Biomedical subjects
Publications and source records attributed to H Vierhapper.
High blood pressure is due to endocrine disorders in only a small fraction of hypertensive patients. However, the recognition of these conditions offers the potential chance to cure hypertension and hence to avoid secondary cardiovascular complications. It is therefore of pivotal importance for the group of patients in question.
Endothelin-1 (ET-1) is known to stimulate glycogenolysis in perfused rat livers and isolated rat hepatocytes. To determine the potential action of endothelin's precursor, big endothelin-1 (big ET-1), isolated rat livers were perfused with big ET-1 in a non-recirculating system. Thereby, big ET-1 (10 nM) induced a maximally three-fold increase (P < 0.01 vs. basal values) in hepatic glucose production at 60 min, which was almost completely abolished by concomitant infusion of 50 microM phosphoramidon, a sensitive inhibitor of the enzymatic cleavage of big ET-1 to ET-1. The corresponding incremental release of glucose by big ET-1 was 20.9-fold higher in the absence of phosphoramidon than in its presence (P < 0.01). In contrast, phosphoramidon did not inhibit hepatic glucose production induced by ET-1 (1 nM), glucagon (1 nM), and phenylephrine (5 microM). Glycogenolytic responses to 1 nM ET-1 (P < 0.01), but not to 1 nM glucagon (n.s.) were blocked by indomethacin (100 microM), indicating that prostaglandin release by non-parenchymal cells is at least in part involved in the hepatic ET-1 action. In conclusion, big ET-1 induces hepatic glucose release, which is suggested to depend on intrahepatic conversion of big ET-1 to ET-1 by a phosphoramidon-sensitive pathway.
Oral high-dose arginine supplementation is used for the experimental immunotherapy of tissue trauma and sepsis. Yet the adequate dosage required for immunomodulation has to be established and the toxicity of high-dose arginine has not been fully elucidated. Following a protocol for the treatment of diabetic long-term complications (oral daily doses of 30 mg/kg BW; blind, placebo-controlled prospective study with crossing-over design) we studied plasma levels of interleukins 1 alpha (IL-1 alpha) and 1 beta reflecting immunostimulation. Arginine supplementation in 29 patients with diabetes mellitus prompted a 2-fold increase of IL-1 alpha from baseline levels (P < 0.001) while IL-1 beta was unaffected. Implications for the treated panel of diabetic patients could be a reduction of collagen accumulation by enhanced collagenolysis and clearance of advanced-stage non-enzymatic glycosylation products. Based upon our data, low-dose arginine protocols for further immunotherapeutical studies should be discussed.
The McCune-Albright syndrome (MAS) comprises a triad of physical signs: localized bone lesions termed polyostotic fibrous dysplasia, café-au-lait pigmentation of the skin, and autonomous hyperfunction of multiple endocrine systems, including overproduction of GH and T4. A somatic activating point mutation in the gene for the alpha-subunit of the G-protein (Gs alpha) in the affected tissue has been claimed to be the underlying defect. A 29-yr-old patient with MAS, showing polyostotic fibrous dysplasia associated with acromegalic features, underwent endocrinological studies, including oral glucose tolerance test and pituitary stimulation test, and magnetic resonance imaging, revealing elevated plasma concentrations of GH, PRL, and secondary hyperthyroidism due to pituitary macroadenoma infiltrating the sphenoid cavity and extending to the suprasellar space. Subsequently, reduction of tumor mass by a transsphenoidal and a subsequent subfrontal operation led to only marginal amelioration of the excessive hormone production. Postsurgery octreotide and bromocriptine therapy induced near-normalization of hormone concentrations. Immunohistochemistry of tumor tissue confirmed the plurihormonal character, but DNA sequence analysis did not detect any of the two known activating mutations in the Gs alpha gene. Furthermore, biochemical tests revealed normal Gs alpha function, ruling out other mutations that lead to constitutive Gs alpha activation. Our study documents that MAS is a heterogeneous disease. Some, but clearly not all, patients have oncogenic mutations of the gene coding for Gs alpha. Any gene acting down-stream of Gs can theoretically be predicted to result in the same phenotype. In addition, hyperthyroidism of MAS may be secondary to a TSH-producing pituitary macroadenoma.
