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Biomedical subjects

I E Karl

Publications and source records attributed to I E Karl.

At least 19 recordsLinked to original sources
PubMed1997

Cecal ligation and puncture (CLP) induces apoptosis in thymus, spleen, lung, and gut by an endotoxin and TNF-independent pathway.

Two challenges (intraperitoneal lipopolysaccharide (LPS) administration and cecal ligation and puncture (CLP)) and two strains of mice (LPS-normoresponder (C3H/HeN) and LPS-hyporesponder (C3H/HeJ)) were used to investigate pathways of cell injury. After intraperitoneal administration of LPS, endotoxin was absorbed into the bloodstream (HeN, 10.4 +/- 9.4 x 10(4) EU/mL; HeJ, 14.7 +/- 6.0 x 10(4) EU/mL), but as expected, only C3H/HeN mice produced serum tumor necrosis factor (TNF) (HeN, 2.5 +/- 2.0 x 10(3)pg/mL; HeJ, 87.0 +/- 38.7 pg/mL). Gel electrophoretic analysis of DNA extracted from six organs demonstrated the apoptotic "ladder" only in the thymus and only in the HeN mice. When the mice were challenged with CLP, both HeN and HeJ produced a small amount of serum TNF (HeN, 5.8 +/- 3.5 x 10(2) pg/mL; HeJ, 2.2 +/- 2.5 x 10(2) pg/mL) and both strains had very mild endotoxemia (HeN, 23.4 +/- 3.8 EU/mL; HeJ, 27.9 +/- 10.1 EU/mL). The DNA fragmentation pattern characteristic of apoptosis was observed not only in thymus but also in spleen, lung, and Peyer's patch of gut of both strains. This organ-specific pattern was more pronounced in the thymus of HeN mice; otherwise, the organ-specific patterns were similar for HeN and HeJ mice challenged by CLP but absent in those same organs when those same mice were challenged with LPS. The data suggest the existence not only of an endotoxin-driven activation for thymic apoptosis, but also of an endotoxin-independent, TNF-independent pathway activating widespread apoptosis in the murine CLP model of sepsis.

Animals↗
PubMed1996

Glutamine interferes with glucocorticoid-induced expression of glutamine synthetase in skeletal muscle.

Skeletal muscle atrophy from glucocorticoids is prevented by glutamine infusion. Because the gene-encoding glutamine synthetase (GS) is glucocorticoid inducible, it represented an appropriate model for resting whether glucocorticoids and glutamine exert opposing actions on the expression of specific genes related to atrophy in muscle tissue. Rats were administered hydrocortisone 21-acetate or the dosing vehicle (carboxymethyl cellulose) and were infused with saline (Sal) or glutamine (Gln, 240 mM, 0.75 ml/h) for 7 days. Hormone treatment did not significantly lower glutamine levels in fast-twitch white or red regions of the quadriceps. Despite higher serum glutamine concentrations with amino acid infusion [1.52 +/- 0.03 (Gln) vs. 1.20 +/- 0.04 (Sal) mumol/ml], muscle glutamine concentrations were not markedly increased in these fiber types. In saline-infused animals, glucocorticoid treatment produced 200-300% increases in plantaris, fast-twitch white, and fast-twitch red muscle GS enzyme activity and mRNA. Moreover, in all muscle types studied, glutamine infusion diminished glucocorticoid effects on GS enzyme activity to 131-159% and on GS mRNA to 110-200% of the values in saline-treated controls. These data demonstrate that glutamine infusion results in inhibiting GS expression, but the absence of changes in muscle glutamine concentration suggests the interplay of additional regulators of the GS gene.

Animals↗
PubMed1996

Alanyl-glutamine prevents muscle atrophy and glutamine synthetase induction by glucocorticoids.

