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J Stadler

Publications and source records attributed to J Stadler.

At least 37 records · Page 2Linked to original sources
PubMed1997

Inhibition of nitric oxide synthesis improves detoxication in inflammatory liver dysfunction in vivo.

Inflammatory stimulation of the liver induces nitric oxide (NO) biosynthesis and suppression of detoxication. In this study the effect of NO biosynthesis on cytochrome P-450 (CYP) enzyme activity was investigated by comparing in vivo and in vitro assays. To establish liver inflammation, CD rats were injected with Corynebacterium parvum (C. parvum) suspension. After 5 days NO biosynthesis was highly induced as indicated by increased NO2- plus NO3- serum concentrations. At the same time the aminopyrine breath test (ABT), measuring CYP activity in vivo, was reduced to 42% and the in vitro assay of aminopyrine turnover was suppressed to 12% of NaCl- injected controls. When C. parvum-injected animals were treated with the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA), CYP activities significantly improved with an ABT of 76% and an in vitro aminopyrine turnover of 47% of controls. Neither C. parvum injections nor L-NMMA treatment resulted in a significant change of CYP protein concentrations. These data indicate that suppression of xenobiotic metabolism can be attenuated by inhibition of NO biosynthesis during an ongoing process of inflammation.

Animals↗
PubMed1996

Stable expression of human inducible nitric oxide synthase in V79 Chinese hamster cells.

A recombinant expression vector containing the full-length cDNA for human inducible nitric oxide (NO) synthase was constructed for constitutive expression in V79 Chinese hamster cells. Expression was followed by Western analyses using three different NO synthase antisera. Activity remained stable during 4 months of continued cultivation. Activities were 25 pmol min-1 mg-1 cytosolic protein with L-arginine and 47 pmol min-1 mg-1 cytosolic protein with NG-hydroxy-L-arginine as substrates. Activity was concentration-dependently inhibited by inhibitors such as NG-methyl-L-arginine, NG-nitro-L-arginine, NG-nitro-L-arginine methyl ester, aminoguanidine, and S-methyl-isothiourea. The rank order of inhibitor potencies was different from published results obtained with rodent inducible NOS. Parental V79 cells do not express and cannot be induced for NO synthase activity. Therefore, the genetically engineered V79 cell line is defined for the cDNA-encoded human inducible NO synthase. The new cell line may serve as a useful tool to study human inducible NO synthase.

Animals↗
PubMed1995

Interleukin-13 effectively down-regulates the monocyte inflammatory potential during traumatic stress.

OBJECTIVES: To determine the potential of interleukin-13 (IL-13) to modify in vitro lipopolysaccharide-induced monocyte-macrophage (MO) activity in human cells from individuals who had sustained either major mechanical or burn injury and to investigate whether the effect of IL-13 is different on MOs that have been preactivated under traumatic stress than on monocytic cells from healthy volunteers. DESIGN: Peripheral MOs from 20 controls and 16 patients after major burn or mechanical trauma were separated on days 1, 3, 5, and 7 after injury and incubated with lipopolysaccharide (1 microgram/mL) in the presence or absence of IL-13 (10 ng/mL) for 4 hours and for 20 hours. Thereafter, the following measures were determined from the culture supernatants: neopterin, nitric oxide, tumor necrosis factor alpha, IL-1 beta, IL-6, and IL-8. RESULTS: Ex vivo lipopolysaccharide-activated MOs, compared with control cells, displayed considerably enhanced inflammatory activity during the immediate posttraumatic course, with a substantial and consistent elevation of levels of tumor necrosis factor alpha and IL-6. The addition of human recombinant IL-13 to the MO cultures resulted in an effective down-regulation of the synthesis of tumor necrosis factor alpha, IL-1 beta, and IL-6 as well as IL-8, showing an average reduction of mediator production to two thirds of the value found in corresponding sole lipopolysaccharide-stimulated cultures. The impact of human recombinant IL-13 on control MOs was almost identical for IL-6 and IL-1 beta, slightly lower for IL-8, and nonexistent for tumor necrosis factor alpha. CONCLUSION: From this study and preexisting findings, we conclude that, based on its biologic properties, IL-13 should be tested as a biologic response modifier for acute states of trauma-induced host defense deficiency.

Adult↗
PubMed1995

Inhibition of biotransformation by nitric oxide (NO) overproduction and toxic consequences.