Diabetic vascular disease is associated with a state of hypercoagulability and altered endothelial properties, leading to elevated plasma levels of endothelium-derived peptides and proteins, e.g. endothelin-1, von Willebrand factor or fibronectin. This study determined dynamic immunoreactive endothelin-1 secretion by human umbilical vein endothelial cells exposed to thrombin (5 x 10(6) mU/l) in the presence (40 mmol/l) and absence (5.5 mmol/l) of excessive glucose in the cell culture medium. Exposure to high glucose and thrombin concentrations was initiated after cell confluency and applied for 24 h for measurements of endothelin-1 and for 2 and 5 h for the determination of preproendothelin-1, von Willebrand factor and fibronectin messenger ribonucleic acid. Comparisons were made versus cells incubated with normal glucose concentrations or with high mannose or NaCl concentrations as osmotic control. Neither preproendothelin-1, fibronectin and von Willebrand factor messenger ribonucleic acid expression nor endothelin-1 release was affected by high concentrations of glucose, mannose or sodium chloride.
To determine the impact of both short- and long-term "near-normoglycaemia" on insulin resistance in Type 1 (insulin-dependent) diabetes hepatic glucose production (mg.kg-1.min-1) and peripheral glucose utilisation ("M-value", mg.kg-1.min-1) were estimated during an euglycaemic hyperinsulinaemic clamp (10 mU.kg.min) in patients with either good (HbA1c < 5.8%, groups A and B) or poor (HbA1c > 7.5%, groups C and D) long-term metabolic control (time > 12 months) and in healthy subjects (HbA1c: 5.08 +/- 0.20%; n = 8). To this end blood glucose was stabilized at 6.7 mmol/l by overnight (t = 12 h) i.v. regular insulin in groups (n = 8 each) A (HbA1c: 5.49 +/- 0.46%) and C (HbA1c: 8.83 +/- 1.20%), while groups B (HbA1c: 5.55 +/- 0.19%) and D (HbA1c: 8.51 +/- 1.09%) were kept overnight on long-acting insulin without feed-back control of blood glucose before euglycaemic clamping. Thereby, pre-equilibration of blood glucose at 6.7 mmol/l was shown to normalize basal hepatic glucose production (A: 2.27 +/- 0.48; C 2.50 +/- 0.57 mg.kg-1.min-1) despite different HbA1c values, whereas basal hepatic glucose production stayed elevated in groups B (3.09 +/- 0.38 mg.kg-1.min-1) and D (3.21 +/- 0.58 mg.kg-1.min-1) with poor actual glycaemia (B: 10.9 +/- 4.6; D: 12.1 +/- 4.6 mmol/l).(ABSTRACT TRUNCATED AT 250 WORDS)
Vanadium compounds exert insulin-like effects on isolated rat adipocytes and skeletal muscle and improve glucose homeostasis in diabetic rats and mice. However, reports on metabolic actions of vanadium in the liver are still contradictory. Thus, the acute effect of sodium orthovanadate infusion on net glucose production was measured in isolated perfused livers of non-fasting, non-diabetic rats. Continuous infusion (0.2 ml/min; 90 min) of vanadate (10-500 mumol/l) rapidly increased hepatic glucose (p < 0.001), but not cyclic AMP output, reaching peak values after 20 min. The cumulative glucose release displayed concentration dependence with a maximal net effect of 394.3 mumol/100 g body weight and an apparent half-maximal effective vanadate concentration of 19.6 mumol/l. The glycogenolytic response to vanadate was almost completely blocked by 100 mU/l insulin (p < 0.005), by 0.1 mmol/l indomethacin (p < 0.05) and in the absence of Ca2+ (p < 0.001). These results indicate that sodium orthovanadate stimulates glycogenolysis in livers of fed, non-diabetic rats by a Ca(2+)-dependent mechanism, which may involve the release of prostaglandins.
