Biomedical subjects

J A Spitzer

Publications and source records attributed to J A Spitzer.

At least 73 records · Page 4Linked to original sources

PubMed1988

Early effects of Escherichia coli endotoxin infusion on vasopressin-stimulated breakdown and metabolism of inositol lipids in rat hepatocytes.

The turnover of vasopressin-stimulated 32P-phosphoinositides and 32P-phosphatidic acid and accumulation of [2-3H]-inositol phosphates were examined in hepatocytes from rats infused i.v. with saline and E. coli endotoxin for 3 hrs. Within 60s of VP stimulation the decrease in phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate labeling as well as the increased uptake of 32P into phosphatidic acid were similar in both groups. However, at a later time (300s) the 32P-phosphatidylinositol turnover was greatly decreased concomitantly with a higher labeling of phosphatidic acid. The accumulation of [2-3H]-inositol phosphates in ET-cells was significantly decreased both at 30s and 600s after VP addition. The distribution of [2-3H]-inositol labeling accumulated in the different inositol phosphate fractions over the first 30s of VP stimulation showed a tendency to lower accumulation of inositol trisphosphate, and a significantly lower accumulation of inositol bisphosphate simultaneously with a higher labeling of the inositol tetrakisphosphate fraction. These observations reflect an early effect of ET-infusion on VP-stimulated inositol lipid turnover and on the subsequent metabolism of the released inositol phosphates.

Animals↗

PubMed1988

Kinetics of diacylglycerol accumulation in response to vasopressin stimulation in hepatocytes of continuously endotoxaemic rats.

The content and composition of 1,2-diacyl-sn-glycerol (1,2-DAG) was determined in hepatocytes from saline (0.9% NaCl)- and Escherichia coli endotoxin (ET)-infused rats upon continuous vasopressin (VP) (10(-8) M) stimulation. In both experimental groups the accumulation of 1,2-DAG was detected after a lag period (2-5 min), was sustained up to the last time analysed (10 min), and C18:0- and C20:4-fatty-acid-containing-DAG accumulation preceded that of DAG containing other acyl groups. In hepatocytes from ET-infused rats the VP-induced accumulation of DAG was delayed and was decreased by 50%, showing a C18:0/C20:4 molar ratio of 1.6 as compared with 1.1 for cells from saline-infused rats. A similar lower cellular response to VP stimulation was observed in cells prelabelled with [14C]C20:4 fatty acid. The accumulation of [14C]C20:4-DAG (lower in ET than in saline-infused rats) was paralleled by a decrease in phosphatidylinositol (PI) labelling, whereas phosphatidic acid showed a transient increase by 5 min in saline- but not in ET-infused rats. The present results demonstrate that the previously reported impairment in the early degradation of poly-PI and later in the 'PI cycle' during VP stimulation [Rodriguez de Turco & Spitzer (1987) Metab. Clin. Exp. 36, 753-760] is also reflected at the level of their phosphodiesteratic product, DAG. Moreover, the kinetics of the accumulation of DAG acyl groups is consistent with the idea that the initial release of C18:0- and C20:4-DAG (possibly derived from inositol lipids) could regulate the subsequent enlargement of this pool by stimulating a phospholipase C-mediated degradation of other phospholipids (e.g. phosphatidylcholine).

Animals↗

PubMed1988

Perturbation of glycerolipid content and biosynthesis in hepatocytes of rats continuously infused with Escherichia coli endotoxin.

The effect of chronic, nonlethal endotoxemia on the endogenous content and de novo biosynthesis of glycerolipids was investigated in rat hepatocytes. Continuous E. coli endotoxin (ET) infusion for 30 hours through a subcutaneously implanted mini-pump greatly altered the composition of membrane phospholipids. Sphingomyelin (SPH) and phosphatidylserine (PS) content increased by 56% and 29%, respectively, while the content of phosphatidylcholine (PC) decreased slightly (6%) as compared with saline-infused rats. These effects contrasted with those observed in pair-fed rats (whose food intake was matched to that voluntarily consumed by ET-infused animals). Food restriction induced a great depletion of phospholipid content, mainly phosphatidylethanolamine (PE), PC, phosphatidylinositol (PI), and PS, with no changes at the level of SPH as compared with control (fed ad libitum) rats. Triacylglycerol (TG) content was greatly decreased (66%) in ET-infused rats and the magnitude of the change and the fatty acid composition followed a pattern similar to that observed in pair-fed rats. The kinetics of [2-3H]-glycerol incorporation reflected efficient utilization of the precursor for de novo biosynthesis of glycerolipids. Labeling of the intermediate metabolite phosphatidic acid (PA) peaked at an earlier time (1 min) in ET-infused, and in pair-fed rats, as compared with saline-infused and control rats (3 min) respectively, and was followed by a later peak in diacylglycerol (DG) labeling. The metabolic flux thereafter in endotoxemia reflected a redirection toward the synthesis of TG and PI, while in pair-fed animals the label went mainly to PC, concomitantly with a great reduction in the uptake of label into PI.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Metabolic fate of arachidonic acid in hepatocytes of continuously endotoxemic rats.

