PubMed Health⌕ Search

Biomedical subjects

H H Schmidt

Publications and source records attributed to H H Schmidt.

At least 73 records · Page 4Linked to original sources
PubMed1999

The soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a] quinoxalin-1-one is a nonselective heme protein inhibitor of nitric oxide synthase and other cytochrome P-450 enzymes involved in nitric oxide donor bioactivation.

Soluble guanylyl cyclase (sGC) is an important effector for nitric oxide (NO). It acts by increasing intracellular cyclic GMP (cGMP) levels to mediate numerous biological functions. Recently, 1H-[1,2, 4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ) was identified as a novel and selective inhibitor of this enzyme. Therefore, ODQ may represent an important pharmacological tool for differentiating cGMP-mediated from cGMP-independent effects of NO. In the present study, we examined the inhibitory action of ODQ both functionally and biochemically. In phenylephrine-preconstricted, endothelium-intact, isolated aortic rings from the rat, ODQ, in a concentration-dependent manner, increased contractile tone and inhibited relaxations to authentic NO with maximal effects at 3 microM. Pretreatment of vascular rings with ODQ induced a parallel, 2-log-order shift to the right of the concentration-response curves (CRCs) to histamine, ATP, NO, the NO-donors S-nitrosoglutathione, S-nitroso-N-acetyl-D,L-penicillamine, and spermine NONOate [N-[4-[1-(3-amino propyl)-2-hydroxy-2-nitroso hydrazino]butyl]-1, 3-propane diamine], and the direct sGC-stimulant [3-(5'-hydroxymethyl-2'furyl)-1-benzyl indazole] YC-1 but did not affect relaxations induced by papaverine and atriopeptin II. Moreover, the rightward shift of the CRCs to Angeli's salt, peroxynitrite, and linsidomine was similar to that of NO. These results suggested that ODQ is specific for sGC. Furthermore, they indicate that NO can cause vasorelaxation independent of cGMP. Three interesting exceptions were observed to the otherwise rather uniform inhibitory effect of ODQ: the responses to acetylcholine, glycerol trinitrate, and sodium nitroprusside. The latter two agents are known to require metabolic activation, possibly by cytochrome P-450-type proteins. The 3- to 5-log-order rightward shift of their CRCs suggests that, in addition to sGC, ODQ may interfere with heme proteins involved in the bioactivation of these NO donors and the mechanism of vasorelaxation mediated by acetylcholine. In support of this notion, ODQ inhibited hepatic microsomal NO production from both glycerol trinitrate and sodium nitroprusside as well as NO synthase activity in aortic homogenates. The latter effect seemed to require biotransformation of ODQ. Collectively, these data reveal that ODQ interferes with various heme protein-dependent processes in vascular and hepatic tissue and lacks specificity for sGC.

Animals↗
PubMed1999

Lipid evaluation in HIV-1-positive patients treated with protease inhibitors.

There is accumulating evidence that human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) can induce hyperlipidaemia. To evaluate the frequency and type of hyperlipidaemia in PI-treated patients, 98 outpatients were prospectively analysed for their lipoprotein characteristics at the Medizinische Hochschule in Hannover, Germany. Fifty-seven percent of the patients studied presented with hyperlipidaemia. Both hypertrigylceridaemia (type IV and V hyperlipoproteinaemia, 33%) and hypercholesterolaemia (type IIa hyperlipoproteinaemia, 6%) were detectable. The remaining 18% had a type IIb hyperlipoproteinaemia. Increased lipid levels were highly statistically significant compared to a control group of PI-naive HIV-1-infected patients [low-density lipoprotein (LDL) 146 mg/dl (range, 53-274 mg/dl) versus 105 mg/dl (range, 22-188 mg/dl; P=0.0006); very-low-density lipoprotein (VLDL) 35.5 mg/dl (5-253 mg/dl) versus 18 mg/dl (range, 3-94 mg/dl; P=0.0002)]. All PIs used (saquinavir, indinavir, nelfinavir and ritonavir) were associated with this variable form of hyperlipidaemia according to the Fredrickson classification. There was no significant correlation of any determined lipid value with the duration of treatment. A higher frequency of the apolipoprotein E2 allele and E4 allele was observed in the hyperlipidaemic subjects. Patients with excessive hypertriglyceridaemia showed a reduced lipoprotein lipase activity. Lipodystrophy was observed especially in hyperlipidaemic patients and to a lesser extent in normolipidaemic subjects. The frequency of hyperlipidaemic risk factors was surprisingly high in the group studied, which in turn may explain the proposed increased risk of atherogenesis in HIV-1 PI-treated patients. Therefore, PI-treated subjects should also be evaluated for their lipoprotein pattern, which may require antihyperlipidaemic interventions.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Anti-pterins as tools to characterize the function of tetrahydrobiopterin in NO synthase.