The effect of endothelin-1 on basal and stimulated serum (plasma) concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyrotropin (TSH), prolactin (PRL), growth hormone (GH), and corticotropin was investigated in healthy male volunteers (n = 5). Intravenous (IV) administration of endothelin-1 (5 ng/kg/min for 15 minutes, followed by 2.5 ng/kg/min for 105 minutes) induced an increase in basal plasma concentrations of corticotropin. Serum concentrations of PRL, TSH, LH, FSH, and GH remained unchanged. The increase in serum concentrations of these pituitary hormones induced by IV administration of LH-releasing hormone ([LH-RH] 100 micrograms), thyrotropin RH ([TRH] 400 micrograms), GH-RH (100 micrograms), and corticotropin-releasing factor ([CRF] 100 micrograms) was suppressed in regard to PRL (P < .01) and GH (P < .01) and enhanced in regard to corticotropin (P < .01). Stimulated serum concentrations of LH and FSH also tended to be higher following administration of endothelin-1 (P < .05), whereas the increase in serum concentrations of TSH remained unchanged. Thus, when administered in pharmacological doses, endothelin-1 influences pituitary hormone secretion in man.
The effects of i.v. human atrial natriuretic factor (alpha-hANF [99-126]) was investigated in 5 conscious calves (age 4 months, weight 94 +/- 14kg) with constant fluid (300 ml/h) and sodium intake over a period of 24 hours before and during the 3 hours of experimentation. We administered 200 micrograms, 400 micrograms and 800 micrograms ANF at hourly intervals. Immediately (+2 min) after the i.v. injection the peptide's serum-concentration rose from, basal 13 +/- 3 to 802 +/- 191 (200 micrograms), 1707 +/- 419 (400 micrograms) and 3483 +/- 878 pmol/l (800 micrograms) (p < 0.0001), respectively. Mean arterial pressure decreased from, basal, 108 +/- 18 to 85 +/- 17, 76 +/- 16 and 69 +/- 18 mmHg (p < 0.0001), and central venous pressure decreased from, basal, 5.1 +/- 3 to 1.2 +/- 1, 0.4 +/- 1 and 0.8 +/- 2 mmHg (p < 0.001). Heart rate increased from, basal, 66 +/- 5 to 84 +/- 23, 111 +/- 29 and 114 +/- 13 b/min (p < 0.001). Following the administration of ANF the urine volume decreased from, basal, 261 +/- 145 to 195 +/- 72, 121 +/- 41 and 102 +/- 33 ml/h (p < 0.0041). The urinary sodium excretion rates decreased from, basal, 50 +/- 17 to 30 +/- 13, 22 +/- 10 and 19 +/- 10 mmol/h (p < 0.007), and the potassium excretion rates decreased from, basal, 43 +/- 19 to 39 +/- 16, 26 +/- 11 and 23 +/- 10 mmol/h (p < 0.0047). Endogenous clearance of creatinine (basal: 182 +/- 30 ml/min) did not change (260 +/- 84, 218 +/- 66 and 224 +/- 76 ml/h) following i.v. ANF. Inspite of this marked fluid retention, the hematocrit, expressed as relative change, was increased by 7.5%, 11.8% and 10.4%. In 2 calves we additionally measured an increased whole blood and plasma density possibly indicating increased liquid permeation to an extravascular compartment. Thus, in calves the hemodynamic effects of ANF are comparable to those seen in man. However, the failure of ANF to stimulate diuresis and natriuresis indicates a dissociation of hemodynamic and renal effects of ANF in calves.
