[Drug therapy of pituitary tumors].
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Acromegaly↗
Biomedical subjects
R D Hesch
Publications and source records attributed to R D Hesch.
pH-dependency of iodothyronine metabolism in isolated perfused rat liver.
1. Isolated livers from fed male rats were perfused for 2 h with T4 (L-thyroxine), T3 (L-3,3',5-tri-iodothyronine) or rT3 (L-3,3',5'-tri-iodothyronine) at different pH values (7.1--7.6) in a fully synthetic medium, whereby normal metabolic functions were maintained without addition of rat blood constituents or albumin. 2. T3 output into the medium and net T3 production reached a maximum at a pH of the medium of 7.2 and significantly decreased with alteration of the pH when livers were perfused with T4 as a substrate. 3. However, the net T4 and T3 uptake by the liver, as well as the hepatic T4 and T3 content after perfusion, were not dependent on the pH of the perfusion when livers were offered T4 or T3 as substrates respectively. 4. Determination of intracellular pH by the analysis of the distribution of the weak acid dimethyloxazolidinedione allows the conclusion that the pH optimum of iodothyronine 5'-deiodinase in the intact perfused liver corresponds to the maximum determined in vitro for the membrane-bound enzyme localized in the endoplasmic reticulum. 5. The rapid 5'-deiodination of rT3 to 3,3'-T2 (L-3,3'-di-iodothyronine), the fast disappearance of 3,3'-T2, and the fact that no net rT3 production from T4 could be detected, supports the hypothesis that in rat liver iodothyronine 5'-deiodinase activity seems to predominate over iodothyronine 5-deiodinase activity. 6. Thus the rat liver can be considered in normal physiological situations as an organ forming T3 from T4 and deiodinating rT3 originating from extrahepatic tissues, whereby the cellular iodothyronine 5'-deiodination rate is controlled by the intracellular pH.
Animals↗
Characterisation of the binding sites of anti-parathyroid hormone antisera using synthetic parathyroid hormone peptides.
Four antisera raised against partly purified PTH preparations all showed a wide range of specificities when reacting with radioiodinated PTH peptides representing several different portions of the intact hormone sequence. In contrast, antisera raised against individual peptides were only able to cross-react with other peptides that contained all or part of their amino acid sequence in common. Cross-reacting peptides were seen to contain one or more amino acid residues having high interspecies variability in common. We have explained the antigenicity and cross-reactivity of the peptides on the basis of these common highly variable amino acid sequences. We have concluded that the selection of hormonal material in radioimmunoassays for PTH should be made on the basis of the highly variable amino acid residue content. This will allow a narrowing of the assay specificities and permit detection of a desired region of the PTH hormone.
Animals↗
Characterization of two anti-human parathyrin antisera.
Two anti-human parathyrin antisera were raised in sheep. These were characterized by radioimmunoassay using two commercially available bovine parathyrin preparations and one synthetic human parathyrin fragment (sequence 42-55 (42-Tyr)) for radioiodination. In addition, four synthetic human parathyrin fragments (sequences 1-34, 32-43, 434-68, 53-84), one bovine parathyrin peptide (sequence 28-48) and a human parathyrin standard from a tissue culture containing the intact hormone were utilized in a competitive inhibition assay against the two radiolabelled bovine parathyrin preparations. On column chromatography, both tracers revealed a difference in molecular weight, which is believed to be related to the extraction technique. The sequence fragment 44-68 of human parathyrin had the highest affinity for the two antisera when using the smaller molecular weight tracer and there were no qualitative changes observed in the presence of plasma. Using the higher molecular weight tracer, the addition of plasma to one of the antisera resulted in a higher affinity for the sequence fragment 1-34 of human parathyrin compared to that of intact parathyrin. Antiserum from a second sheep remained specific only for the mid-region (sequence 44-68) of the parathyrin molecule independent of the tracer used. Due to the antiserum's constant characteristic, it revealed a high reliability for the discrimination between plasma parathyrin levels in normal probands and in patients with hyperparathyroidism. Our data demonstrate that the specificity of the radioimmunoassay for human parathyrin is not exclusively dependent on the antibody source, but also on the tracer preparation and the protein content of the incubation medium.
