Biomedical subjects

C H Lang

Publications and source records attributed to C H Lang.

At least 163 records · Page 9Linked to original sources

PubMed1988

In vivo glucose utilization by individual tissues during nonlethal hypermetabolic sepsis.

Febrile sepsis was induced in rats by repeated s.c. injections of live Escherichia coli bacteria. Glucose utilization of different tissues was investigated in vivo by using the 2-deoxyglucose tracer technique. In septic rats the rate of glucose utilization was increased in macrophage-rich tissues, including the liver (2.7-fold), spleen (2.4-fold), and ileum (1.6-fold), compared with tissues from time-matched nonseptic animals. A smaller increase in glucose utilization was evident in the abdominal muscle (1.3-fold) and in the white portion of the quadriceps muscle (1.3-fold). Changes were not significant in nine other tissues, including the brain. We postulate that in sepsis the mononuclear phagocyte system may be responsible for most of the increment of glucose utilization, and the latter provides metabolic support for the increased antibacterial activity of these cells.

Animals↗

PubMed1988

Adrenergic blockade does not abolish elevated glucose turnover during bacterial infection.

Infusions of adrenergic antagonists were used to investigate the role of catecholamines in infection-induced elevations of glucose kinetics. Infection was produced in conscious catheterized rats by repeated subcutaneous injections of live Escherichia coli over 24 h. Glucose kinetics were measured by the constant intravenous infusion of [6-3H]- and [U-14C]glucose. Compared with noninfected rats, infected animals were hyperthermic (+1.4 degrees C) and showed increased rates of glucose appearance (45%), clearance (43%), and recycling (140%) as well as mild hyperlacticacidemia. Plasma catecholamine concentrations were increased by 50-70% in the infected rats, but there were no differences in plasma glucagon, corticosterone, and insulin levels. Adrenergic blockade was produced by primed constant infusion of both propranolol (beta-blocker) and phentolamine (alpha-blocker). A 2-h administration of adrenergic antagonists did not attenuate the elevated glucose kinetics or plasma lactate concentration in the infected rats, although it abolished the hyperthermia. In a second experiment, animals were infused with propranolol and phentolamine beginning 1 h before the first injection of E. coli and throughout the course of infection. Continuous adrenergic blockade failed to attenuate infection-induced elevations in glucose kinetics and plasma lactate. These results indicate that the adrenergic system does not mediate the elevated glucose metabolism observed in this mild model of infection.

Animals↗

PubMed1988

Platelet-activating factor-induced increases in glucose kinetics.

Platelet-activating factor (PAF) is a postulated mediator of many of the early hemodynamic effects of endotoxin. The aim of the present study was to determine whether in vivo administration of PAF could produce alterations in whole-body glucose metabolism that would mimic those seen during endotoxemia. Glucose kinetics were assessed in chronically catheterized conscious rats by the constant infusion of [6-3H]- and [U-14C]glucose before and for 4 h after either a bolus injection (300 ng/kg) or a constant infusion (20 or 220 ng.min-1.kg-1) of PAF. The bolus injection of PAF produced a 30% decrease in blood pressure by 5 min that returned to control levels by 30 min. Increased plasma glucose (40%) and lactate (150%) levels after injection of PAF were also transient. In contrast, the bolus injection of PAF elevated the rate of glucose appearance (Ra; 44%) for 1.5 h. The lower PAF infusion rate decreased blood pressure 11% to 104 mmHg, whereas the higher infusion rate decreased pressure 34% to 77 mmHg. Both PAF infusion rates produced elevations in plasma glucose (28, 150%) and glucose Ra (20, 60%) throughout the 4-h infusion period in a dose-related manner. The PAF infusions also induced dose-related increases in plasma glucagon and catecholamine levels throughout the infusion period. In a separate group of experiments a complete adrenergic blockade, produced by the constant infusion of propranolol and phentolamine, completely prevented PAF-induced increases in glucose kinetics and the hyperglucagonemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Adrenergic blockade prevents endotoxin-induced increases in glucose metabolism.