In order to investigate the effect of euglycemic hyperinsulinemia on skeletal muscle blood flow and renal blood flow, catheters were inserted into both femoral arteries, one femoral vein and one renal vein of 7 healthy men. Constant infusions of indocyanine-green dye (intraarterial) and of p-aminohippuric acid (intra-venous) were used to estimate leg plasma flow (ELPF) and renal blood flow (ERPF), respectively, prior to and during a euglycemic, hyperinsulinemic clamp (1.0 mU/kg.min of human insulin, serum concentrations of insulin before and during the clamp: 4.6 +/- 0.9 microU/ml and 65.5 +/- 20.6 microU/ml, respectively, t = 120 min). ERPF (basal: 1220 +/- 320 ml/min) remained unchanged throughout the period of induced hyperinsulinemia in each volunteer (mean: 1135 +/- 490 ml/min), whereas mean leg plasma flow (ELPF) rose from basal 206 +/- 99 ml/min up to 275 ml/min 90 minutes after the beginning of the euglycemic clamp study (p < 0.01). This was due to the marked rise in ELPF from 149 +/- 24 ml/min up to 243 +/- 25 ml/min (p < 0.01) seen in 5 subjects. In two men, who presented a markedly higher basal ELPF (332 and 365 ml/min, respectively), no further rise in ELPF was seen during induced hyperinsulinemia. Fractional renal extraction of insulin was unchanged during induced hyperinsulinemia (28 +/- 5%; basal: 22 +/- 18%), as was fractional extraction of insulin by the leg (10 +/- 5%; basal: 13 +/- 11%). The observed dissociation of ERPF and ELPF suggests a differential response to insulin in renal vs. leg vasculature which possibly is due to increased peripheral glucose metabolism.
In permanent night shift workers the impact of environmental time cues on the circadian system is conflicting. Rhythm adjustments to the nocturnal work schedule have been described, and their significance for tolerance to shift work is under discussion. Reports concerning the effect of this work situation on the setting of the endogenous clock are, however, inconsistent. We examined nine healthy young male permanent shift workers with high work satisfaction at the end of a week on night work and seven male controls with normal diurnal working hours. All subjects were admitted to a research facility for 28 h, and blood was collected with a continuous-withdrawal pump in portions taken hourly for the estimation of the circadian melatonin (MT) and cortisol secretion pattern. One control did not exhibit a circadian secretion pattern. When compared with the other controls (n = 6), all except one of the shift workers showed no difference in the phase or phase relationship of their hormonal profiles. In the shift workers, a minor trend toward elevation of the MT amplitude and an increase in two indicators for the amount of MT secreted were noticed. One individual displayed inverse hormone rhythms with an undisturbed phase relationship of MT and cortisol and inconspicuous hormone amplitudes. He showed, however, an inverse day-night rhythm in his private life, too. The data collected suggest that even permanent night workers with a high degree of work satisfaction do not usually lose the diurnal orientation of their endogenous clock. Factors other than reorientation of the circadian system may be more important for high tolerance to shift work.
Suramin, a polyanionic compound, which has been in clinical use for the treatment of African trypanosomiasis for several decades, has recently been introduced in clinical oncology. Its effects on the immune system seemed therefore of interest. In the present study we tried to elucidate in vitro how suramin affected different functions of human peripheral blood mononuclear cells (PBMC). Suramin suppressed the proliferation of PBMC in response to various stimuli, including OKT3, phytohemagglutinin (PHA), phorbolmyristate-acetate (PMA) and ionomycin, purified protein derivate of Mycobacterium tuberculosis (PPD) and antibodies against CD2. It also inhibited the binding of monoclonal antibodies to T cell surface antigens. This effect was not dependent on the isotype of the antibody, but seemed to be highly epitope-specific. Among a panel of antibodies against one antigen, only a few were affected by the compound. Whereas the binding of Leu3a and OKT3 was for instance fully suppressed by suramin, OKT4 and Leu4 binding was only slightly affected. Suramin also decreased the expression of T cell surface molecules such as CD2, CD25 and CD4 in preactivated PBMC and had pronounced effects on cytokine production. Interestingly the compound had adverse regulatory effects on different cytokines. Whereas the secretion of interferon-gamma was completely suppressed by suramin, interleukin-2 (IL-2) and IL-4 production was stimulated. These results demonstrate that suramin affects T cell function in multiple different ways. This will have to be considered, when suramin is used in the treatment of cancer patients.
