of the ratio of hepatic production and peripheral usage, a pneumococcal sepsis model was used in rats to measure the complex metabolic events that could account for this failure, including the effects of infection on lipolysis and esterification in adipose tissue, fatty acid transport in plasma and the rates of hepatic ketogenesis and whole body oxidation of ketones. Some of the studies were repeated with tularemia as the model infection. ⋯ Ketone body usage (oxidation) was either unaffected or reduced during pneumococcal sepsis in rats. Thus, a reduced rate of ketone production in the infected host was primarily responsible for the failure to develop starvation ketonemia under these conditions. The liver of the infected rat host appears to shuttle the fatty acids away from beta-oxidation and ketogenesis and toward triglyceride production, with resulting hepatocellular fatty metamorphosis.
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Comparative Study
Purinogenic immunodeficiency diseases. Differential effects of deoxyadenosine and deoxyguanosine on DNA synthesis in human T lymphoblasts.
Deoxyadenosine and deoxyguanosine are toxic to human lymphoid cells in culture and have been implicated in the pathogenesis of the immunodeficiency states associated with adenosine deaminase and purine nucleoside phosphorylase deficiency, respectively. We have studied the relative incorporation of several labeled nucleosides into DNA and into nucleotide pools to further elucidate the mechanism of deoxyribonucleoside toxicity. In the presence of an inhibitor of adenosine deaminase [erythro-9-(2-hydroxy-3-nonyl)adenine [EHNA], 5 muM], deoxyadenosine (1-50 muM) progressively decreased the incorporation of thymidine, uridine, and deoxyuridine into DNA, but did not affect uridine incorporation into RNA. ⋯ In contrast, deoxyadenosine plus EHNA did not show this differential inhibition of [(3)H]uridine incorporation into DNA, and the alteration in [(3)H]cytidine incorporation into nucleotide pools was less impressive. These data show an association between accumulation of dATP or dGTP and a primary inhibition of DNA synthesis, and they provide support for ribonucleotide reductase inhibition as the mechanism responsible for deoxyguanosine toxicity. Deoxyadenosine toxicity, however, appears to result from another, or perhaps a combination of, molecular event(s).
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This free-flow micropuncture study examined the dependence of bicarbonate reabsorption in the rat superficial proximal convoluted tubule to changes in filtered bicarbonate load, and thereby the contribution of the proximal tubule to the whole kidney's response to such changes. The independent effects of extracellular fluid (ECF) volume expansion and of acidosis on proximal bicarbonate reabsorption were also examined. When the plasma volume contraction incurred by the micropuncture preparatory surgery was corrected by isoncotic plasma infusion ( congruent with1.3% body wt), single nephron glomerular filtration rate (SNGFR), and the filtered total CO(2) load increased by 50%. ⋯ In conclusion, bicarbonate reabsorption in the superficial proximal convoluted tubule is highly load-dependent (75-90%) in normal and acidotic rats. No inhibitory effect of ECF volume per se on proximal bicarbonate reabsorption, independent of altering the filtered bicarbonate load, could be discerned. Acidosis enabled the end-proximal luminal bicarbonate concentration to fall below normal values and reduced distal bicarbonate delivery.
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Beneficial effects of nitroprusside infusion in heart failure are purportedly a result of decreased afterload through "impedance" reduction. To study the effect of nitroprusside on vascular factors that determine the total load opposing left ventricular ejection, the total aortic input impedance spectrum was examined in 12 patients with heart failure (cardiac index <2.0 liters/min per m(2) and left ventricular end diastolic pressure >20 mm Hg). This input impedance spectrum expresses both mean flow (resistance) and pulsatile flow (compliance and wave reflections) components of vascular load. ⋯ Improved ventricular function persisted when aortic pressure was restored to control values with simultaneous phenylephrine infusion in three patients. These data indicate that nitroprusside acutely alters both the mean and pulsatile components of vascular load to effect improvement in ventricular function in patients with heart failure. The evidence presented suggests that it may be possible to reduce vascular load and improve ventricular function independent of aortic pressure reduction.
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We have examined whether lung hyperinflation in the anesthetized dog reflexly depresses cardiac output, stroke volume, heart rate, and blood pressure and whether these changes persist for more than a minute. To eliminate any mechanical restriction to venous return and pulmonary blood flow during lung hyperinflation, a model was developed in which all pulmonary artery blood flow and all ventilation were directed to the right lung in dogs with widely open chest and the left lung was hyperinflated before and after left cervical vagotomy. Heart rate, stroke volume, and blood pressure decreased by 24, 20, and 27%, respectively, within 15 s of left lung inflation to 30 cm H(2)O. ⋯ After left cervical vagotomy the transient fall in heart rate, stroke volume, and blood pressure during left lung hyperinflation was greatly reduced or eliminated. These results suggest that unilateral lung hyperinflation reflexly depresses heart rate and blood pressure, which are partially compensated with time, and reflexly depresses stroke volume, which persists uncompensated until the lung is deflated. These findings may explain the depressed cardiovascular function observed during regional lung overdistention especially when it occurs during positive pressure ventilation.