The present experiments were designed to characterize the kinetics of [1-14C]arachidonic acid (AA) metabolism as a function of time in hepatocytes obtained from rats infused continuously for 30 h with a nonlethal dose of Escherichia coli endotoxin (ET). Chronic endotoxemia greatly reduces the ability of hepatocytes to utilize [1-14C]AA, which is reflected from the earliest times of incubation in very low labeling of intermediates in the biosynthetic pathways of glycerolipids (phosphatidic acid and diacylglycerol) and slower removal of [1-14C]AA from the free fatty acid pool as compared with saline-infused rats. At later times of incubation, the labeling of phospholipids (especially phosphatidylethanolamine and phosphatidylinositol [PI]), but not of triacylglycerides is decreased. Analysis of fatty acid composition of individual phospholipids from cells of ET-infused rats reveals that the content of AA is significantly reduced only in PI. Hence an impairment in activation/acylation enzymatic mechanisms could affect the turnover of metabolically active phospholipid pools, i.e., PI, involved in signal transmission processes, and result in increased availability of 20:4 for eicosanoid synthesis, contributing to cellular metabolic perturbations in endotoxicosis.

Animals↗

PubMed1988

Impairments in vasopressin-stimulated inositol lipid metabolism in hepatocytes of septic rats.

Vasopressin (VP)-stimulated 32P-inositol lipid metabolism was studied in hepatocytes obtained from rats rendered septic by cecal ligation and puncture. Basal 32P-phosphatidylinositol (PI) labeling, as well as its hormone-stimulated turnover, were greatly reduced in septic rats compared with sham-operated rats. The earliest VP-induced degradation of 32P-polyphosphoinositides (poly-PI) was greatly attenuated in septic rats. Moreover, while 32P-poly-PI labeling reached its lowest value by 60 sec of VP stimulation in cells from sham-operated rats, maximal changes in 32P-phosphatidylinositol 4,5-bisphosphate (32PIP2) occurred within 30 sec in septic rats. In contrast, the recovery of 32PIP2 labeling was more active in cells from septic rats, overcoming the impairment in its resynthesis triggered by surgical trauma in cells from sham-operated rats. The lower uptake of 32P into phosphatidic acid (PA) at the different time points analyzed was a sensitive indicator of the lower production of diacylglycerols from the VP-induced degradation of inositol phospholipids in septic rats. These observations support the idea that sepsis is associated with perturbations in the earliest events of the hepatocyte signal transmission pathway, namely, at the level of a receptor coupled to inositol lipid metabolism. Such perturbations are likely to be involved in the previously reported defective cell physiologic response to external hormone stimulation.

Animals↗

PubMed1988

Further characterization of a model of chronic endotoxemia in the rat: adenine nucleotide content in liver.

Male Sprague-Dawley rats (320-380 g) were treated with Escherichia coli endotoxin (ET) either acutely (3 and 4.5 mg/100 g b.w.,) or chronically (0.1 mg/100 g b.w./24 h, i.v. from subcutaneously implanted osmotic pumps). Control rats received only sterile saline. At 6 h after injection and after 30, 54, 126, and 198 h of continuous ET infusion, the animals were sacrificed, and adenine nucleotide content in liver was assayed. Acute ET treatment with either dose produced a slight decrease in ATP content (15% and 11% with 3 mg and 4.5 mg ET/100 g b.w., respectively) associated with an increase of ADP and AMP content and a fall of the energy charge (by 9.2% and 6.4%, with the two ET doses, respectively). Chronic ET treatment did not affect either of the measured parameters. However, in both saline- and ET-infused rats a decrease of ATP content paralleled by an increased level of ADP and AMP and by a fall of energy charge were seen when compared to acutely saline-injected rats. Such changes can be attributed to the surgical trauma associated with pump implantation. It is concluded that the energy status of the liver during endotoxemia cannot account for metabolic disturbances associated with this pathophysiological state.