Endothelin-1 (ET-1), a potent vasoconstrictor peptide produced by endothelial cells and degraded predominantly in the pulmonary vasculature, has been implicated in the development of various organ dysfunctions. To determine the pathophysiologic role of ET-1 in adult respiratory distress syndrome (ARDS) and the impact of impaired lung function on transpulmonary peptide handling, we compared plasma levels and pulmonary ET-1 balance in 14 patients with ARDS and in seven healthy control subjects. To obtain comparable conditions in both groups, the ET-1 level was raised in the control group by exogenous infusion (0.4 pmol/kg/min) to 9.4 +/- 0.8 pmol/L. ARDS was accompanied by a hyperdynamic circulatory pattern with increased cardiac output and depressed total vascular resistance but, simultaneously, pulmonary hypertension. Venous ET-1 concentration was massively increased in ARDS (9.8 +/- 1.2 versus 2.1 +/- 0.2 pmol/L, p < 0.001). In control subjects, the lung cleared the major fraction of ET-1 (fractional extraction 43 +/- 8.8%, uptake 12.5 +/- 2.5 pmol/min). In contrast, in ARDS there was a pronounced pulmonary releases into the circulation (32.8 +/- 10.3 pmol/min). We conclude that ET-1 concentrations are elevated in ARDS as the result of both increased formation and decreased disposal. Lung failure affects not only gas exchange but also nonrespiratory, metabolic pulmonary functions.
This study evaluates stimulated insulin production rate (incremental AUC x MCR (metabolic clearance rate) of C-peptide) and blood glucose (BG) response after i.v. administration of glimepiride (Hoe 490, GLI, CAS 93479-97-1) (0.25, 0.50, 0.75, 1.00, 1.25, 1.50 mg) in healthy man (27 +/- 4 yrs). It was shown that i.v. bolus administration of GLI (0.25, 0.50, 1.25 and 1.50 mg) caused a dose-related rise in insulin production from 18 +/- 17 to 25 +/- 13, 36 +/- 14 and 54 +/- 34 pmol/kg body weight, respectively. This effect did not yet plateau at 1.5 mg GLI and was paralleled by a fall in BG (decremental area below BG baseline) by 40 +/- 36, 69 +/- 20, 161 +/- 47 and 113 +/- 62 mmol.min/l. It is concluded that insulin release is increased by i.v. GLI in a dose related manner, while a parallel decline in BG was induced only up to 1.25 mg GLI. The less marked fall of BG after injection of 1.50 mg GLI may reflect interference by insulin-counterregulatory hormones secondary to induced hypoglycaemia.
In the past anabolic steroids were the first-choice treatment for pancytopenic disorders that were often poorly classified. They are now superseded by other more recently developed methods of treatment--for example bone marrow transplantation and immunosuppression. This contrasts to the authors' experience, and to that of many other haematologists, who have noted anabolic steroid-induced responses in patients who were unsuitable for or unresponsive to the new treatments. Anabolic steroids did not, however, demonstrate an obvious effect in recent controlled trials involving patients with aplastic anaemia. Their use with immunosuppressive treatment is currently under investigation. Although anabolic steroids rarely reverse the course of anaemia in a myelodysplastic syndrome, even a slight haemopoietic improvement is desirable. Children with Fanconi's anaemia may benefit from a reduced transfusion requirement. Uraemic patients may experience significant side effects on standard erythropoietin (epo) treatment. There have been no controlled trials comparing epo versus anabolic steroids or epo versus epo in conjunction with anabolic steroids. Data from uncontrolled studies indicate a better response to anabolic steroids in children and females than in men. In spite of the fact that anabolic steroids have been used for almost 30 years, they should be carefully re-evaluated in scientifically controlled trials to test their efficacy and to compare them with the new treatments. Such trials, however, are impeded by the limited knowledge available with regard to pharmacological parameters and optimal treatment schedules.
