Specific aims of this proposal are: a) relating changes in cellular calcium homeostasis to prevailing derangements in the hormonal regulation of some aspects of carbohydrate and lipid metabolism at the cellular level in sepsis, and b) helping to define the extent to which these changes cna be attributed to endotoxin actions. Some of these alterations also occur in trauma and burn injury, while others do not. A clinically relevant form of experimental peritonitis will serve as a model for intra-abdominal sepsis. Endotoxicosis will be produced by i.v. injection of a bolus of endotoxin and also by slow delivery of endotoxin via an osmotic minipump over a period of several hours. The latter is a novel approach. Perturbations in calcium homeostasis and selected metabolic parameters will be investigated in isolated adipocytes and hepatocytes. Calcium uptake and efflux will be monitored in whole cells. The uptake and release of free CA++ will be quantitated in subcellular fractions (plasma membrane, mitochonria and endoplasmic reticulum) with antipyrylazo III in a dual wavelength spectrophotometer. Calcium contents of tissues, cells and organelles will be measured by atomic absorption spectrometry. In adipocytes catecholamine-stimulated lipolysis and insulin-stimulated glucose oxidation and antilipolysis will be assessed. In hepatocytes glycogenolysis as well as catecholamine and glucagon-stimulated gluconeogenesis from various substrates will be followed. The proposed studies will further our understanding of the pathophysiology of sepsis. By possibly implicating derangements in CA++ fluxes as mediating mechanisms of metabolic complications in the septic state, we may provide a rational basis for the use of calcium antagonists (e.g. Verapamil) and/or substances of calcium ionophoric activity as beneficial therapeutic agents in septic patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM030312-05
Application #
3277978
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1982-01-01
Project End
1986-12-31
Budget Start
1986-01-01
Budget End
1986-12-31
Support Year
5
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Louisiana State University Hsc New Orleans
Department
Type
School of Medicine & Dentistry
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112
Spitzer, J A (1994) Cytokine stimulation of nitric oxide formation and differential regulation in hepatocytes and nonparenchymal cells of endotoxemic rats. Hepatology 19:217-28
Etheredge, E E; Spitzer, J A (1993) Chronic endotoxemia reversibly alters respiratory burst activity of circulating neutrophils. J Surg Res 55:261-8
Hagar, A F; duSapin, K; Spitzer, J A (1993) Endotoxin infusion primes elicited neutrophils and Kupffer cells for platelet-activating factor-induced and tripeptide formyl-methionine-leucine-phenylalanine-induced basal free intracellular calcium concentration responses. Crit Care Med 21:1750-7
Hagar, A F; Spitzer, J A (1992) The effect of endotoxemia on concanavalin A induced alterations in cytoplasmic free calcium in rat spleen cells as determined with Fluo-3. Cell Calcium 13:123-30
Friedman, H; Newton, C; Pross, S et al. (1992) Continuous infusion of endotoxin depresses splenic blastogenesis. Immunopharmacol Immunotoxicol 14:689-706
Spitzer, J A; Deaciuc, I V (1992) Protein kinase C activity and lipogenesis from glucose in isolated adipocytes of endotoxemic rats. Circ Shock 37:111-6
Pross, S; Newton, C; Widen, R et al. (1992) Splenocyte blastogenesis suppressed in rats implanted with an osmotic pump. Life Sci 50:99-108
Deaciuc, I V; Spitzer, J A (1991) Insulin-like, antilipolytic effect of 12-O-tetradecanoyl phorbol 13-acetate in rat white adipocytes. Proc Soc Exp Biol Med 197:193-6
Rodriguez de Turco, E B; Spitzer, J A (1991) Hepatic phosphatidylinositol kinase activity in continuously endotoxemic rats. Biochim Biophys Acta 1093:216-22
Deaciuc, I V; Spitzer, J A (1991) Down-regulation of prostaglandin F2 alpha receptors in rat liver during chronic endotoxemia. Prostaglandins Leukot Essent Fatty Acids 42:191-5

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