Amino Acid Sequence↗
[Endocrine reaction pattern in the course of a one-phase tramadol-N2O combination anesthesia].
The effects of Tramadol-N2O-anaesthesia on the per- and postoperative change in blood concentrations of cortisol, prolactin, thyroxine, triiodothyronine, cyclic AMP, glucagon, antidiuretic hormone, PTH-peptide (44-68), glucose, lactate, pyruvate and free fatty acids (FFA) were investigated in connection with elective orthopaedic surgery. Anaesthesia in man with Tramadol and nitrous oxide were found to be associated with a significant elevation of plasma cortisol and plasma prolactin in man. However, cortisol secretion during anaesthesia is associated with an inhibition in T4-T3 conversion. No significant alterations in plasma glucagon concentrations were observed. Generally, surgical trauma induced a significant increase in plasma cyclic AMP with intraoperative levels between 26.4 and 34.3 pmol/ml. At the end of surgery a significant fall in plasma PTH-peptide (44-68) occurred. There was also a significant change in plasma ADH levels following induction of anaesthesia. During surgery we found plasma ADH levels up to 56 pg/ml. In addition stress and surgical trauma increased blood glucose and FFA while plasma pyruvate and plasma lactate nearly remained unchanged. The data would suggest that the non-specific stress response attributed to anaesthesia may in fact be reflecting a response to relatively light anaesthesia.
Adult↗
[Synthesis of two median segments of human parathyrin (author's transl)].
Human parathyrin-(32-43)-dodecapeptide (H-His-Asn-Phe-Val-Ala-Leu-Gly-Ala-Pro-Leu-Ala-Pro-OH) and tyrosyl-[human parathyrin-(43-55)-tridecapeptide] (H-Tyr-Pro-Arg-Asp-Ala-Gly-Ser-Gln-Arg-Pro-Arg-Lys-Lys-Glu-OH) were prepared, using the strategy of segment condensation in combination with acid-labile protecting groups. The peptides will be utilized for radioimmunoassay and receptor-binding studies.
Amino Acid Sequence↗
[Therapeutic considerations in vascular diseases of the inner ear].
I propose an analogy between vascular diseases of the inner ear and those of other organs like brain, heart or peripheral vessel diseases in which functional and organic alteration can be objectively demonstrated. Symptomatic disturbances of inner ear circulation are monoform in its clinical appearance and the term of 'otangina' is proposed for the functional result. Three types of vascular distribution are discussed for the different regulatory entities, (I) the proximal cerebral vascular type, (II) the predistal innervated regulatory type and the (III) capillary regulatory type. The formal etiology of inner ear vascular diseases is is developed on the base of organic vascular lesions, i.e. arteriosclerosis, functional alterations, i.e. vasospastic disease, and finally change in the microcirculation by alterations of the rheology of the blood. Hypertension is portrayed as a main example for cardiovascular risk factors with respect to inner ear circulatory damage but diabetes mellitus, cigarette smoking and other metabolic diseases leading to vascular disturbances have to be considered. From these considerations I have developed a basic program for the diagnosis of vascular metabolic risk factors which should be realized before any treatment is advocated. I have critically evaluated the benefit and possible hazardous effects of so called 'vasoactive' and 'cephalotropic' drugs. For most inner ear circulatory disease such therapy is contraindicated. The models of drug treatment of acute deafness and the chronic or persistent inner ear deafness should be evaluated in prospective studies.
Arteriosclerosis↗
[Standardisation of TRH test for the exact determination of thyroxine treatment (author's transl)].