New immunochemiluminometric assays (ICMA) of thyrotropin (TSH) have been reported to facilitate the diagnosis of hyperthyroidism. To compare the accuracy of ICMA-TSH with that of a conventional immunoradiometric assay (IRMA-TSH), we examined 115 consecutive patients of a thyroid outpatient clinic. On the basis of complete thyroid-function testing, including thyroliberin tests, the untreated patients (n = 89) were subclinically hyperthyroid (n = 21), subclinically hypothyroid (n = 13), or euthyroid (n = 55). The receiver-operating characteristic (ROC) curve, used for comparing the TSH values obtained by these two methods, was shifted to the left for the IRMA-TSH. The area under the curve was greater for IRMA-TSH than for ICMA-TSH (0.984 vs 0.869, respectively), which suggests equal or better clinical performance of IRMA-TSH vs ICMA-TSH in discriminating between hyperthyroidism and euthyroidism. Both assays displayed similar clinical sensitivity/specificity for evaluating thyroid function in hypothyroid and treated patients. We conclude that the ICMA-TSH tested is not more accurate than an IRMA in distinguishing between hyperthyroidism and euthyroidism.
The aim of this study was to determine the permeability of endothelial monolayers for endothelin-1 and a possible directionality of the endothelin-1 secretion process. Human umbilical vein endothelial cells were cultured on acellular amniotic membranes, dividing the tissue culture wells into an apical (luminal) and a basolateral (abluminal) compartment. Whereas in the absence of endothelial monolayers 44.9 +/- 2.3 and 43.5 +/- 2.0% of the unilaterally added endothelin-1 permeated from the apical to the basolateral side and from the basolateral to the apical side, respectively, only 6.5 +/- 0.6 and 6.6 +/- 0.4% diffused in the presence of endothelial cells. Analyzing endothelin-1 secretion, approximately 80% of the total amount of synthesized endothelin-1 was found in the basolateral compartment; thrombin (10 units/ml) stimulated the production of endothelin-1 approximately 2-fold, but did not change the relative distribution of endothelin-1 between the apical and basolateral compartments. In the presence of dexamethasone (10(-7) M), a decrease in the level of endothelin-1 was found in the apical compartment, whereas the total amount of endothelin-1 produced was not affected. Dexamethasone did not influence the permeability of human umbilical vein endothelial cell monolayers for endothelin-1. These results strongly support the hypothesis that endothelin-1 is a local paracrine regulator of vasotone.
The vasoactive peptide endothelin-1 (ET-1) which is present in high concentrations in the colon, causes concentration-dependent electrogenic Cl- secretion in rabbit descending colon. This effect is half-maximal at 0.11 mumol/l. Like other secretagogues, ET-1 also stimulates K+ secretion. The secretory effect of ET-1 is associated with increased release of prostaglandin E2 from the serosal surface of the mucosa. ET-1-induced Cl- secretion is completely inhibited by the loop diuretic bumetanide and by indomethacin and quinacrine, inhibitors of prostaglandin synthesis. Neuronal mechanisms do not seem to be involved, as tetrodotoxin did not affect the secretory response to ET-1 significantly. On the other hand, neither the catalytic activity nor the transport function of the Na+/K(+)-ATPase of rabbit colon epithelium is affected by endothelin-1 (ET-1) in concentrations up to 10 mumol/l. It is concluded that ET-1 causes Cl- and K+ secretion by stimulating phospholipase A2 and release of prostaglandins, whereas Na+ transport is not altered.