Nitric oxide synthases (NOS) are homodimeric enzymes that NADPH-dependently convert L-arginine to nitric oxide and L-citrulline. Interestingly, all NOS also require (6R)-5,6,7, 8-tetrahydro-L-biopterin (H4Bip) for maximal activity although the mechanism is not fully understood. Basal NOS activity, i.e. that in the absence of exogenous H4Bip, has been attributed to enzyme-associated H4Bip. To elucidate further H4Bip function in purified NOS, we developed two types of pterin-based NOS inhibitors, termed anti-pterins. In contrast to type II anti-pterins, type I anti-pterins specifically displaced enzyme-associated H4Bip and inhibited H4Bip-stimulated NOS activity in a fully competitive manner but, surprisingly, had no effect on basal NOS activity. Moreover, for a number of different NOS preparations basal activity (percent of Vmax) was frequently higher than the percentage of pterin saturation and was not affected by preincubation of enzyme with H4Bip. Thus, basal NOS activity appeared to be independent of enzyme-associated H4Bip. The lack of intrinsic 4a-pterincarbinolamine dehydratase activity argued against classical H4Bip redox cycling in NOS. Rather, H4Bip was required for both maximal activity and stability of NOS by binding to the oxygenase/dimerization domain and preventing monomerization and inactivation during L-arginine turnover. Since anti-pterins were also effective in intact cells, they may become useful in modulating states of pathologically high nitric oxide formation.

Animals↗
PubMed1998

[Xanthoma disseminatum with marked mucocutaneous involvement].

HISTORY AND CLINICAL FINDINGS: When aged 23 years, a now 36-year-old man was first diagnosed as having xanthomas on the upper arms and shoulders. Xanthomas then progressed, affecting both the skin and the laryngo-pharyngeal mucosa. They were so marked that several laser-surgical interventions for their removal in the phayngo-laryngeal tract were necessary to ensure unimpaired breathing. There were also extensive confluent symmetrical cutaneous xanthomas over the upper and lower arms, the face, neck and trunk. Xanthomas and scars in the pharynx and larynx necessitated marked nasal breathing. INVESTIGATIONS: There was no laboratory evidence of abnormal lipid metabolism. The concentrations of cholesterol, triglycerides, lipoprotein (a), apolipoprotein A-1, apolipoprotein B, apolipoprotein E phenotype and steroles were all normal. The biochemical composition of LDL, VLDL and HDL particle was also unremarkable. Histological examination of resected xanthomas revealed dense infiltrations of the interstitial spaces by foam-cell histiocytes with multiple lipid vacuoles, typical of xanthoma disseminatum. TREATMENT AND COURSE: Neither probucol nor cholesterol synthesis enzyme inhibitors nor glucocorticoid medication influenced the xanthomas. The only effective treatment was removal of the most unsightly or obstructing lesions. But the sars left removal in the mucocutaneous regions caused obstruction in the laryngopharyngeal tract. CONCLUSION: The cause of xanthoma disseminatum remains unknown. Skeletal muscle can also be extensively infiltrated. This case shows similarities to Erdheim-Chester disease, another are xanthomatous condition.

Adult↗
PubMed1998

Human soluble guanylate cyclase: functional expression and revised isoenzyme family.

Soluble guanylate cyclase (sGC), a heterodimeric (alpha/beta) haem protein that converts GTP to the second messenger cGMP, functions as the receptor for nitric oxide (NO) and nitrovasodilator drugs. Three distinct cDNA species of each subunit (alpha1-alpha3, beta1-beta3) have been reported from various species. From human sources, none of these have been expressed as functionally active enzyme. Here we describe the expression of human alpha/beta heterodimeric sGC in Sf9 cells yielding active recombinant enzyme that was stimulated by the nitrovasodilator sodium nitroprusside or the NO-independent activator 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1). At the protein level, both alpha and beta subunits were detected in human tissues, suggesting co-expression also in vivo. Moreover, resequencing of the human cDNA clones [originally termed alpha3 and beta3; Giuili, Scholl, Bulle and Guellaen (1992) FEBS Lett. 304, 83-88] revealed several sequencing errors in human alpha3; correction of these eliminated major regions of divergence from rat and bovine alpha1. As human beta3 also displays more than 98% similarity to rat and bovine beta1 at the amino acid level, alpha3 and beta3 represent the human homologues of rat and bovine alpha1 and beta1, and the isoenzyme family is decreased to two isoforms for each subunit (alpha1, alpha2; beta1, beta2). Having access to the human key enzyme of NO signalling will now permit the study of novel sGC-modulating compounds with therapeutic potential.