The aims of this work were to establish whether glutamine infusion via alanyl-glutamine dipeptide provides effective therapy against muscle atrophy from glucorticoids and whether the glucocorticoid induction of glutamine synthetase (GS) is downregulated by dipeptide supplementation. Rats were given hydrocortisone 21-acetate or the dosing vehicle and were infused with alanine (AA) or alanyl-glutamine (AG) at the same concentrations and rates (1.15 mumol.min-1.100 g body wt-1, 0.75 ml/h) for 7 days. Compared with AA infusion in hormone-treated animals, AG infusion prevented total body and fast-twitch muscle mass losses by over 70%. Glucocorticoid treatment did not reduce muscle glutamine levels. Higher serum glutamine was found in the AG-infused (1.72 +/- 0.28 mumol/ml) compared with the AA-infused group (1.32 +/- 0.06 mumol/ml), but muscle glutamine concentrations were not elevated by AG infusion. Following glucocorticoid injections, GS enzyme activity was increased by two- to threefold in plantaris, fast-twitch white (superficial quadriceps), and fast-twitch red (deep quadriceps) muscle/fiber types of the AA group. Similarly, GS mRNA was elevated by 3.3- to 4.1-fold in these same muscles of hormone-treated, AA-infused rats. AG infusion diminished glucocorticoid effects on GS enzyme activity to 52-65% and on GS mRNA to 31-37% of the values with AA infusion. These results provide firsthand evidence of atrophy prevention from a catabolic state using glutamine in dipeptide form. Despite higher serum and muscle alanine levels with AA infusion than with AG infusion, alanine alone is not a sufficient stimulus to counteract muscle atrophy. The AG-induced muscle sparing is accompanied by diminished expression of a glucocorticoid-inducible gene in skeletal muscle. However, glutamine regulation of GS appears complex and may involve more regulators than muscle glutamine concentration alone.

Alanine↗
PubMed1996

Calcium: a regulator of the inflammatory response in endotoxemia and sepsis.

Calcium functions as a critical intracellular second messenger and regulates many cellular processes such as muscle contractility, glycogen and protein turnover, hormone secretion, and vascular smooth muscle tone which are markedly abnormal during sepsis/endotoxemia. There also is increasing recognition of the role of calcium in the production of a variety of cytokines such as tumor necrosis factor alpha and interleukin-1 beta, which are important mediators of sepsis. Our hypothesis is that disturbances in cellular calcium regulation are responsible for or contribute to many of the metabolic manifestations of sepsis/endotoxemia and may be the driving force behind the development of multiorgan failure. In this article, we focus on a) new insights into calcium's regulation of the inflammatory cascade, b) the controversy concerning whether free cytosolic calcium concentration ([Ca2+]i) is increased in the disorder, and c) the potential therapeutic uses of calcium antagonists. An important message is that there are fundamental differences in the pathophysiology of the endotoxin model versus the cecal ligation and perforation (CLP) model of sepsis. Although calcium antagonists improve survival in the endotoxin model, they increase mortality in the CLP model of sepsis. Possible reasons for the differences in the effect of the drugs in the two different models and insight into the mechanisms of cell injury in endotoxin versus sepsis are presented.

Animals↗
PubMed1995

Calcium antagonists decrease plasma and tissue concentrations of tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-1 alpha in a mouse model of endotoxin.

Calcium plays an important role in the toxic effects of endotoxin, and calcium antagonists also have been shown to improve survival in animals challenged with endotoxin. Calcium may be involved in regulating cytokine production. Therefore, the protective effect of calcium-antagonists in endotoxin may be due to decreased cytokine formation and/or systemic release. In a mouse model of endotoxin, dantrolene (10 mg/kg) and azumolene (20 mg/kg), drugs that decrease calcium release from intracellular stores, or diltiazem (20 mg/kg), a calcium channel blocker, decreased plasma tumor necrosis factor-alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha), and IL-1 beta (47.2, 63.2, and 62.4%, respectively, p < .05) when the animals were injected intraperitoneally with endotoxin. Dantrolene and azumolene decreased IL-1 alpha by 56.6 and 65.4%, respectively, (p < .05) and IL-1 beta by 51.7 and 69.7%, respectively (p < .05). Diltiazem had no effect on IL-1 alpha or IL-1 beta. Dantrolene decreased TNF-alpha in lung (26.1%), liver (29.4%), and spleen (35.4%) (p < .05) and IL-1 alpha in lung (30.0%) and liver (25.4%) (p < .05). The present findings indicate that calcium-antagonists may be efficacious in treating cytokine mediated inflammatory disorders.

Animals↗
PubMed1994

Dantrolene ameliorates the metabolic hallmarks of sepsis in rats and improves survival in a mouse model of endotoxemia.