Hepatic nitric oxide (NO) biosynthesis is induced by local or systemic inflammation. The highly reactive NO radical binds to prosthetic iron groups such as heme or iron-sulfur clusters leading to either activation or inhibition of enzymes such as guanylate cyclase, cyclooxygenase and aconitase. It has been known for years that NO also binds to the heme moiety of cytochrome P450s (CYP) with high affinity. However, it was demonstrated recently that binding of NO to CYPs also inhibits their enzymatic activity. This is true for exogenously applied as well as for endogenously synthesized NO. Suppression of CYP-dependent metabolism, which is a major problem of inflammatory liver diseases, can be significantly reversed by inhibition of NO synthesis in vivo under experimental conditions. We investigated whether these findings are applicable as a novel therapeutic principle in severe inflammatory liver dysfunction.

Animals↗
PubMed1995

Hepatocyte nitric oxide biosynthesis inhibits glucose output and competes with urea synthesis for L-arginine.

Inflammatory stimulation of the liver is known to induce nitric oxide (NO) biosynthesis. NO can interfere with the activity of a number of enzymes important to cellular metabolism. This study was carried out to investigate the influence of NO on rat hepatocyte glucose output and urea production. Induction of NO synthesis by incubation with a combination of cytokines and lipopolysaccharide led to a 48.8 +/- 2.4% inhibition of glucose output and to a 45.0 +/- 6.4% suppression of urea production. Inhibition of NO synthesis with NG-monomethyl-L-arginine was able to totally prevent these effects. High concentrations of L-arginine overcame the inhibition of urea production caused by endogenous NO synthesis. Exposure of HC to NO donors resulted in a concentration-dependent inhibition of glucose output, without having any effect on urea production. Hepatocellular glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity was also found to be inhibited by endogenously produced NO (33.5 +/- 5.2%), as well as by exogenously applied NO. However, an exact correlation between GAPDH activity and glucose output could not be established. These data indicate that NO biosynthesis may contribute to the development of hepatic dysfunction in chronic sepsis.

Animals↗
PubMed1995

Homovanillic acid and monoamine oxidase in sons of substance-abusing fathers: relationship to conduct disorder.

OBJECTIVE: Children of substance-abusing (SA) fathers have been found to have increased rates of conduct disorder (CD). Substance abuse and antisocial behavior have been linked to alterations in dopaminergic regulation and to monoamine oxidase (MAO) in adults. This study assessed the relationship between homovanillic acid (HVA), the metabolite of dopamine (DA), and MAO, the enzyme facilitating the conversion of DA to HVA, with CD in boys of SA and non-SA fathers. METHOD: Male youths (N = 65), between the ages of 6 and 15 years, admitted to a residential setting because of behavior problems, were studied through peripheral blood samples and structured interviews. RESULTS: The findings indicated that MAO activity was significantly higher in boys of SA fathers with CD than (1) in boys of non-SA fathers with CD and (2) in boys of SA fathers without CD. HVA levels did not differ significantly among the groups. CONCLUSIONS: In the context of previous studies, the findings support the concept of dopaminergic dysregulation in sons of SA fathers, manifested by alterations in MAO activity levels in those youths with CD.

Adolescent↗
PubMed1995

Homovanillic acid and dopamine-beta-hydroxylase in male youth: relationships with paternal substance abuse and antisocial behavior.

Recent research suggests that dopaminergic/noradrenergic system dysfunction may be associated with substance abuse and/or antisocial behavior. In order to determine whether male youth of fathers with these disorders would manifest differences in these systems when compared with youth of nonsubstance-abusing or nonantisocial fathers, levels of homovanillic acid (HVA), the metabolite of dopamine (DA) and dopamine-beta-hydroxylase (DBH), the enzyme facilitating the conversion of dopamine to norepineprhine, were studied in offspring blood samples. The subjects were 65 male youth aged 6-15 years admitted to a residential center because of behavioral disorders. Parental substance abuse and antisocial behavior were assessed through interviews, rating scales, and/or chart review. HVA and DBH were determined from blood samples obtained after admission. The findings indicated that youth of substance-abusing fathers had significantly greater levels of HVA than yough of nonsubstance-abusing fathers. Younger (< 12.0 years) boys of antisocial fathers had significantly lower DBH activity than comparably aged youth of nonantisocial fathers. The results suggest that common generational links in substance abuse and antisocial behavior in males may be associated with detectable biological parameters in susceptible youth.