Amino Acid Sequence↗
PubMed1998

Translocation (3;5)(p26;q13) in a patient with chronic T-cell lymphoproliferative disorder.

A 67-year-old patient with large granular lymphocyte (LGL) leukemia is described. At fluorescence-activated cell sorting (FACS) analysis of the peripheral blood, the lymphocytes were positive for CD3, CD4, CD5, CD29, CD45RA, CD57, and TCR alpha/beta and negative for CD7, CD8, CD16, CD56, CD19, CD22, and TCR gamma/delta. Bone marrow histology and immunohistochemistry did not reveal any lymphocyte infiltration. Cytogenetic examination of peripheral blood cultures showed a clone with the karyotype 46,XY,t(3;5)(p26;q13). Molecular analysis revealed rearrangement of the gamma-T-cell-receptor chain. The region 3p25-3p26 which harbors the von Hippel-Lindau tumor suppressor gene and the RAF1 oncogene has been rearranged in a few cases of T-cell leukemia. The translocation in this case has not yet been described and may reflect an alternative mechanism in the pathogenesis of these disorders.

Aged↗
PubMed1998

Apolipoprotein A-I induced amyloidosis.

Amyloidosis is characterized by extracellular deposits of protein fibrils with a high content of beta-sheets in secondary structure. The protein forms together with proteoglycans amyloid fibrils causing organ damage and serious morbidity. Intact apolipoprotein A-I (apoA-I) is an important protein in lipid metabolism regulating the synthesis and catabolism of high density lipoproteins (HDL). Usually, apoA-I is not associated with amyloidosis. However, four naturally occurring mutant forms of apoA-I are known so far resulting in amyloidosis. The most important feature of all variants is the very similar formation of N-terminal fragments which were found in the amyloid deposits (residues 1-83 to 1-94). The new insights in the understanding of the association of apoA-I with HDL, its metabolism, and its hypothesized structural findings may explain a common mechanism for the genesis of apoA-I induced amyloidosis. Here we summarized the specific features of all known amyloidogenic variants of apoA-I and speculate about its metabolic pathway, which may have general implications for the metabolism of apoA-I.

Amyloidosis↗
PubMed1998

Renal toxicity of the neuron-blocking and mitochondriotropic agent m-iodobenzylguanidine.

meta-Iodobenzylguanidine (MIBG) is a multipotent drug used in its radiolabeled form as a tumor-seeking radiopharmaceutical in the diagnosis and treatment of pheochromocytoma and neuroblastoma. Nonradiolabeled MIBG has also proved to be effective in the palliation of carcinoid syndromes and, on a predosing schedule, in enhancing the relative tumor uptake of a subsequent [131I]-MIBG dose in tumors of neuroadrenergic origin. In addition, MIBG is under investigation as an inhibitor of mitochondrial respiration and, as such, for its use in tumor-specific acidification. In this report we describe the side effects of nonradiolabeled MIBG on kidney function in mice. High doses of MIBG (40 mg/kg) reduced renal blood perfusion as measured by 86Rb distribution by 50%, which could be antagonized by the bioamine receptor blockers prazosin and cyproheptadine. MIBG also induced reversible renal damage as evidenced from a decrease in [51Cr]-ethylenediaminetetraacetic acid (EDTA) clearance and from histological damage, which was most pronounced in the distal tubuli. These effects were unrelated to reduced perfusion, however, and could not be antagonized by bioamine receptor blockers, Ca2+-channel blockers, or diuretics. Clearance effects of MIBG were mimicked by N-nitro-L-arginine methyl ester (L-NAME), a known inhibitor of nitric oxide synthase (NOS), and MIBG itself (100 microM) also inhibited NOS in vitro, suggesting that NOS inhibition by MIBG may have contributed to the observed reduction in renal clearance. The MIBG analog benzylguanidine (BG), which is equipotent in terms of mitochondrial inhibition, did not affect renal clearance, thus excluding mitochondrial inhibition as the main mechanism of MIBG-induced damage. MIBG, however, was much more cytotoxic than BG to kidney tubular cells in primary cultures. Although the renal effects of high-dose MIBG were reversible, alterations in the pharmacokinetics of concomitant medications by a temporary reduction in renal function should be taken into account in its clinical application.

