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Biomedical subjects

H Engler

Publications and source records attributed to H Engler.

At least 73 records · Page 4Linked to original sources
PubMed1983

Mechanism of action of thioureylene antithyroid drugs in the rat: possible inactivation of thyroid peroxidase by propylthiouracil.

We have previously shown that the thioureylene antithyroid drugs 6-propyl-2-thiouracil (PTU) and 1-methyl-2-mercaptoimidazole (MMI) can inactivate thyroid peroxidase (TPO) in a model iodination system containing relatively high concentrations of iodide. The purpose of the present study was to determine whether these drugs may also inactivate TPO in vivo in rats. Assays for total TPO activity after injection of PTU or MMI did not prove to be a valid approach. As TPO inactivation might be expected to result in a relatively prolonged inhibition of enzyme activity, most of our experiments involved measurement of the duration of the inhibitory effect of a single injection of drug. Young rats were injected with low doses of PTU or MMI, and the effect on thyroidal organic iodine formation was determined at intervals after injection, either by 1-h pulse labeling with 131I- in vivo or by incubation of excised thyroid lobes in a medium containing 131I-. Results of both types of experiment demonstrated that the inhibitory effect of a small dose of PTU (1 mumol/100 g BW) was still very marked 17-18 h after injection. Moreover, an inhibitory effect of this small dose of PTU on the metabolism of [35S]MMI could also be demonstrated. Administration of MMI to rats, on the other hand, did not show the prolonged inhibitory effect observed with PTU. This is most likely attributable to the much lower thyroidal uptake of MMI than of PTU in rats. Intrathyroidal metabolism of [35S]PTU and [35S]MMI was also investigated. In contrast to the rapid disappearance of 35S from plasma, both drugs showed accumulation and retention of 35S in the thyroid. However, we obtained no evidence that thyroidal accumulation of PTU or one of its metabolites could explain the prolonged inhibitory effect of this drug. It seemed more likely that this was attributable to TPO inactivation. The clinical implications of our findings are discussed with relation to the dosage schedule commonly employed in the treatment of Graves' disease with antithyroid drugs.

Animals↗
PubMed1982

Mechanism of inactivation of thyroid peroxidase by thioureylene drugs.

We have investigated the mechanism by which the thioureylene drugs, 1-methyl-2-mercaptoimidazole (MMI) and 6-n-propylthiouracil (PTU), inactivate thyroid peroxidase (TPO). Our results indicate that inactivation of TPO by MMI and PTU involves a reaction between the drugs and the oxidized heme group produced by interaction between TPO and H2O2. This conclusion is supported by the following observations. First, addition of a low concentration of H2O2 to a solution of TPO shifted lambda max of the Soret band from 411 to 420 nm, reflecting the formation of an oxidized form of TPO (TPOox). Addition of MMI or PTU to TPOox produced a Soret spectrum that was significantly different from the spectrum of native TPO or TPOox, whereas addition of MMI or PTU to native TPO produced no significant change in the heme spectrum. Second, studies with radiolabeled MMI and PTU combined with simultaneous assays of enzyme activity (guaiacol assay) showed that firm binding of the drugs to TPO and inactivation of the enzyme occurred on addition of the drugs to TPOox. However, neither binding nor inactivation occurred on addition of the drugs to native TPO. Third, the presence of a low concentration of iodide prevented the shift in the Soret spectrum, the binding of labeled drug, and the loss of enzyme activity associated with the addition of thioureylene drugs to TPO + H2O2. Under these conditions we assume that the enzyme was present as TPO X Iox, a form in which the heme is present in the same reduced state as in native TPO. This would explain the protective action of iodide on the inactivation of TPOox by MMI and PTU.

Antithyroid Agents↗
PubMed1982

Experimental infection of inbred mice with herpes simplex virus. IV. Comparison of interferon production and natural killer cell activity in susceptible and resistant adult mice.