Adolescent↗
PubMed1995

[Immunosuppression and infection].

The course of prolonged sepsis is characterized by an initial activation of the immune system followed by the transition into a state of immunosuppression. Accordingly, a series of immunosuppressive substances can be detected in the serum of septic patients. On the cellular level many important functions of the unspecific as well as the specific defense systems of the organism are inhibited. As a consequence, immunosuppression may be contributing to the fact, that patients suffering from prolonged sepsis hardly recover with a high risk to end in multiple organ dysfunction. However, increasing efforts to investigate this problem may result in therapeutic approaches which may help to improve the bad prognosis of sepsis.

Humans↗
PubMed1994

Inhibition of cytochromes P4501A by nitric oxide.

Inflammatory stimulation of the liver leads to the induction of nitric oxide (NO) biosynthesis. Because NO binds to the catalytic heme moiety of cytochromes P450 (CYPs), we investigated whether NO interferes with specific CYP-dependent metabolic pathways. In a first experimental approach V79 Chinese hamster cells genetically engineered for stable expression of rat and human CYP1A1 and -1A2 were used. Incubation with the NO donors sodium nitroprusside and S-nitrosylacetylpenicillamine led to a concentration-dependent inhibition of all four CYP enzymes. CYP1A1 was more sensitive to the inhibitory effect of NO than CYP1A2. In the second part of the study, endogenous NO synthesis was induced in rat hepatocytes by incubation with a mixture of cytokines and endotoxin. Concurrently, as NO production in hepatocytes increased within 24 hr, a decrease in CYP1A1-dependent benzo[a]pyrene turnover was observed to almost undetectable levels. The competitive inhibitor of NO synthesis, NG-monomethyl-L-arginine, was able to significantly restore CYP1A1 activity in the presence of cytokines and endotoxin. Inhibition of hepatocellular CYP activity by NO was predominantly due to a direct effect on the enzymes. However, NO-dependent inhibition of CYP expression at a transcriptional level was also demonstrated. Our results indicate that inhibition of NO biosynthesis in patients suffering from systemic inflammatory response syndromes may help to restore biotransformation capacity of the liver.

Animals↗
PubMed1994

Nitric oxide and energy production in articular chondrocytes.

Addition of human, recombinant interleukin-1 beta (hrIL-1 beta) to cultures of lapine articular chondrocytes provoked a delayed increase in the production of both nitric oxide (NO) and lactate. These two phenomena followed a similar time course and shared a parallel dose-response sensitivity to hrIL-1 beta. A causal relationship is suggested by the ability of N-monomethyl-L-arginine (NMA), an inhibitor of NO synthase, to blunt the glycolytic response to hrIL-1 beta. Furthermore, addition of S-nitroso-N-acetylpenicillamine (SNAP), which spontaneously generates NO in culture, increased lactate production to the same degree as IL-1. However, 8-Br-cGMP and isobutylmethylxanthine (IBMX) had no effect either in the presence or absence of IL-1. Even under standard, aerobic, cell culture conditions, chondrocytes consumed little oxygen, either in the presence or absence of IL-1 or NMA. Furthermore, cyanide at concentrations up to 100 microM had no effect upon NO synthesis or lactate production. Thus, the increases in glycolysis under study were not secondary to reduced mitochondrial activity. Although cells treated with IL-1 had increased rates of glycolysis, their concentrations of ATP fell below those of untreated chondrocytes in a time-dependent, but NMA-independent, manner. Transforming growth factor-beta (TGF-beta) and synovial cytokines (CAF) also increased lactate production. However, TGF-beta failed to induce NO, and its effect on glycolysis was independent of NMA. Furthermore, cells treated with TGF-beta were not depleted in ATP. These data are consistent with hypotheses that rates of proteoglycan synthesis are, in part, regulated by the intracellular concentration of ATP or by changes in pericellular pH. These two possibilities are not mutually exclusive.

Animals↗
PubMed1994

Sensation seeking in psychiatrically disturbed youth: relationship to biochemical parameters and behavior problems.