3-Iodobenzylguanidine↗
PubMed1998

Upregulated synthesis of both apolipoprotein A-I and apolipoprotein B in familial hyperalphalipoproteinemia and hyperbetalipoproteinemia.

A family was identified with vertical transmission through three generations with simultaneous increases of apolipoprotein A-I (apoA-I), apolipoprotein B (apoB), low-density lipoprotein (LDL)-cholesterol, and high-density lipoprotein (HDL)-cholesterol, which we have designated familial hyperalphalipoproteinemia and hyperbetalipoproteinemia (HA/HBL). Affected patients develop xanthomas and coronary artery disease (CAD). HA/HBL apoA-I and LDL-apoB were isolated and characterized. The in vivo kinetics of radiolabeled apoA-I and LDL-apoB were evaluated in two HA/HBL probands and three controls. Structural and metabolic characterization showed normal apoA-I and LDL-apoB. The kinetics of metabolism of HA/HBL apoA-I in the HA/HBL subjects showed that elevated apoA-I levels were solely due to an increased synthesis rate (15.2 to 17.6 mg/kg/d v 11.1 to 11.4 mg/kg/d) with a normal apoA-I residence time in plasma (4.2 to 5.4 days v 5.1 to 5.3 days). The elevation of LDL-apoB levels resulted from both an increased synthetic rate (16.6 to 22.9 mg/kg/d v 12.3 to 13.8 mg/kg/d) and a prolonged residence time (3.3 to 3.8 days v 1.4 to 1.9 days). In addition, we evaluated another HA/HBL proband of an unrelated family with HA/HBL to confirm the kinetic data. LDL-receptor binding studies of HA/HBL fibroblasts showed normal binding, uptake, and degradation of LDL isolated from a normolipemic control. The serum concentration of the cholesterol ester transfer protein (CETP) was normal in the studied probands. An apoB 3500 and apoB 3531 mutant, respectively, was ruled out by polymerase chain reaction (PCR). In conclusion, the site of the molecular defect in HA/HBL subjects may be involved in the coordinate regulation of metabolism for both LDL and HDL.

Adult↗
PubMed1998

Distribution of nitric oxide synthase and nitric oxide-receptive, cyclic GMP-producing structures in the rat brain.

The structures capable of synthesizing cyclic GMP in response to nitric oxide in the rat brain were compared relative to the anatomical localization of neuronal nitric oxide synthase. In order to do this, we used brain slices incubated in vitro, where cyclic GMP-synthesis was stimulated using sodium nitroprusside as a nitric oxide-donor compound, in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine. Nitric oxide-stimulated cyclic GMP synthesis was found in cells and fibers, but was especially prominent in varicose fibers throughout the rat brain. Fibers containing the nitric oxide-stimulated cyclic GMP production were present in virtually every area of the rat brain although there were large regional variations in the density of the fiber networks. When compared with the localization of nitric oxide synthase, it was observed that although nitric oxide-responsive and the nitric oxide-producing structures were found in similar locations in general this distribution was complementary. Only occasionally was nitric oxide-mediated cyclic GMP synthesis observed in structures which also contained nitric oxide synthase. We conclude that the nitric oxide-responsive soluble guanylyl cyclase and nitric oxide synthase are usually juxtaposed at very short distances in the rat brain. These findings very strongly support the proposed role of nitric oxide as an endogenous activator of the soluble guanylyl cyclase in the central nervous system and convincingly demonstrate the presence of the nitric oxide-cyclic GMP signal transduction pathway in virtually every area of the rat brain.

1-Methyl-3-isobutylxanthine↗
PubMed1998

Delayed low density lipoprotein (LDL) catabolism despite a functional intact LDL-apolipoprotein B particle and LDL-receptor in a subject with clinical homozygous familial hypercholesterolemia.