Inbred mouse strains differ in susceptibility to infection with herpes simplex virus type 1 or type 2 (HSV-1, HSV-2). In this study interferon production was tested in the peritoneal exudate of mice after intraperitoneal (i.p.) injection of HSV-1 or HSV-2. In HSV-resistant mice (C57 BL/6, C3 H/HeJ) high titers of interferon were already present 2 to 4 hours after injection. In comparison, less resistant mice (DBA/2, AKR) lacked this early response. There was no correlation between interferon titers and resistance at post-infection times later than twelve hours. At twelve hours, however, high titers of HSV were detected in the peritoneum of DBA/2 mice and significantly lower titers in C57 BL/6 mice. In a comparative analysis of eight different inbred mouse strains, again early (2 to 4 hours) interferon production was correlated to resistance. In assays of HSV-stimulated early (24 hours) NK cell responses not only the good interferon producer strains but also one of the less resistant low interferon producers (BALB/c) showed significant cytotoxic activities. Conversely, SJL mice that are very low in HSV-induced NK cell activity are resistant and show high early interferon responses at the local site.

Animals↗
PubMed1982

Influence of nonsteroidal anti-inflammatory compounds on healing of chronic gastric ulcers in rats.

Pre-treatment with NOSAC led to an increase of ulcer index in a dose-dependent manner indicating the aggravation of gastric lesions under the influence of NOSAC. The severity of mucosal lesions was diminished by lengthening the time between the last day of pre-treatment with NOSAC and the day on which ulcers were induced. When NOSAC were administered after the induction of gastric ulcers, the healing of the latter was significantly delayed.

Animals↗
PubMed1982

Experimental infection of inbred mice with herpes simplex virus. III. Comparison between newborn and adult C57BL/6 mice.

We have previously shown that adult C57BL/6 mice are relatively resistant to intraperitoneal (i.p.) infection with herpes simplex virus type 1 (HSV-1). Here we show that newborn mice of the strain C57BL/6 are highly susceptible to i.p. infection with HSV-1. Newborn C57BL/6 mice, in contrast to adult mice, did not develop natural killer cell activity in the peritoneal cavity 24 h after i.p injection of HSV-1, and showed only minimal titres of interferon in the peritoneal fluid after 4 h. After 24 h the peritoneal fluid of newborn mice contained high amounts of interferon and high titres of HSV-1. In contrast, the virus titres in the peritoneal cavity of adult mice were significantly lower. It is suggested that the early titres of interferon at the infection site that are observed in adult, resistant C57BL/6 mice but not in susceptible, newborn mice play a decisive role in resistance.

Aging↗
PubMed1982

Activation of natural killer cells and induction of interferon after injection of mouse hepatitis virus type 3 in mice.

High levels of natural killer (NK) cell activity and high titers of interferon were observed in the peritoneal exudate of C57BL/6 mice 20 to 50 h after injection of mouse hepatitis virus type 3 (MHV3) but not during the first 10 h after infection. C57BL/6 mice were susceptible to MHV3 infection and showed high titers of MHV3 in the peritoneal exudate 48 h after infection. A/J mice, in contrast, were resistant to the dose that killed 100% of the C57BL/6 mice (10 macrophage-infecting doses) and showed considerably lower virus titers than those shown by C57BL/6 mice. NK cell activity and interferon titers were significantly lower in the peritoneal exudate of A/J mice than in that of C57BL/6 mice. Serum interferon titers were also lower in A/J mice. Thus, our data show an inverse relationship between resistance and the levels of these two parameters. The data suggest that, in contrast to the situation observed with certain herpesviruses, interferon and NK cells may not be of overwhelming importance in the defense of mice against MHV3.

Animals↗
PubMed1982

Preferential inhibition of thyroxine and 3,5,3'-triiodothyronine formation by propylthiouracil and methylmercaptoimidazole in thyroid peroxidase-catalyzed iodination of thyroglobulin.