Combined alpha- and beta-adrenergic blockade was used to investigate the role of catecholamines in endotoxin-induced elevations in glucose kinetics. Glucose kinetics were measured before and for 4 h after the injection of endotoxin [100 micrograms/100 g body wt iv, 30% lethal dose (LD30) at 24 h]. Adrenergic blockade was achieved by the bolus injection of phentolamine and propranolol followed by their continuous infusion. Endotoxin-treated rats exhibited a transient hyperglycemia and sustained (greater than 4 h) increase in plasma lactate concentration, as well as elevated rates of glucose appearance (Ra, 83%), disappearance (Rd, 58%), recycling (160%), and metabolic clearance (23%). Adrenergic blockade prevented endotoxin-induced increases in plasma glucose concentration, Ra, Rd, and recycling but not glucose clearance. The increase in plasma lactate concentration was blunted by 35%. After 2 h, endotoxic animals infused with adrenergic antagonists developed hypoglycemia, which may have resulted from an increased plasma insulin concentration. The attenuation of elevated glucose turnover by adrenergic blockade in the endotoxin-treated animals was not due to a reduction in plasma glucagon level or differences in plasma insulin concentration. Administration of the alpha- or beta-adrenergic antagonists separately blunted but did not prevent endotoxin-induced changes in glucose kinetics, and therefore the efficacy of the adrenergic blockade could not be assigned to a single receptor class. These results indicate that catecholamines are important contributory factors to many of the early alterations in carbohydrate metabolism observed during endotoxemia.

Adrenergic alpha-Antagonists↗

PubMed1988

Glucose kinetics in rats infused with endotoxin-induced monokines or tumor necrosis factor.

This study was conducted to determine if macrophage elaborated monokines in general, and human recombinant tumor necrosis factor (hrTNF alpha) in particular alter glucose metabolism in a manner analogous to that observed in endotoxin-treated animals. Endotoxin-tolerant rats were infused for 3 hr with saline, E. coli endotoxin (100 micrograms/l weight) or monokines contained in conditioned media from endotoxin-stimulated RAW 264.7 cells (1 microgram/ml). Compared to saline- and endotoxin-infused rats, animals receiving the monokine mixture had no change in mean arterial blood pressure or heart rate but exhibited overt signs of morbidity including stupor and diarrhea. Monokine-infused rats remained euglycemic but had elevated lactate concentrations and a 15-30% increase in glucose rate of appearance (Ra). Nontolerant rats received a 3 hr infusion of saline, hrTNF alpha (15 micrograms/100 g), or heat-treated hrTNF alpha. HrTNF alpha infusion increased glucose Ra about 25% compared to the two control groups but did so without producing signs of morbidity seen in the monokine infused animals. Serum TNF levels were 6-fold higher in rats infused with the monokine mixture compared to animals infused with hrTNF alpha, and this reflected the different levels of TNF contained in the monokine mixture and hrTNF alpha infusates. Plasma insulin, glucagon, and catecholamine concentrations were increased in rats infused with either the monokine mixture or hrTNF alpha, but the increases were more pronounced in rats receiving the monokine mixture. The results demonstrate that monokines and hrTNF alpha increase glucose production in vivo, and that the effect may be mediated by endocrine changes known to influence glucose homeostasis.

Animals↗

PubMed1987

Tumor necrosis factor increases in vivo glucose utilization of macrophage-rich tissues.

Glucose utilization of different tissues was investigated in vivo by the 2-deoxyglucose tracer technique. After infusion of a non-lethal dose of recombinant human TNF-alpha (150 micrograms/kg) to rats, glucose utilization was increased by 80-100% in spleen, liver, kidney, by 60% in skin and by 30-40% in lung and ileum. The largest increase (150%) was observed in the diaphragm. There was no significant change in glucose utilization by skeletal muscles, testis and brain. These data show that TNF exerts metabolic effects on macrophage-rich tissues, and suggest that enhanced secretion of TNF may be one of the important factors in eliciting the metabolic changes in sepsis and endotoxicosis.

Animals↗

PubMed1987

Contribution of different organs to increased glucose consumption after endotoxin administration.