Sepsis is the systemic inflammatory response resulting from serious infection and is the most common cause of death in intensive care units. Intracellular free calcium concentration ([Ca2+]i) is an important regulator of numerous cellular processes and when increased excessively may act as a potent cellular toxin. To determine if [Ca2+]i is responsible for the major metabolic changes which are hallmarks of sepsis, we examined if sodium dantrolene, a drug which decreases release of calcium from sarcoplasmic reticulum, affected the metabolic abnormalities in plasma and epitrochlearis muscles of rats made septic by cecal ligation and perforation. Dantrolene when added in vitro or when given in vivo decreases many of the metabolic hallmarks of sepsis--i.e., muscle protein breakdown approximately 30%, muscle glucose transport approximately 38%, muscle lactate formation approximately 28%, and plasma lactate approximately 29% (P < 0.05). In addition, we examined the ability of dantrolene to improve survival in a mouse model of endotoxemia. Dantrolene caused > 2-fold improvement in survival when it was administered concurrently with endotoxin (54% vs. 20% survival in dantrolene-treated and control mice, respectively (P < 0.001). Our results are consistent with the hypothesis that an increase in [Ca2+]i plays an important role in the metabolic abnormalities which occur during sepsis and that dantrolene administration may be an effective therapeutic strategy.

Animals↗
PubMed1994

Low plasma and renal tissue levels of L-arginine in rats with obstructive nephropathy.

Rats with bilateral ureteral obstruction (BUO) of 24 hours duration had significantly lower plasma levels of L-arginine than at baseline (P < 0.0001), but no significant changes occurred in sham-operated rats (SOR). In contrast, rats with bilateral nephrectomy had greater plasma levels of L-arginine four hours (P < 0.03) and 24 hours (not significant) after nephrectomy than at baseline. Total body irradiation prior to obstruction prevented the decrease in plasma levels of L-arginine in rats with BUO but had no effect on these values in SOR. Renal tissue levels of L-arginine were 20% lower in rats with BUO than in SOR. Total body irradiation prior to BUO resulted in greater renal tissue levels of L-arginine than occurred in nonirradiated rats with BUO (P < 0.002). Total body irradiation did not effect renal tissue levels of L-arginine in SOR. Excretion of reactive nitrogen intermediates in urine (URNI), indicative of L-arginine metabolism through the nitric oxide pathway, was lower in rats with BUO than in SOR (P < 0.001). Proximal tubules from rats with BUO synthesized less L-arginine than those from SOR (P < 0.02). The results indicate that: (1) decreased levels of L-arginine in plasma and renal tissue of rats with BUO correlate with leukocyte infiltration of the kidney, and (2) decreased synthesis of L-arginine occurs in proximal tubules of rats with BUO when compared to tubules from SOR.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Effect of ethanol and sodium arsenite on HSP-72 formation and on survival in a murine endotoxin model.

Recently, investigators reported that prophylactic hyperthermia and induction of heat shock proteins (HSPs) decreased mortality from endotoxin. Although the mechanism by which hyperthermia protects is unknown, two possible etiologies are induction of HSPs and/or production of cytokines, interleukin-1 alpha (IL-1 alpha) or tumor necrosis factor-alpha (TNF-alpha). The purpose of this study was to determine if in vivo administration of sodium arsenite (NaAsO2) or ethanol, inducers of HSPs in isolated cells, induced HSP-72 production in lung, liver, kidney, and duodenum (organs known to induce HSP-72 by heat) and improved survival from endotoxin. Female ND4 mice were injected intraperitoneally with either NaAsO2 (5.25 mg/kg body weight) or ethanol (4.0 g/kg), immediately, 8 or 18 h prior to Escherichia coli endotoxin injection (20 mg/kg). Both compounds improved short-term (24 h) survival twofold (p < .01), but failed to improve long-term (7 days) survival. Simultaneous injection of ethanol with endotoxin improved both short-term survival twofold (p < .01), and long-term survival 5-fold (p < .001). Ethanol induced HSP-72 in kidney, 50% that of the standard (i.e., pooled livers isolated from heat-treated mice); NaAsO2 induced HSP-72 in kidney (approximately 50% of standard) and liver (approximately 21% of standard). Neither ethanol nor NaAsO2 alone increased circulating concentrations of IL-1 alpha or TNF-alpha. However, ethanol given concurrently with endotoxin produced a significant decrease in TNF-alpha compared to endotoxin alone (p < .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Sepsis decreases phenylephrine- and KCl-induced aortic ring contraction and decreases the frequency of oscillations in active wall tension.