The present study was undertaken to determine whether the thioureylene antithyroid drugs propylthiouracil [6-propyl-2-thiouracil (PTU)] and methylmercaptoimidazole [1-methyl-2-mercaptoimidazole (MMI)] have a specific inhibitory effect on the thyroid peroxidase (TPO)-catalyzed conversion of diiodotyrosine to T4 (coupling reaction) independent of their well known inhibitory effect on peroxidase-catalyzed iodination. We have employed model incubation systems containing highly purified TPO to examine this question. Most experiments were performed with a model iodination system containing TPO, low iodine thyroglobulin, [131]iodide, and glucose-glucose oxidase. Both PTU and MMI are effective inhibitors of iodination of this system at physiological concentrations, and the system is well suited for studying the simultaneous action of these drugs on iodination and coupling. The addition of graded doses of the drugs to the iodination system demonstrated a relatively greater inhibitory effect on iodothyronine than on iodotyrosine formation. However, this observation in itself does not establish a specific inhibitory effect on coupling, since the formation of T4 involves a reaction between two molecules of 3,5-diiodotyrosine (DIT). The rate of this reaction, therefore, is second order with respect to DIT concentration, and the inhibition of DIT formation by thioureylene drugs would be expected to result in a disproportionately greater reduction in T4 formation even id there were no selective inhibitory effect of the drugs on the coupling reaction. Under certain conditions of incubation, however, it was possible to demonstrate a significant inhibitory effect on T4 and T3 formation without any decrease (in fact, a slight increase) in diiodotyrosine formation. These observations indicate that, at least under some conditions, PTU and MMI can exert a specific inhibitory effect on the coupling reaction. In the case of PTU, a specific inhibitory effect on coupling was also demonstrated with an incubation system in which TPO-catalyzed coupling was measured in the absence of iodination.

Animals↗
PubMed1982

Pirenzepine inhibits acid and pepsinogen secretion by the isolated perfused mouse stomach.

Acid and pepsinogen secretion were studied in the isolated luminally perfused mouse stomach. Stimulation was obtained with bethanechol 10(-5)M. Pirenzepine blocked the effect of bethanechol in a dose dependent manner. The minimal blocking dose was 10(-5)M. Atropine 10(-6)M blocked secretion to a similar extent as pirenzepine 10(-5)M. Addition of tetrodotoxin did not change the response to bethanechol or to bethanechol together with pirenzepine. It is concluded that acid and pepsinogen secretion stimulated by bethanechol are inhibited by atropine and pirenzepine. There is at present no evidence that bethanechol stimulation or antimuscarinic inhibition act via intramural nerves.

Animals↗
PubMed1982

[Synthesis and h2-antihistaminic activity of n,n'-bisimidazole-substituted thioureas, cyanoguanidines and 2-nitro-1,1-ethenediamines 10. C: H2-antihistaminics].

In studies on structure-activity relationships of histamine H2-receptor antagonists, N,N'-bis(2-[(4-imidazolyl)-methylthio]-ethyl)-substituted thioureas, cyanoguinidines, and 2-nitro-1,1-ethenediamines with different C-5 methylation of the imidazole rings were prepared and tested for their H2-antihistaminic activity on the isolated guinea-pig atrium and the stimulated gastric acid secretion of the anaesthetized rat. When tested on isolated guinea-pig atrium, substances with both C-5 positions methylated (5b, 7b, 9b) proved to be up to seven times more active than metiamide, whereas inhibition of gastric acid secretion turned out to be less marked. While equally methylated thioureas and cyanoguanidines showed same potency, the 2-nitro-1,1-ethenediamines clearly possessed lower activity.

Animals↗
PubMed1981

Influence of metiamide and atropine on acid and pepsin secretion in the anaesthetized Heidenhain cat.

The inhibition of acid and pepsin secretion by metiamide and atropine was studied in the anaesthetized Heidenhain-pouch cat. Metiamide strongly inhibited acid secretion induced by histamine, pentagastrin or carbachol. Metiamide had not effect on pepsin secretion stimulated by pentagastrin and carbachol but was effective on histamine-stimulated pepsin secretion. Atropine strongly inhibited pepsin secretion but was not as effective as metiamide in the inhibition of acid secretion. Reperfusion of the pouch with acid + salicylic acid also increased pepsin secretion. This increased pepsin output was abolished by atropine, but not by metiamide. It is postulated that (1) the peptic cell probably has only cholinergic receptors which can be additionally triggered by HCl passing the peptic cell, and (2) H2-antagonists only inhibit pepsin secretion indirectly via reduction of acid output.