Adenine Nucleotides↗

PubMed1987

Glucose kinetics and development of endotoxin tolerance during long-term continuous endotoxin infusion.

Alterations in glucose metabolism are seen following the acute administration of lethal doses (LD) and nonlethal doses of endotoxin, but relatively little information is available concerning glucose kinetics during long-term continuous endotoxin infusion. A nonlethal dose of endotoxin was administered intravenously to catheterized rats for up to 54 hours via a subcutaneously implanted osmotic pump; time-matched control animals were saline-infused. Glucose kinetics were assessed in vivo after 6, 30, and 54 hours of endotoxin by the constant infusion of [6-3H, U-14C]-glucose. The endotoxemic animals were hemodynamically stable throughout the experimental protocol and exhibited a febrile response at six and 30 hours of endotoxin infusion. Elevations in glucose turnover (50% and 42%) and recycling (140% to 150%) were seen after six and 30 hours of endotoxin infusion, but had returned to control values by 54 hours. A major portion (53% to 62%) of the increased glucose turnover in endotoxemic rats was accounted for by the elevated rate of recycling. The increased turnover appeared to be almost entirely due to enhanced gluconeogenesis and is consistent with the 160% to 170% elevation in plasma glucagon and increased lactate availability. After 54 hours, the plasma concentrations of glucose and lactate, glucose kinetics, and body temperature were not different between endotoxemic and control animals. In separate groups of rats, a bolus injection of endotoxin (LD 100) was administered to determine the presence of endotoxin tolerance. Endotoxin-infused animals showed improved survival after 30 and 54 hours (LD 20 and LD 0).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Impairments in hepatocyte phosphoinositide metabolism in endotoxemia.

The status of phospholipid metabolism and inositol lipids-mediated transmembrane signaling in rat hepatocytes was analyzed during chronic, nonlethal endotoxemia. Rats were infused intravenously (IV) with Escherichia coli endotoxin (ET) via subcutaneously implanted osmotic pumps at a rate of 0.1 mg/100 g bw/day. The experiments were performed after 30 hours of ET or sterile saline (NaCl) infusion, in hepatocytes prelabelled "in vitro" with 32P (15 microCi/mL) and further stimulated with vasopressin (VP, 0.23 mumol/L). Similar experiments were done with food-restricted animals, whose food intake was matched with the voluntary intake of ET-infused rats. Uptake of 32P label into phosphatidic acid (PA), phosphatidylinositol 4-phosphate (PIP), and phosphatidylinositol 4,5-bisphosphate (PIP2) occurs rapidly in cells from pair-fed, saline and ET-infused animals, and reaches a plateau between 60 and 80 minutes of incubation. Labeling of phosphatidylinositol (PI), phosphatidylethanolamine (PE), and phosphatidylcholine (PC) proceeds linearly after a ten-minute lag period for PI and 20 minutes for the two other lipids. The nutritional state greatly affects the distribution of 32P uptake into lipids, resulting in very low labeling of PA and PI and a high labeling of poly-PI as compared with control (taken from untreated rats) cells. In ET-v saline-infused rats, the labeling of PI and PE was depressed concomitantly with a proportional increase in the labeling of PIP and PC. The ability of VP to induce polyphosphoinositide (poly-PI) degradation in hepatocytes from saline-infused animals was similar to that observed in control cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Calcium content in liver and heart and its intracellular distribution in liver during endotoxicosis and sepsis in rats.