A TRH test was performed on 50 patients treated on a daily thyroxine dose of 50-200 microgram. Results were compared with a test performed at the earliest three weeks on the same thyroxine dosage, but the latter having been interrupted for 24 hours. In the first case T4 was 8.96 +/- 2.9 microgram/dl, in the second 7.08 +/- 2.0 microgram/dl; T3 in the first case 1.28 +/- 0.3 ng/ml, in the second 1.03 +/- 0.25 ng/ml. This indicates that with both thyroid hormones the levels were higher on the day of administration than 24 hours later. Correspondingly, TRH-stimulated TSH secretion was definitely lower on the day of treatment. delta TSH (TSH after 30 minutes minus TSH zero value) was 16.1 +/- 26.5 on day of treatment, 27.3 +/- 35.6 micro U/ml after pause. Accordingly, to achieve "fine tuning" of T4 treatment, such as for euthyroid goitre, the TRH tests standardised on 200 microgram TRH should be performed after a T4-free 24-hour interval. delta TSH should then not be more regimen, drug-induced hyperthyroidism can be definitely avoided.
Female↗
Autoregulation of 3, 3',5'-triiodothyronine production by rat liver microsomes.
Conversion of thyroxine (T4) to 3,3',5'-triiodothyronine (rT3) was studied in rat liver microsomes. Addition of rT3 at a physiological concentration to the incubation medium inhibited the deiodination of thyroxine to rT3. With a concentration of rT3 greater than 37.6 nM no net rT3 production at pH 8.0 was observed. Further increases in rT3 concentration resulted only in degradation of added rT3 and no net synthesis of rT3 from T4 could be detected. The inhibitory effect of rT3 upon its own production from T4 was pH dependent, 5 fold lower amounts of hormone being required to inhibit completely rT3 production at pH 7.4 than at pH 8.0. With the same experimental conditions no significant effect of rT3 on the conversion of T4 to 3,5,3'-triiodothyronine (T3) could be observed at pH 8.0 with all concentrations of added iodothyronine. A linear production of 3,3'-T2 from added rT3 was determined over the whole range of rT3 concentration, suggesting a lack of saturation of deiodinating enzyme. Binding of rT3 by anti-rT3 antibody added to the incubation mixture enhanced rT3 production from T4 by protecting rT3 from being degraded and/or diminishing the inhibitory effect of this iodothyronine on its own production. It was concluded that rT3 influenced its own production and that this effect may represent an important autoregulatory process in the iodothyronine metabolism.
Animals↗
Treatment of dopamine-dependent shock with triiodothyronine.
At the present time dopamine is the most frequently used treatment in patients with septic shock. The effects of dopamine are mediated by alpha-, beta- and dopaminergic receptors. It has been suggested that these receptors are controlled by triiodothyronine (T3). In acute septic shock circulating T3-concentrations are decreased. We have, therefore, treated in a preliminary study 11 such patients with T2-replacement by continuous infusion of T3 (100-200 micrograms/24h). Dopamine dependence was terminated. In all patients there was an increase of arterial blood pressure (BP) within 24 hrs (systolic BP rose by 34 +/- 4.2 mmHg, diastolic BP by 14.0 +/- 8.2 mmHg, resulting in an increase of the mean BP by 25 +/- 6.1 (SEM mmHg). The pulse rate was not influenced suggesting an effect on minute volume. A hypothesis is offered which explains the T3-effects as a result of its decarboxylation to a dopaminergic iodothyronine which is disturbed during the "low T3-syndrome".
Dopamine↗
Different handling of parathyrin by basal-lateral and brush-border membranes of the bovine kidney cortex.
The two parts of the bovine kidney cortex plasma membrane, the basal-lateral and the brush-border membrane, were simultaneously prepared from the same organ. Both types of membrane bound parathyrin, but only from the basal-lateral fraction was the hormone displaceable by its bioactive N-terminal fragment. In parallel, parathyrin-stimulated adenylate cyclase was predominantly found in basal-lateral membranes. The hormone was fragmented by both membrane types. Basal-lateral membranes generated fragments with a rather uniform size distribution (somewhat smaller than the intact peptide) and apparently preferred the hormone itself as a substrate. In contrast, the fragments produced by brush-border membranes were numberous small peptides.
Adenylyl Cyclases↗
Acute hyperparathyroidism. Clinical, laboratory and ultrastructural findings in a variant of primary hyperparathyroidism.