Impaired vascular contractility is a hallmark of sepsis and endotoxemia. The purpose of the present investigation was to determine mechanisms responsible for the abnormal contractility in sepsis using the rat cecal ligation and perforation (CLP) model. 24 h after CLP or sham surgery, rats were anesthetized with halothane and a segment of the thoracic aorta removed. Aortic rings measuring 1.6-2.0 mm in length were mounted in a water bath and stretched to optimal diameter. Aortic rings from control rats demonstrated a 57% increase in maximum contraction to phenylephrine and a 68% increase to KCl compared to aortic rings from rats with sepsis (p < .01). There was no difference in the concentrations of phenylephrine or KCl which elicited a half-maximal contraction (EC50) in control versus septic aortic rings. Removal of the endothelium increased the sensitivity of aortas to both phenylephrine and KCl in septic and control aortic rings but did not reverse the defects in contraction in sepsis. Treatment of the aortic rings with N gamma-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, increased contraction in aortic rings from both septic and control rats but also failed to correct the contractile defect in sepsis. The frequency and amplitude of the oscillations in wall tension which occurred with phenylephrine were slower, i.e., .07 +/- .10 vs. .17 +/- .02 Hz, for septic and control rings, respectively (p < .05), and had a greater amplitude .65 +/- .01 vs. .41 +/- .09 mN/mm, for septic and control rings, respectively (p < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1994

Role of arginine in health and in renal disease.

In addition to participating in protein synthesis in cells and tissues, L-arginine is essential for the synthesis of urea, creatine, creatinine, nitric oxide, and agmatine and influences hormonal release and the synthesis of pyrimidine bases. This places L-arginine, its precursors and its metabolites at the center of the interaction of different metabolic pathways and interorgan communication. Thus L-arginine participates in changing the internal environment in different but simultaneous ways, ranging from disposal of protein metabolic waste, muscle metabolism, vascular regulation, immune system function, and neurotransmission, to RNA synthesis and hormone-mediated regulation of the internal milieu. In normal rats, inhibition of the nitric oxide pathway results in systemic hypertension and decreased glomerular filtration rate and effective renal plasma flow. If the inhibition of this pathway is sustained, then glomerulosclerosis and death from uremia follow. Dietary intervention with L-arginine has resulted in amelioration of a number of experimental kidney diseases, such as those caused by subtotal nephrectomy, diabetic, nephropathy, cyclosporin A administration, salt-sensitive hypertension, ureteral obstruction, puromycin amino-nucleoside nephrosis, kidney hypertrophy due to high-protein feeding, and glomerular thrombosis due to administration of lipopolysaccharide. The present review addresses the current evidence for the beneficial effects of dietary intervention with L-arginine in a number of experimental renal diseases and describes the basis for the concept of L-arginine deficiency (absolute or relative) in certain settings in which supplementation of the diet with this amino acid may be beneficial.

Animal Nutritional Physiological Phenomena↗
PubMed1993

Increased intracellular Ca2+: a critical link in the pathophysiology of sepsis?

Severe bloodstream-borne infection--i.e., sepsis--and the resulting multiorgan failure are now the most common cause of death in many intensive care units. One of the most fundamentally important and controversial issues concerning the pathophysiology of sepsis is the role of intracellular free calcium concentration ([Ca2+]i) in this disorder. Because of the critical role of calcium as an intracellular second messenger and as a potential cellular toxin, resolution of this issue is crucial. Using 19F NMR spectroscopy and the calcium indicator 5,5'-difluoro-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetate we demonstrate in the intact perfused organ, the rat thoracic aorta, that [Ca2+]i in aortic smooth muscle is increased > 2-fold during sepsis. Furthermore, we determined that sodium dantrolene, a drug that decreases release of calcium from the sarcoplasmic reticulum and that is lifesaving in malignant hyperthermia (a disorder due to increased [Ca2+]i), is able to reduce the elevated [Ca2+]i in sepsis to control values when added in vitro or when given in vivo to the animal. These results suggest that an increase in [Ca2+]i is an early event in sepsis and that increased [Ca2+]i may be responsible for, or contribute to, cellular injury. Dantrolene may offer a therapeutic strategy in the treatment of sepsis.