The hypothesis was tested that several metabolic and functional alterations associated with endotoxicosis and sepsis could be due to a Ca overload of liver and heart in rats. Male rats were given intravenously E. coli endotoxin (ET) or rendered septic by cecal ligation and puncture. At various intervals after ET injection and 16-18 h after the onset of peritonitis the animals were sacrificed and the liver and heart sampled for assay of the total Ca content. Also, livers of saline- or ET-treated rats were perfused in vitro to study several aspects of Ca movements as affected by phenylephrine infusion. Livers, were also fractionated to study the subcellular distribution of Ca. ET treatment produced a slight, but significant increase in total hepatic Ca content (12.6% at 4 h and 7.7% at 24 h after ET injection). Sepsis did not affect this parameter in either liver or heart. ET also produced a decrease of Ca content in the microsomal fraction of liver, while sepsis was associated with an elevated Ca content of liver mitochondria. Perfused livers of saline-treated rats responded to phenylephrine by accumulating Ca, while the perfused organs of ET-treated rats did not display such a response to agonist infusion. We conclude that impairment of intracellular Ca homeostasis--under the conditions studied--consists of a slight Ca overload in endotoxicosis, associated with discrete alterations of Ca fluxes and compartmentalization within the cell both in endotoxicosis and sepsis.

Animals↗

PubMed1987

Lipolysis and beta-adrenergic receptor binding on adipocytes of spontaneously hypertensive rats.

Adipocytes from spontaneously hypertensive rats demonstrated a blunted lipolytic response to isoproterenol and dibutyryl cyclic AMP. (-)-[3H]Dihydroalprenolol binding was examined in adipocytes from normotensive and spontaneously hypertensive rats. Increasing concentrations of isoproterenol decreased total (-)-[3H]dihydroalprenolol binding to intact cells from normotensive rats, and the efficacy of competition was decreased in adipocytes from spontaneously hypertensive rats. Scatchard analysis indicated that the number of (-)-[3H]dihydroalprenolol binding sites and the affinity of dihydroalprenolol binding were comparable between normotensive and spontaneously hypertensive rats. Isoproterenol- and Gpp(NH)p-stimulated adenylate cyclase activity was consistently depressed in adipocyte membranes from spontaneously hypertensive rats as compared to normotensive rats. No difference in fluoride-stimulated adenylate cyclase activity was observed. The blunted lipolytic and cyclic AMP response to isoproterenol in these cells suggest a postreceptor lesion of the lipolytic pathway (possibly the guanine nucleotide regulatory protein) in adipocytes from spontaneously hypertensive rats. The blunted lipolytic response to dibutyryl cyclic AMP suggests defective regulation of lipolytic enzymes at the protein kinase-hormone-sensitive lipase level.

Adipose Tissue↗

PubMed1987

Altered hepatic vasopressin and alpha 1-adrenergic receptors after chronic endotoxin infusion.

Sepsis and septic shock are complicated by a number of hemodynamic and metabolic aberrations. These include catecholamine refractoriness and altered glucose metabolism. Recently, a nonshock rat model of continuous endotoxin infusion via an implanted osmotic pump was developed that reproduces some of the metabolic and cardiovascular findings of human sepsis. By using this model, we have found a decreased number of hepatic plasma membrane alpha 1-adrenergic and [Arg8]vasopressin receptors in rats continuously infused with endotoxin. There was a significant decrease in [3H]prazosin (35 +/- 7%) and [3H] [Arg8]vasopressin (43 +/- 8%) receptors after 30 h of continuous endotoxin infusion with no change in affinity. The ability of norepinephrine to form the high-affinity complex with alpha 1-adrenergic receptors was not altered after chronic endotoxin infusion. The results are consistent with the concept that alterations in receptor number might underlie certain of the metabolic consequences of chronic sepsis.

Animals↗

PubMed1987

IP3-dependent Ca2+ release in permeabilized hepatocytes of endotoxemic and septic rats.

Inositol trisphosphate-dependent Ca2+ release was measured in saponin-permeabilized hepatocytes isolated from acutely (2 mg/100 g body wt iv) or chronically (0.1 mg X 100 g body wt-1 X 24 h-1 for 30 h) endotoxin-treated (ET, Escherichia coli) rats or from animals rendered septic by cecal ligation and puncture. A decrease of this parameter was observed in acutely ET-treated rats (52%, P less than 0.01) and after 30 h of continuous ET infusion (33%, P less than 0.01). Sepsis was associated with an elevated Ca2+ release (34%, P less than 0.01) as compared with the sham-operated animals. We conclude that during endotoxicosis and sepsis alterations of intracellular Ca homeostasis take place, reaching sites beyond the level of the plasma membrane. Such alterations could account in part for metabolic and functional changes associated with these pathologic states. In addition, ET treatment provides the first known intervention resulting in the modulation of inositol trisphosphate-dependent Ca2+ release.