Glucose utilization of different organs (spleen, liver, ileum, kidney, skin, lung, and testis) was investigated in vivo in conscious rats 3, 24, or 48 h after treatment with 100 micrograms of endotoxin/100 g of body weight. Glucose uptake was determined by the 2-deoxyglucose technique, which was validated by demonstrating that endotoxin treatment did not alter either the intracellular retention of the phosphorylated metabolites (P-2-dGlc) of the tracer or the discrimination against 2-deoxyglucose in pathways of glucose metabolism. At 3 h after endotoxin the accumulation of P-2-dGlc was markedly increased in the liver (4.8-fold), spleen and skin (2.9-fold), lung (2.4-fold), and ileum and kidney (2.1-fold), as compared to time-matched controls. This effect was sustained in the liver at 24 and 48 h, was diminishing but still significant in spleen, ileum, and kidney, and absent in skin and lung. Accumulation of P-2-dGlc in the testis remained unchanged after endotoxin. Glucose uptake by individual organs and their contribution to whole body glucose utilization in control and endotoxin-treated rats were compared based on P-2-dGlc accumulation data. Organs rich in mononuclear phagocytes (liver and spleen) exhibited a marked and prolonged increase in glucose uptake after endotoxin. Yet the bulk of the increment in the whole body glucose disappearance rate (Rd) was due to three large tissues (skin, intestine, and muscle, accounting for more than 80% of the total P-2-dGlc accumulation in soft tissues), which showed a more moderate and transient increase in glucose utilization.

Animals↗

PubMed1987

The contribution of gluconeogenesis to glycogen repletion during glucose infusion in endotoxemia.

Glycogen repletion rates in liver and skeletal muscle were quantitated, and the contribution of gluconeogenesis to hepatic glycogen repletion and glucose output were determined during glucose infusion in hemodynamically stable endotoxemic animals. Four hours after the injection of endotoxin (or saline), rats were infused with 235 mumol/min/kg of glucose (or saline) containing [6-3H]-glucose for up to four additional hours. Glucose infusion increased the plasma glucose concentration, which plateaued between 14 to 17 mmol/L, in the control rats. The glucose concentration of the endotoxin group receiving glucose was consistently greater than in control rats and failed to reach a plateau. The rate of muscle glycogen synthesis was not altered after endotoxin, but hepatic glycogen repletion was decreased by 55%. The percentage of glycogen repletion derived directly from blood glucose in liver and muscle was similar in control and endotoxin-treated rats receiving glucose. Therefore, the direct incorporation of glucose into glycogen appeared to predominate over the contribution by gluconeogenesis. However, gluconeogenesis continued during the glucose infusion in both control and endotoxemic animals. The calculated rate of total gluconeogenesis was 160% higher in the endotoxin glucose-infused rats compared to the control animals receiving glucose. This increase was due primarily to the attenuated suppression of hepatic glucose output in the endotoxin group (52 +/- 4%) compared to controls (84 +/- 3%). Thus, gluconeogenically derived glucose-6-phosphate appears to be diverted from hepatic glycogen storage to glucose output in endotoxin-treated rats during glucose infusion.

Animals↗

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

Increased uptake and phosphorylation of 2-deoxyglucose by skeletal muscles in endotoxin-treated rats.

Glucose metabolism of respiratory and nonrespiratory muscles of different fiber composition was investigated in conscious rats. The accumulation of phosphorylated 2-deoxyglucose (2DGP) was increased in skeletal muscles by 56-102% and in diaphragm by 236% at 3 h after treatment with 100 micrograms/100 g endotoxin. The increase was still marked at 24 h, whereas it diminished at 48 h in the diaphragm, abdominal muscle, and white portion of the quadriceps. In the red portion of this muscle 2DGP accumulation was less than that in time-matched controls at 24 and 48 h. Whole gastrocnemius (mixed-fiber types) showed no changes after 24 h. The high 2DGP accumulation in brain remained stable. The retention of 2DGP in tissues, studied by sequential double labeling, did not change 3 h after endotoxin. The lumped constant was similar in the isolated epitrochlear muscles of endotoxemic and control rats. Whole-body glucose utilization (Rd) was increased by 68% 3 h after endotoxin, but it was normal at 24 and 48 h. The increase of glucose utilization by the entire skeletal muscle mass was responsible for approximately 25% of the increase in Rd; therefore it appears that other tissues also contributed significantly to the endotoxin-induced alterations in carbohydrate metabolism.