OBJECTIVE: Relatively little research has been conducted on the relationship of personality traits or behavioral tendencies with biological parameters in youth. This study was intended to determine whether relationships exist between self-reported sensation-seeking tendencies and biochemical parameters in boys. METHOD: Twenty-five male youth aged 8 to 15 years admitted to a residential diagnostic center because of noncompliant, disruptive, and/or antisocial behavior were studied. Biochemical parameters associated with sensation seeking in adults or antisocial behavior were measured along with diagnoses, behavior ratings, and self-reported sensation seeking. RESULTS: High sensation seeking, as assessed on a newly developed sensation-seeking scale for children, was inversely correlated with 3-methoxy-4-hydroxyphenylglycol (MHPG) levels in the older youth (> or = 12.0 years) but not in the younger boys (< 12.0 years) in the group. Elevations on the sensation seeking scale also correlated marginally in these older youth with parent-reported problems on a behavior rating scale, reflecting "delinquent" behavioral tendencies. CONCLUSIONS: The findings support hypothesized noradrenergic dysregulation in some sensation-seeking persons (including youth > or = 12.0 years) and the relationship between high sensation-seeking tendencies and antisocial or disruptive behavioral disorder.

Adolescent↗
PubMed1994

Serum levels of end products of nitric oxide synthesis correlate positively with tumor necrosis factor alpha and negatively with body temperature in patients with postoperative abdominal sepsis.

Nitric oxide (NO) has been implicated as the principal mediator of the catecholamine resistant vasodilation in septic shock. In this pilot study, we wanted to know if the serum values of nitrite/nitrate (NO2/NO3), the stable endproducts of NO biosynthesis, are elevated in patients with septic shock. Furthermore, we investigated whether there is a correlation between NO2/NO3 serum levels and tumor necrosis factor alpha or interleukin 6. NO2/NO3 serum values were significantly elevated in septic patients compared to controls (72.1 +/- 6.1 vs. 35.7 +/- 9.2 microM, p < .001). There was a significant positive correlation between serum values of NO2/NO3 and tumor necrosis factor alpha (rs = 0.59, p < .001). In contrast, no correlation between NO2/NO3 and interleukin 6 was found. With the exception of body core temperature, which showed a negative correlation with NO2/NO3 levels, no clinical variable turned out to be significantly related to NO biosynthesis. These data indicate a potential role for NO in the clinical course of abdominal sepsis, but points out that more specific data has to be evaluated by prospective clinical studies in order to understand the complex pathophysiologic role of this novel mediator.

Abdomen↗
PubMed1994

Monoamine oxidase and homovanillic acid in boys with predispositions to substance abuse.

Both dopaminergic dysregulation and abnormalities in monoamine oxidase (MAO) have been postulated as etiological factors in substance abuse. This study assessed whether MAO activity differed in sons of substance-abusing fathers compared with sons of nonsubstance-abusing fathers. It also assessed the levels of homovanillic acid (HVA), the metabolite of dopamine, and MAO in a group of substance-using/-abusing boys compared with peers without this history in the same setting. Sixty-five boys admitted to a residential center were evaluated on blood tests for HVA and MAO, and on a series of diagnostic instruments and questionnaires designed to elicit information about parental substance abuse and about the subject's own substance use/abuse. The results indicated tentatively that younger (< 12.0 years) sons of substance-abusing fathers had higher levels of MAO than younger sons of nonsubstance-abusing fathers. Levels of MAO in older (> or = 12.0 years) sons of substance-abusing and nonsubstance-abusing fathers did not differ. Boys with histories of significant use/abuse of substances themselves had significantly higher MAO levels and significantly lower HVA levels than peers of the same age without substance use/abuse histories.

Adolescent↗
PubMed1994

Nitric oxide and prostaglandins interact to prevent hepatic damage during murine endotoxemia.