Animals↗

PubMed1987

Suppressed in vitro blastogenic responsiveness of rat spleen cells after continuous infusion of endotoxin by an implanted osmotic pump.

Continuous infusion of a gram-negative bacterial endotoxin in relatively small doses into rats by means of an implanted osmotic pump was studied. The model system was designed to examine the effects of endotoxin on the blastogenic response of spleen cells to the endotoxin itself and to a nonspecific T-cell mitogen, concanavalin A (Con A). Rats were implanted with an osmotic pump which delivered saline for the first 42 hr to provide postsurgical recovery before the onset of endotoxin infusion. Previous studies had shown that during the first 1-4 days after administration of endotoxin marked alterations of metabolism and some changes in physiologic parameters such as blood pressure and in vitro myocardial performance occurred. In the present study the blastogenic responsiveness of spleen cells to endotoxin itself as well as to the nonspecific T-cell mitogen Con A was markedly decreased after several days of continuous administration of endotoxin. Control animals receiving only saline for the same period of time showed a similar depression of blastogenic responsiveness to the lipopolysaccharide (LPS), as well as to Con A, however, with a delay of 2-4 days before comparable levels of suppression became evident. These results indicate that marked alterations of immune competence as measured by blastogenesis of spleen cells to Escherichia coli LPS and to a mitogen such as Con A may occur after implantation of an osmotic pump, with or without continuous infusion of endotoxin. Further studies seem warranted to determine the role of the foreign body reaction to the osmotic pump as well as to the endotoxin administered by the pump.

Animals↗

PubMed1987

Perturbation of transmembrane signaling mechanisms in acute and chronic endotoxemia.

Our results reviewed here may be summarized as follows: 1. Continuous endotoxemia significantly interferes with Ca2+-dependent information flow in the liver. 2. The subcellular sites where these molecular lesions can be localized include: a.) the plasma membrane-there are effects at the level of alpha 1-adrenergic and vasopressin binding, and also in the coupling of receptor activation to inositol lipid metabolism in terms of PIP2 degradation and resynthesis b.) the endoplasmic reticulum in terms of Ca2+ release and PI synthesis. Another one of the sequelae of Ca2+-associated receptor activation, namely, cytosolic ionized Ca2+ concentration is also affected. 3. Finally, in addition to seeing the impact of acute or continuous endotoxemia at the level of receptor activation and signal generation, we can also document alterations in the expression of physiologic function subserved by these Ca2+- and inositol lipid-associated signaling processes--i.e. in glycogen phosphorylase activity-being consistent with the above described changes. In conclusion, we state that a causal link is shown between receptor binding, agonist-induced phosphoinositide hydrolysis, intracellular Ca2+ mobilization and activation of phosphorylase a in the liver, suggesting that these alterations may underlie some of the metabolic consequences of chronic sepsis.

Acute Disease↗

PubMed1986

Rat liver free cytosolic Ca2+ and glycogen phosphorylase in endotoxicosis and sepsis.

Rats were treated with Escherichia coli endotoxin (ET) either acutely or chronically or rendered septic by cecal ligation and puncture. At 6 h after ET injection, at various intervals of continuous ET infusion, and at 17-18 h after the onset of peritonitis, animals were killed and hepatocytes were isolated. Cytosolic [Ca2+] ([Ca2+]c) was measured by quin 2 during the resting state and after stimulation with epinephrine and vasopressin. Basal and epinephrine-, vasopressin- and glucagon-stimulated glycogen phosphorylase activity were also determined. In hepatocytes from acutely ET-treated rats, resting levels of [Ca2+]c were decreased 46% from 245.8 +/- 11.0 to 131.0 +/- 8.5 nM (n = 4-6, P less than 0.05). In septic rats a 39.5% decrease was noted [i.e., from 154.0 +/- 17.7 (n = 4, sham) to 93.3 +/- 91 nM (n = 5, septic, P less than 0.05)]. These decreased [Ca2+]c levels were associated with changes of glycogen phosphorylase activity in a manner suggesting a cause and effect relationship; e.g., acute ET treatment resulted in greater than 80% depression of phosphorylase a activity, whereas sepsis induced a 58% decrease in the activity of this enzyme. In ET-infused rats the resting level of [Ca2+]c and its response to hormonal stimulation were not different from hepatocytes of saline-infused rats, although glycogen phosphorylase activity was less responsive to these hormones. The effect on the enzyme's response to Ca2+-mobilizing hormones was more marked than to glucagon. This is consistent with the concept that information flow in the Ca2+-messenger system is a site of metabolic lesions produced by endotoxicosis and sepsis.