Animals↗

PubMed1987

Altered glucose kinetics in diabetic rats during gram-negative infection.

The present study examined the purported exacerbating effect of sepsis on glucose metabolism in diabetes. Diabetes was induced in rats by an intravenous injection of 70 or 45 mg/kg streptozotocin. The higher dose produced "severe" diabetes, whereas the lower dose of streptozotocin produced a milder, "latent" diabetes. After a chronic diabetic state had developed for 4 wk, rats had catheters implanted and sepsis induced by intraperitoneal injections of live Escherichia coli. After 24 h of sepsis the blood glucose concentration was unchanged in nondiabetics and latent diabetics, but glucose decreased from 15 to 8 mM in the septic severe diabetic group. This decrease in blood glucose was not accompanied by alterations in the plasma insulin concentration. Glucose turnover, assessed by the constant intravenous infusion of [6-3H]- and [U-14C]glucose, was elevated in the severe diabetic group, compared with either latent diabetics or nondiabetics. Induction of sepsis produced a slight decrease in the glucose turnover in the severe diabetic group but did not alter turnover in the latent diabetics. The rate of glucose disappearance, used to quantitate the alterations in plasma glucose after an intravenous glucose tolerance test, was decreased in both groups of diabetics and was proportional to the severity of the diabetic state. Sepsis increased the rate of glucose disappearance in nondiabetic rats but had no effect in either group of diabetic animals. Sepsis also failed to alter the insulinogenic index, used to estimate the insulin secretory capacity, in diabetic rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Alterations in glucose kinetics induced by pentobarbital anesthesia.

Because pentobarbital is often used in investigations related to carbohydrate metabolism, the in vivo effect of this drug on glucose homeostasis was studied. Glucose kinetics, assessed by the constant intravenous infusion of [6-3H]- and [U-14C]glucose, were determined in three groups of catheterized fasted rats: conscious, anesthetized and body temperature maintained, and anesthetized but body temperature not maintained. After induction of anesthesia, marked hypothermia (5 degrees C decrease in core temperature) developed in rats not provided with external heat. Anesthetized rats that developed hypothermia showed a decrease in mean arterial blood pressure (25%) and heart rate (40%), whereas no differences were seen in blood pressure and heart rate of conscious and euthermic anesthetized rats. Likewise, the plasma lactate concentration and the rates of glucose appearance, recycling, and metabolic clearance were reduced by 30-50% in the hypothermic anesthetized rats. Changes in whole-body carbohydrate metabolism were prevented when body temperature was maintained. Because plasma pentobarbital levels were similar between the euthermic and hypothermic rats during the first 2 h of the experiment, the rapid reduction in glucose metabolism in this latter group appears related to the decrease in body temperature. The continuous infusion of epinephrine produced alterations in glucose kinetics that were not different between conscious animals and anesthetized rats with body temperature maintained. However, marked differences were seen in hypothermic rats. Thus pentobarbital-anesthetized rats became hypothermic when kept at room temperature and exhibited marked decreases in glucose metabolism. Such changes were absent when body temperature was maintained during anesthesia.

Animals↗

PubMed1987

Myocardial adrenergic responsiveness after lethal and nonlethal doses of endotoxin.

A dose-dependent impairment of intrinsic myocardial performance has been observed following in vivo administration of endotoxin. The present study reports a dose-dependent increase in plasma catecholamines following endotoxin (ET) that may impair beta-adrenergic responsiveness. Hearts were removed from pentobarbital-anesthetized rats 4 h after a bolus injection of saline or ET (1,000, 100, or 10 micrograms/100 g body wt) and were studied as isolated cell preparations following collagenase digestion. Responsiveness of isoproterenol-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in myocytes prepared from hearts of animals injected with 10 and 100 micrograms ET was decreased when compared with control rats and was significantly blunted in myocytes prepared from animals receiving 1,000 micrograms ET. Similar sensitivities of the cAMP system existed, as judged by similar half-maximum effective concentration values. cAMP accumulation in the presence of 1 microM forskolin was depressed in myocytes from the 1,000-microgram ET animals; beta-adrenergic receptor density was decreased 25% (P less than 0.05) in myocytes from high-dose ET animals when compared with control animals. This was accompanied by a nonsignificant reduction in the affinity of binding sites for (+/-) [3H]CGP 12177. The blunted myocyte hormonal responsiveness following ET challenge appears to be related to the decreased activity of the adenylate cyclase that may be attributed to alterations in both receptor density and in the adenylate cyclase itself.