In a series of 6 patients out of 47 cases with extrarenal hyperparathyroidism we investigated the clinical, laboratory and ultrastructural peculiarities of acute hyperparathyroidism. It was found that there are characteristic differences between both entities which, however, are fluid. Clinically more severe were neuromuscular psychiatric and mental signs. In the laboratory parameters PTH determined by radioimmunoassay and calcium were higher whereas hemoglobin was lower. The weights of the adenomas did not differ in both groups and this was also true for light microscopy findings. Electron microscopy revealed accelerated hormone extrusion and autodigestion of retrived membrane material in the cases of acute hyperparathyroidism similar to characteristics of parathyroid cells stimulated by hypocalcemia in tissue culture.
Acute Disease↗
[Extraglandular causes of hyperparathyroidism].
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Gastrointestinal Diseases↗
[Plasma parathyroid hormone after kidney transplantation. A sensitive parameter for the estimation of graft function (author's transl)].
Patients after kidney transplantation were investigated for parameters for kidney function and calcium metabolism including a definitively characterized parathyroid hormone (PTH) radioimmunoassay, of which quality criteria have been documented. In 72 transplanted patients 3 months to 7 years after operation a close correlation between graft function and plasma PTH concentrations was found. Patients with clearly elevated PTH revealed definitively decreased graft function. Three patients with normal GFR and clearly elevated PTH showed - at least transiently - all criteria of an autonomous hyperparathyroidism including hypercalcaemia and hypophosphataemia. Borderline PTH elevations associated with normal GFR can be explained by corticosteroid treatment. In 100 patients, which were investigated before and during the first 10 days after transplantation, again a close correlation was documented between the development of PTH concentrations and the function of the transplanted kidney. PTH concentrations are not only a very sensitive parameter of graft function; in various situations plasma PTH concentrations additionally allow an estimate of graft prognosis. This is particularly true in primary graft failure and in early rejection episodes.
Adolescent↗
Parathormone receptor binding and the influence of membrane degradation of the hormone.
Concentration of receptor bound parathormone was determined using a labelled-antibody-membrane-assay (LAMA). 4.2-31.2 fmol PTH per mg membrane protein (0.42-3.12 fmol/tube) were bound at apparent PTH concentrations of 15.6-500 fmol/tube. Only 0.65%-3.2% of PTH could be detected at the receptor sites. The amount of free hormone was corrected for inactivation of intact immunologically reactive PTH and of intact biologically reactive PTH. Only after the latter correction were values for binding affinity (Kd = 1.1 x 10(-12) mol/mg) and number of binding sites (Bmax = 5.8 x 10(-14) mol/mg) obtainable. These results indicate that allowance must be made for loss of biological activity of hormone at membrane receptor sites if binding parameters are to be defined free of artifacts. Binding data may otherwise be misinterpreted as indicating negative cooperativity, heterogeneity of binding sites or multi-step reactions.
Animals↗
Human parathyroid hormone: antibody characterization.
PTH antibodies were raised in two sheep (S 469 and S 478) by immunizing with porcine and bovine parathyroid extracts. Both antisera were characterized with various PTH preparations and fragments. Both antisera cross react with human, bovine and porcine PTH, one antiserum also binds rat PTH. Region specificity could be attributed to the mid region of the PTH molecule with particularly high affinities of both antisera for the fragment 44-68 hPTH. S 478 has similarly high affinity for intact hormone (affinity constants 0.6 x 10(13) l/mol), while S 469 has much higher affinity for the 44-68 fragment (affinity constant 0.84 x 10(13) l/mol) than for intact hormone. The antibodies are useful not only for clinical radioimmunoassay, but also for experimental work. They have been distributed to many laboratories.
Animals↗
Parathyroid hormone fragments in secretory granules of human parathyroid adenomata.
The composition of human parathyroid hormone immunoreactivity in the secretory granule fraction of parathyroid hormone adenomata was investigated. Granular extracts were separated by gel filtration and the eluates assayed by radioimmunoassay and sequence specific immunoradiometric assays detecting aminoterminal and carboxyterminal activity. About half of the extracted adenomata contained fragments besides intact hormone. The fragment composition varied from adenoma to adenoma.
Adenoma↗