Animals↗
PubMed1993

L-arginine administration prevents glomerular hyperfiltration and decreases proteinuria in diabetic rats.

The effect(s) of L-arginine administration on the renal function of rats with untreated diabetes mellitus was examined. Rats received streptozotocin (N = 11) or vehicle (N = 12): Group 1 (normal rats, N = 6) drank tap water; Group 2 (normal rats, N = 6) drank tap water containing 1% L-arginine; Group 3 (diabetic rats, N = 5) drank tap water; and Group 4 (diabetic rats, N = 6) drank tap water with 1% L-arginine. Rats were fed a standard rat chow diet (22.8% protein, 142% L-arginine) with free access to food and water for 14 wk. Diabetic rats gained less weight, had significantly lower plasma levels of albumin and L-arginine, and had greater values for 24-h urine volumes and urine excretion of glucose, protein, urea, creatinine, nitrate, and nitrite than control rats. Diabetic rats given L-arginine (Group 4) had significantly lower protein and cGMP excretion in the urine than did rats of Group 3. The administration of L-arginine did not affect the plasma levels of glucose or L-arginine in Groups 2 or 4 compared with those of their respective controls. Group 3 had significantly higher values for GFR than did the other three groups of rats, but values for effective RPF, mean arterial pressure, hematocrit, and renal vascular resistance were not significantly different between Groups 3 and 4. There was no significant difference in glomerular morphology among the four groups of rats as determined by light microscopy, and both groups of diabetic rats exhibited the Armanni-Ebstein lesion in their tubules.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Reevaluation of the role of cellular hypoxia and bioenergetic failure in sepsis.

Sepsis is frequently characterized by a number of metabolic abnormalities: increased plasma lactate concentration, metabolic acidosis, increased glycolysis, and an abnormal "delivery-dependent" oxygen consumption. Two hypotheses have been advanced to explain these metabolic abnormalities: (1) cellular hypoxia resulting from abnormal microcirculatory blood flow or (2) defect(s) in energy-producing metabolic pathways of cells. Results of our studies on rat muscle, liver, heart, brain, and plasma suggest that there is no evidence of bioenergetic failure in these septic tissues and that the increase in lactate production is not necessarily due to cellular hypoxia. The adequacy of cellular oxygenation and bioenergetics was verified using in vivo phosphorus 31 nuclear magnetic resonance spectroscopy, [18F]fluoromisonidazole, and microfluorometric enzymatic techniques. Findings from these studies as well as results from several clinical investigations indicate that neither hypothesis can adequately account for the metabolic features typical of sepsis and that the pathophysiology of sepsis awaits further clarification. These studies and important clinical implications are discussed.

Acidosis, Lactic↗
PubMed1992

Concurrent quantification of tissue metabolism and blood flow via 2H/31P NMR in vivo. III. Alterations of muscle blood flow and metabolism during sepsis.

In the conclusion of this series of reports, the application of 31P/2H NMR to investigate the pathophysiology of sepsis in rat hindlimb muscle is demonstrated. Sepsis decreased muscle [PCr] by 18%, 18 +/- 4 SD vs 22 +/- 4 SD mmol/kg tissue wet wt (P = 0.01) in control rats but [ATP] was unchanged, 6 mmol/kg tissue wet wt (P = 0.2). The derived free cytosolic [ADP] in the two groups was similar, [ADP]septic = 0.023 +/- 0.004 SD and [ADP]control = 0.021 +/- 0.003 SD mmol/kg tissue wet wt, and not statistically different (P = 0.14). Likewise [Pi] in the septic and control groups was not statistically different, [Pi]septic = 1.1 +/- 0.5 SD and [Pi]control = 1.2 +/- 0.4 SD mmol/kg tissue wet wt (P = 0.2). Septic rats presented the symptom of respiratory alkalosis evidenced by elevated blood pH. Sepsis decreased muscle blood flow by 33%, P = 0.003, but examination of individual subjects did not demonstrate a correlation with the reduction in [PCr]. Thus, a metabolic energy deficit caused by cellular ischemia/hypoxia is not a likely cause of cellular abnormality in rat hindlimb muscle during sepsis.

Adenosine Diphosphate↗