Adenosine Triphosphate↗

PubMed1987

Enhanced myocardial depression in diabetic rats during E. coli sepsis.

The aim of this study was to determine whether diabetes enhanced the sensitivity of the myocardium to the deleterious effects of in vivo-administered Escherichia coli. Diabetes was induced in two groups of animals. One group received 70 mg/kg streptozotocin (iv) and exhibited a severe diabetes with elevated fasting and fed blood glucose concentrations and a markedly abnormal response to an oral glucose load. The second group received 45 mg/kg streptozotocin, was mildly diabetic (termed "latent" diabetes), and was characterized by normal fasting blood glucose but slightly elevated fed blood glucose and an abnormal response to a glucose load. A third group of rats received vehicle and served as time-matched control animals. Four weeks after induction of diabetes, all animals were catheterized under ether anesthesia and some received intraperitoneal injections of live E. coli. In vitro myocardial performance was assessed using the isolated, perfused working heart preparation. Ventricular function curves were generated by changing left atrial filling pressure and measuring changes in heart rate, cardiac output, and aortic peak systolic pressure. Cardiac performance in the severe diabetic group was depressed at the highest preload but was unchanged at lower preloads. Function in the latent diabetic group was not different from control. Sepsis induced a slight decrease in cardiac performance in the control group and resulted in larger reductions in the latent and severe diabetic groups. A depression in aortic flow was the major consequence of sepsis in the latent diabetic group, whereas decreased coronary flow was the primary change in the severe diabetic group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Fever is not responsible for the elevated glucose kinetics in sepsis.

Previous studies have suggested that alterations in the classical neuroendocrine system may not be responsible for the increased glucose metabolism observed during hypermetabolic sepsis. The purpose of the present study was to determine whether inhibition of the cyclooxygenase pathway with indomethacin, which prevents the production of arachidonic acid metabolites by this pathway and the sepsis-induced increase in body temperature, would abolish the increases in glucose appearance (Ra), recycling, and hyperlactacidemia. Sepsis was induced in chronically catheterized conscious rats by multiple injections of live Escherichia coli via a subcutaneous catheter. Septic animals received iv injections of indomethacin (5 mg/kg) every 6-8 hr to block the cyclooxygenase pathway. Glucose kinetics were assessed in 24-hr fasted rats using a constant iv infusion of [6-3H]- and [U-14C]glucose. Treatment with indomethacin prevented the 1-2 degrees C increase in body temperature observed in septic animals. Septic rats exhibited an elevated plasma lactate concentration and increased rates of glucose appearance and recycling. The sepsis-induced alterations in these variables were not attenuated by indomethacin. These results suggest that neither elevated body temperature nor the generation of arachidonic acid metabolites of the cyclooxygenase pathway is responsible for increasing glucose production in hypermetabolic septic rats.

Animals↗

PubMed1987

Inhibition of eicosanoid production by BW755C does not attenuate sepsis-induced alterations in glucose kinetics.

Previous studies have indicated that various arachidonic acid metabolites are involved in the cardiovascular dysfunction seen during endotoxemia and sepsis. However, the possible role of these metabolites in mediating the metabolic alterations under similar conditions remains to be elucidated. Thus, the purpose of the present study was to determine if cyclooxygenase and lipoxygenase blockade could prevent the elevated rates of glucose appearance (Ra), glucose recycling, and hyperlactacidemia seen during hypermetabolic sepsis. Sepsis was induced in chronically catheterized conscious rats by multiple injections of live Escherichia coli via a subcutaneous catheter. Septic animals received intravenous (i.v.) injections of BW755C every 6-8 h to block both the cyclooxygenase and lipoxygenase pathways. Glucose kinetics were assessed in 24-h fasted rats by using a constant i.v. infusion of [6-3H] and [U-14C]-glucose. Treatment with BW755C prevented the 1-2 degrees C increase in body temperature induced by sepsis in the vehicle-treated animals. Septic rats receiving saline instead of BW755C exhibited an elevated plasma lactate concentration and increased rates of glucose appearance, recycling, and metabolic clearance. The sepsis-induced alterations in these variables were not attenuated by BW755C. These results suggest that neither arachidonic acid metabolites nor elevated body temperature are responsible for increasing glucose production and utilization in hypermetabolic septic rats.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗

PubMed1987

Glucose kinetics and pyruvate dehydrogenase activity in septic rats treated with dichloroacetate.

Decreased pyruvate dehydrogenase (PDH) activity in skeletal muscle has been observed during sepsis and may contribute to the altered glucose kinetics seen in this condition. The purpose of the present study was to determine if dichloroacetate (DCA), a known stimulator of PDH activity, could reverse the sepsis-induced increase in glucose metabolism. Hypermetabolic sepsis was produced in chronically catheterized rats by repeated subcutaneous injections of live Escherichia coli. Whole body glucose kinetics, assessed by a constant iv infusion of [6-3H and U-14C]-glucose, were determined in fasted septic and nonseptic rats before and for 4 hr after an injection of DCA (30 mg/100 g BW, iv). Sepsis produced hyperthermia (+1.6 degrees C) and increased the rates of glucose appearance (Ra; 95%), recycling (318%), metabolic clearance (MCR; 114%), and elevated plasma lactate levels (295%) compared to nonseptic controls. After injection of DCA into septic rats, glucose levels gradually fell, and the sepsis-induced hyperlactacidemia was completely reversed. Treatment of septic rats with DCA reversed the elevated glucose Ra; recycling, although reduced, was still elevated by 50% compared to control animals. DCA did not alter the hyperglucagonemia seen in septic animals, but it did reduce the plasma insulin levels by 60%. Hepatic and muscle PDH activities were not different in saline-treated septic and nonseptic animals. DCA elevated PDH activity in muscle from septic rats, but the increase was smaller than that seen in control animals. This may explain the smaller decline in glucose recycling and plasma lactate in septic animals. These results are consistent with DCA reducing the elevated glucose Ra in sepsis by partial activation of PDH, which reduces the elevated precursor (lactate) supply for gluconeogenesis. However, alterations in PDH activity did not appear to contribute to the underlying increase in glucose Ra and recycling observed in sepsis.

Acetates↗

PubMed1987

Attenuation of endotoxin-induced increase in glucose metabolism by platelet-activating factor antagonist.

Platelet-activating factor (PAF) has recently been proposed as a putative mediator of various pathophysiologic events during endotoxemia. The aim of the present study was to determine the relative importance of PAF in producing the alterations in carbohydrate metabolism following endotoxin. Chronically catheterized conscious rats were treated with SRI 63-441, a specific PAF receptor antagonist, or saline prior to Escherichia coli endotoxin (100 micrograms/100 g body weight, LD10) administration. Hemodynamic and whole-body glucose kinetic changes, the latter assessed by a constant intravenous infusion of [6-3H] glucose, were determined throughout the 4-hr experimental protocol. Endotoxin induced a transient 30-35% reduction in mean arterial blood pressure (MABP) in animals treated with saline. The PAF-antagonist attenuated this hypotensive effect, and MABP was only reduced by 14-18%. Endotoxin increased plasma glucose and lactate levels, as well as the rate of glucose appearance (Ra) in saline-treated rats. The PAF antagonist reduced the hyperglycemia by 60-75% and tended to prevent the hyperlactacidemia. The endotoxin-induced elevation in glucose Ra was also attenuated by 55%. A similar degree of hyperglucagonemia was observed following endotoxin in both groups, and plasma insulin concentrations were not different. However, plasma catecholamine levels were significantly lower (30-70%) in endotoxemic rats treated with the PAF antagonist. These results suggest that the enhanced production of PAF following endotoxin may be responsible, at least in part, for the early hemodynamic changes. The role of PAF as a mediator of endotoxin-induced glucose dyshomeostasis, however, may be secondary to its hemodynamic effects.

Animals↗