Nitric oxide (NO) and prostaglandins (PG) both possess the ability to induce vasodilatation and prevent the aggregation of platelets. The synthesis of these substances is increased following in vivo lipopolysaccharide (LPS) infusion, but their function during sepsis is incompletely understood. We studied the role of NO and PG in a murine model of chronic hepatic inflammation (Corynebacterium parvum injection), which is known to progress to sudden hepatic necrosis after LPS injection. NO synthesis, which is induced in hepatocytes by C. parvum treatment and in nonparenchymal cells by LPS treatment, was inhibited using NG-monomethyl-L-arginine (L-NMMA). High-dose aspirin (ASA) was used to block PG synthesis. Treatment with L-NMMA or ASA alone, in the absence of LPS, resulted in no increase in hepatic injury. C. parvum-treated mice that received both L-NMMA and ASA without LPS developed marked hepatic damage as reflected by increased hepatocellular enzyme release (aspartate aminotransferase and L-ornithine carbamoyl-transferase). Marked hepatic damage was seen after LPS administration, and ASA pretreatment alone had no effect on the LPS-induced hepatic injury, whereas L-NMMA markedly increased the hepatic damage. The combination of L-NMMA and ASA after LPS resulted in the greatest hepatocellular enzyme release, characterized histologically by intravascular thrombosis with diffuse infarction and necrosis. Simultaneous treatment with either PGI2 or L-arginine partially prevented this injury. These data demonstrate that NO and PG function synergistically to maintain hepatocellular integrity; thus increased synthesis of these mediators protects the liver from the pathophysiological effects of LPS in this model.

Animals↗
PubMed1994

[Metabolism and function of nitric oxide in the liver].

Nitric oxide (NO) is rapidly gaining importance as an ubiquitous biological mediator. Very different physiologic and pathophysiologic reactions are regulated by the endogenous biosynthesis or the release of NO from drugs. Besides its functions as an endothelium derived relaxing factor and inhibitory neurotransmitter, NO plays a key role in inflammation and immunity. The liver appears to have a central position in this complex scenario as both parenchymal and non-parenchymal cells synthesize NO under immune stimulation. Many aspects of the metabolism and the mode of action of NO, which are still unclear, remain to be further investigated and confirmed in the human system. Recent cloning of an inducible human NO synthase reveals new perspectives. The following article reviews the present scientific knowledge of the metabolism and function of hepatic NO.

Amino Acid Oxidoreductases↗
PubMed1994

Nitric oxide synthesis and its regulation by rabbit synoviocytes.

OBJECTIVE: To determine whether rabbit synovial fibroblasts can synthesize nitric oxide (NO) and, if so, how production is regulated by cytokines. METHODS: Primary cultures of synovial fibroblasts (type B synoviocytes) were established from synovia excised from the knee joints of New Zealand white rabbits. Synthesis of NO was measured as nitrite accumulation in conditioned media in the presence or absence of various cytokines and other activators. RESULTS: Resting cultures of synoviocytes normally produced little or no NO. However, production of this free radical was induced by interleukin 1 (IL-1), tumor necrosis factor alpha (TNF-alpha) or the phagocytosis of latex beads; in some cultures, the synthesis of NO occurred spontaneously. In each case, NO synthesis began approximately 9 h after the addition of cytokines, suggesting the involvement of an inducible form of NO synthase. Antagonists of this phenomenon included interferon gamma (IFN-gamma), which weakly inhibited NO production, and transforming growth factor beta (TGF-beta), a very strong inhibitor. Platelet derived growth factor (PDGF) inhibited NO synthesis by cells stimulated with IL-1, but not by cells stimulated with TNF-alpha. Synovial autocrine factors (CAF) modestly induced NO synthesis, but inhibited synthesis by IL-1; TGF-beta was identified as an inhibitory component of CAF. Phorbol myristate acetate (PMA) had only a small inductive effect, and inhibited induction by IL-1. However, the protein kinase inhibitor staurosporin was a strong inducer. Modulators of cyclic nucleotides, in contrast, had relatively modest effects on NO synthesis. Inhibition of NO biosynthesis by NG-monomethyl-L-arginine (NMA) had no effect upon the increase in the production of prostaglandin E2 (PGE2), matrix metalloproteinases (MMP) or lactate by synoviocytes responding to IL-1. The rabbit synoviocyte cell line, HIG-82, did not synthesize detectable NO under any of the culture conditions tested. CONCLUSION: Synoviocytes are a potential source of NO in arthritic joints.

Alkaloids↗
PubMed1994

[Causes of organ failure in infection].

Causes of septic multiple organ failure are endotoxin induced mechanisms, exotoxin induced mechanisms and sepsis associated immunosuppression. Pharmacological intervention is limited. Therapy is restricted to aggressive surgical treatment in terms of eradication of the source of infection combined with supportive intensive care medicine. The prevention of systemic infections is mandatory. Approaches to new therapeutical concepts are outlined.

Adolescent↗