Acute Disease↗

PubMed1986

Effect of endotoxicosis and sepsis on intracellular calcium homeostasis in rat liver. Mitochondrial and microsomal calcium uptake.

Male rats were treated with endotoxin (ET; Escherichia coli, 026:B6) either acutely (2 mg/100 gm bw, iv) or chronically (0.1 mg/100 gm bw/24 hr from implanted osmotic pumps; [Fish R, Spitzer JA: Circ Shock 12;135, 1984]). At 6 hr after iv injection and at 6, 30, and 100 hr after ET infusion from the pumps, the animals were sacrificed and the livers removed for studies on the respiratory activity (respiratory control index [RCI] with either succinate or malate + glutamate) of isolated mitochondria and Ca uptake as well as Ca content of isolated mitochondria and microsomal vesicles. The same measurements were performed in the livers of rats at 14-16 hr after the onset of peritonitis induced by cecal ligation and perforation. The only changes in RCI specifically ascribable to ET treatment were observed with succinate in continuously infused animals, and they were not associated with changes of mitochondria Ca uptake or content. On the other hand, microsomal Ca uptake was inhibited by ET after both acute and continuous treatment. Neither Ca content nor Ca2+-activated, Mg2+-dependent ATPase in microsomes was affected by ET. No changes in any of these parameters were observed in septic animals. The data suggest that endoplasmic reticulum rather than mitochondria represents the site of interference of ET with intracellular calcium homeostasis in rat liver.

Animals↗

PubMed1986

Lipolytic patterns in isolated adipocytes of continuously endotoxemic rats.

Lipolytic patterns were studied in adipocytes isolated from rats after 6 and 30 hr of continuous Escherichia coli endotoxin (ET) or saline infusion via a subcutaneously implanted osmotic pump. By 6 hr, ET cells responded to norepinephrine (NE) stimulation with significantly greater increase above basal rates of glycerol and free fatty acid (FFA) release than did control adipocytes. By 30 hr of continuous infusion, basal glycerol release was enhanced; the in vitro lipolytic response evoked by NE was significantly reduced in ET cells compared to rates on the previous day, and NE-stimulated lipolysis in ET cells was significantly below that of controls. At the same time, the in vitro antilipolytic effect of insulin was attenuated. We conclude that 1) an initial metabolic response can be observed within a few hours of a continuous, low dose ET infusion, 2) the biphasic nature of the sequential changes in lipolysis is likely to reflect alterations in the hormonal environment in vivo, and 3) these features are consonant with some aspects of the metabolic profile of septic patients.

Adipose Tissue↗

PubMed1986

Regional blood flow during continuous low-dose endotoxin infusion.

Escherichia coli endotoxin (ET) was administered to adult rats by continuous IV infusion from a subcutaneously implanted osmotic pump (Alzet). Cardiac output and regional blood flow were determined by the radiolabeled microsphere method after 6 and 30 hr of ET or saline infusion. Cardiac output (CO) of ET rats was not different from time-matched controls, whereas arterial pressure was 13% lower after 30 hr of infusion. After both 6 and 30 hr of ET, pancreatic blood flow and percentage of cardiac output were lower than in controls. Estimated portal venous flow was decreased at each time point, and an increased hepatic arterial flow (significant after 30 hr) resulted in an unchanged total hepatic blood flow. Blood flow to most other tissues, including epididymal fat, muscle, kidneys, adrenals, and gastrointestinal tract, was similar between treatments. Maintenance of blood flow to metabolically important tissues indicates that the previously reported alterations in in vitro cellular metabolism are not due to tissue hypoperfusion. Earlier observations of in vitro myocardial dysfunction, coexistent with the significant impairment in pancreatic flow, raise the possibility that release of a myocardial depressant factor occurs not only in profound shock but also under less severe conditions of sepsis and endotoxemia.

Animals↗