Anesthesia↗
PubMed1981

Protection of mice by an apathogenic strain HSV-1 against lethal infection by a pathogenic strain of HSV-1.

DBA/2 and C57BL/6 mice were infected intraperitoneally with two different strains of herpes simplex virus type 1, HSV-1 ANG and HSV-1 WAL. Unlike HSV-1 WAL, HSV-1 ANG was apathogenic by this mode of infection. Furthermore, infection with HSV-1 ANG protected mice of both inbred strains against infections with lethal doses of pathogenic HSV-1 WAL. This protection was observed when the apathogenic virus was given with the pathogenic virus or 4 to 24 h before it.

Animals↗
PubMed1981

Experimental infection of inbred mice with herpes simplex virus. II. Interferon production and activation of natural killer cells in the peritoneal exudate.

The peritoneal exudate cells (PEC) represent the first line of defence against the virus in the mouse model of intraperitoneal (i.p.) infection with herpes simplex virus (HSV). We have therefore studied interferon production and activation of natural killer (NK) cells in vitro in PEC of HSV-injected mice. Injection of HSV caused a marked increase in NK cell activity, as reported by others. PEC from HSV-injected mice also produced high titres of interferon. This observation may be important since induction of interferon appears to be the primary event whereas activation of NK cells - as generally accepted - represents a secondary effect of the interferon produced. The HSV-induced NK cells shared the properties of NK cells in that they were sensitive to a monoclonal anti-theta antibody and to a monoclonal anti-Qa 5 antibody. In contrast, the cells producing interferon were not sensitive to either antibody. Irradiation (200 R) of the mice 24 h before injection of the virus decreased interferon production by more than 90%. The identity of the interferon-producing cells is unknown, but they may represent B cells.

Animals↗
PubMed1981

Reaccumulation of thyroglobulin and colloid in rat and mouse thyroid follicles during intense thyrotropin stimulation. A clue to the pathogenesis of colloid goiters.

Since Marine's observations some 50 years ago, it has been generally accepted that colloid goiters invariably result from colloid repletion of originally hyperplastic goiters after cessation of the goitrogenic stimulus. However, clinical observations suggest that many goiters never go through a stage of hyperplasia, but are colloid-rich from the beginning. We have injected rats and mice with thyrotropin (TSH), three times a day for 4 d, while the animals were kept on an iodine-rich diet (HID). Additional groups of animals were fed an iodine-poor diet (LID) or a diet containing 0.15% propylthiouracil (PTU) or 1% sodium perchlorate (ClO4). At intervals, thyroid weight, DNA, iodine and thyroglobulin content, thyroglobulin iodination, and intracellular droplet formation were measured. Histologic sections were also prepared and stained with periodic acid Schiff. Furthermore, thyroxine concentration was measured in the serum. Thyroglobulin content dropped by approximately 30% in HID animals but by 60% in all other groups 1 d after starting TSH. Thereafter, thyroglobulin reaccumulation occurred and droplet formation correspondingly decreased despite continuous heavy TSH stimulation. The largest amount of thyroglobulin was reaccumulated in HID animals followed by the PTU/LID groups, whereas no reaccumulation was observed in the ClO4 group. Reaccumulation of thyroglobulin only occurred if there was concomitant organification of at least some iodine. The subsequent phases of depletion and reaccumulation of thyroglobulin were mirrored by the morphology of the follicular lumina, the staining properties of the colloid and the serum T4 concentration. These observations suggest that endocytosis gradually becomes refractory to continuous TSH stimulation if a certain minimal amount of iodine is available for organic binding. Thus, primarily colloid-rich goiters may form in the presence of continuously higher than normal thyrotropin levels without a previous stage of follicular hyperplasia. The view should be revised that accumulation of colloid and intense thyrotropin stimulation are mutually exclusive events.

Animals↗