We identified a 38-yr-old male patient with the clinical expression of homozygous familial hypercholesterolemia presenting as severe coronary artery disease, tendon and skin xanthomas, arcus lipoides, and joint pain. The genetic trait seems to be autosomal recessive. Interestingly, serum concentrations of cholesterol responded well to diet and statins. We had no evidence of an abnormal low density lipoprotein (LDL)-apolipoprotein B (apoB) particle, which was isolated from the patient using the U937 proliferation assay as a functional test of the LDL-binding capacity. The apoB 3500 and apoB 3531 defects were ruled out by PCR. In addition, we found no evidence for a defect within the LDL-receptor by skin fibroblast analysis, linkage analysis, single-strand conformational polymorphism and Southern blot screening across the entire LDL-receptor gene. The in vivo kinetics of radioiodinated LDL-apoB were evaluated in the proband and three normal controls, subsequently. The LDL-apoB isolated from the patient showed a normal catabolism, confirming an intact LDL particle. In contrast the fractional catabolic rate (d-1) of autologous LDL in the subject and the normal controls revealed a remarkable delayed catabolism of the patient's LDL (0.15 vs. 0.33-0.43 d-1). In addition, the elevation of LDL-cholesterol in the patient resulted from an increased production rate with 22.8 mg/kg per day vs. 12.7-15.7 mg/kg per day. These data indicate that there is another catabolic defect beyond the apoB and LDL-receptor gene causing familial hypercholesterolemia.

Adult↗
PubMed1998

Outcome of 22 successful pregnancies after liver transplantation.

To evaluate course and outcome of pregnancies in liver transplanted patients and to provide a brief summary on the development of these children, 22 pregnancies and 23 children (1 month-99 months old) of 16 patients who had been liver transplanted at our institution (mean interval from transplantation to pregnancy 43.1 months) were reviewed. Standard immunosuppressive regimen during pregnancy consisted of cyclosporine A (CyA), tacrolimus (FK), azathioprine (Aza) and/or a low-dose steroid therapy. CyA and FK whole blood trough levels were monitored on a routinely basis to keep therapeutic range (CyA 80-150 ng/mL; FK 4-8 ng/mL). No patient had a graft loss and there were no lethal complications. Beside de novo hypertension (n = 3) and preeclampsia (n = 3) problems during pregnancy included one steroid-sensitive rejection at 36 wk gestation, one case of tacrolimus toxicity at 24 wk with complete reconstitution, and one case of de novo choledocholithiasis with recurrent cholangitis. Three cases of infections occurred. In total, 23 children, including one set of twins, were born. Terms of gestation (mean = 38.1 wk, +/- 2.2 SD), deliveries (spontaneous n = 13, cesarean section n = 7, forceps n = 1, vacuum extraction (VE) n = 1) and birth weights (2876 g, +/- 589.3 SD) were typical. Three pregnancies were preterm, one being a twin pregnancy. Neither congenital malformations nor unusual infections were seen in the children. Postnatal follow-up revealed appropriate physical growth to date. Psychological development seems to be adequate. Our data indicate that successful pregnancies after liver transplantation (LTX) under careful management by transplant specialists, obstetricians and perinatalogists have a good outcome. So far, neither pre- nor postnatal child development appear to be influenced by maternal immunosuppressive therapy during pregnancy.

Adult↗
PubMed1997

In vivo kinetics as a sensitive method for testing physiologically intact human recombinant apolipoprotein A-I: comparison of three different expression systems.

In order to assess the structural and functional integrity of recombinant human apoA-I, we expressed apoA-I using three different expression systems: Baculovirus transfected Spodoptera frugiperda (Sf9) cells, stably transfected Chinese hamster ovary (CHO) cells, and transformed Escherichia coli (E. coli). Purified apoA-I from the three expression systems was radioiodinated and their catabolism was compared in normolipemic rabbits. The kinetic turnover studies of radiolabelled apoA-I in normolipemic rabbits revealed that highly purified recombinant apoA-I had an identical decay curve compared to native apoA-I, regardless whether it was purified from Sf9 cells, CHO cells, or E. coli. We also determined the association of the three recombinant apoA-I forms with both rabbit and human HDL. All three recombinant apoA-I forms were associated with HDL2 and HDL3 after injection into the rabbits and after incubation with human serum using both a Superose 6 column separation system and density gradient ultracentrifugation. The addition of the pro-segment or the addition of methionine at the amino-terminal end of apoA-I did not alter its metabolism and association to HDL. In conclusion, all studied expression systems are capable of producing high levels of physiologically intact recombinant human apoA-I. The aminoterminal addition of the prosegment of apoA-I or methionine did not alter the in vivo metabolism of apoA-I or its association to HDL.

Animals↗