The Formation of Tri-Iodothyronine and Reverse Triiodothyronine from Thyroxine in Isolated Rat Renal Tubules

1978 ◽  
Vol 55 (6) ◽  
pp. 567-572
Author(s):  
P. Heyma ◽  
R. G. Larkins ◽  
J. R. Stockigt ◽  
D. G. Campbell
Keyword(s):  
Therapeutic Range ◽  
Inhibitory Effect ◽  
Renal Tubules ◽  
Intact Cells ◽  
Reverse Triiodothyronine ◽  
Collagenase Digestion ◽  
Subsequent Degradation ◽  
Isolated Rat

1. Conversion of thyroxine into triiodothyronine and reverse tri-iodothyronine in intact cells was studied with isolated renal tubules prepared by collagenase digestion. 2. Conversion of thyroxine into triiodothyronine and reverse tri-iodothyronine increased progressively for at least 90 min. 3. Studies of tri-iodothyronine production from increasing amounts of thyroxine revealed that the thyroxine to tri-iodothyronine conversion is saturable. 4. Iodide and carbimazole had no effect on the thyroxine to tri-iodothyronine conversion. 5. 6-Propyl-2-thiouracil had a direct noncompetitive inhibitory effect on the conversion of thyroxine into tri-iodothyronine with a 75% inhibition of the conversion at a propylthiouracil concentration within the therapeutic range in vivo. Propylthiouracil also inhibited the net formation of reverse tri-iodothyronine from thyroxine at a similar propylthiouracil concentration, as well as inhibiting the subsequent degradation of reverse triiodothyronine.

scholarly journals Degradation of Myogenic Transcription Factor MyoD by the Ubiquitin Pathway In Vivo and In Vitro: Regulation by Specific DNA Binding

1998 ◽  
Vol 18 (10) ◽  
pp. 5670-5677 ◽  
Author(s):  
Ossama Abu Hatoum ◽  
Shlomit Gross-Mesilaty ◽  
Kristin Breitschopf ◽  
Aviad Hoffman ◽  
Hedva Gonen ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Dna Binding ◽  
Specific Inhibitor ◽  
Inhibitory Effect ◽  
26S Proteasome ◽  
Intact Cells ◽  
Free System ◽  
Ubiquitin System

ABSTRACT MyoD is a tissue-specific transcriptional activator that acts as a master switch for skeletal muscle differentiation. Its activity is induced during the transition from proliferating, nondifferentiated myoblasts to resting, well-differentiated myotubes. Like many other transcriptional regulators, it is a short-lived protein; however, the targeting proteolytic pathway and the underlying regulatory mechanisms involved in the process have remained obscure. It has recently been shown that many short-lived regulatory proteins are degraded by the ubiquitin system. Degradation of a protein by the ubiquitin system proceeds via two distinct and successive steps, conjugation of multiple molecules of ubiquitin to the target protein and degradation of the tagged substrate by the 26S proteasome. Here we show that MyoD is degraded by the ubiquitin system both in vivo and in vitro. In intact cells, the degradation is inhibited by lactacystin, a specific inhibitor of the 26S proteasome. Inhibition is accompanied by accumulation of high-molecular-mass MyoD-ubiquitin conjugates. In a cell-free system, the proteolytic process requires both ATP and ubiquitin and, like the in vivo process, is preceded by formation of ubiquitin conjugates of the transcription factor. Interestingly, the process is inhibited by the specific DNA sequence to which MyoD binds: conjugation and degradation of a MyoD mutant protein which lacks the DNA-binding domain are not inhibited. The inhibitory effect of the DNA requires the formation of a complex between the DNA and the MyoD protein. Id1, which inhibits the binding of MyoD complexes to DNA, abrogates the effect of DNA on stabilization of the protein.

Glucocorticoids Decrease the Conversion of Thyroxine into 3,5,3′-Tri-Iodothyronine by Isolated Rat Renal Tubules

1982 ◽  
Vol 62 (2) ◽  
pp. 215-220 ◽  
Author(s):  
P. Heyma ◽  
R. G. Larkins
Keyword(s):  
Strong Evidence ◽  
Glucocorticoid Receptors ◽  
Actinomycin D ◽  
Time Dependent ◽  
Renal Tubules ◽  
Short Term ◽  
Collagenase Digestion ◽  
Isolated Rat

1. The effect of glucocorticoids on the deiodination of thyroxine (T4) to 3,5,3′-tri-iodothyronine (T3) was studied in rat renal tubules prepared by collagenase digestion. 2. In short-term (6 h) experiments, cortisol and dexamethasone inhibited the conversion of T4 into T3 at concentrations of 2 × 10-4 mol/l and 2 × 10-5 mol/l respectively. The inhibition by cortisol and dexamethasone was time dependent and was prevented by actinomycin D and progesterone, suggesting that the inhibition is mediated by an effect on nuclear transcription dependent on binding to glucocorticoid receptors. 3. In long-term (16 h) experiments, cortisol and dexamethasone inhibited T4 to T3 conversion by the tubules at concentrations of 1 × 10-12 mol/l and above. In addition, physiological concentrations of corticosterone (1 × 10-8 mol/l) were able to decrease T3 generation from T4. 4. Our data provide strong evidence that physiological concentrations of glucocorticoids are able to affect T3 production from T4 directly and suggest that they may be important regulators of T4 deiodination.

INHIBITORY EFFECT OF O-ALKYLATED ANALOGUES OF OXYTOCIN AND VASOPRESSIN ON HUMAN AND RAT MYOMETRIAL ACTIVITY

1981 ◽  
Vol 88 (2) ◽  
pp. 173-180 ◽  
Author(s):  
P. MELIN ◽  
H. VILHARDT ◽  
G. LINDEBERG ◽  
L.-E. LARSSON ◽  
M. ÅKERLUND
Keyword(s):  
Alkyl Chain ◽  
Inhibitory Effect ◽  
Test System ◽  
Peptide Chain ◽  
Methyl Ethyl ◽  
Clinical Value ◽  
Rat Uterus ◽  
Dose Dependent ◽  
Isolated Rat

Analogues of oxytocin and vasopressin modified through O-alkylation (methyl, ethyl and butyl) at position 2 of the peptide chain were synthesized and tested for effects on the rat uterus in vivo and on isolated rat and human myometrial preparations. None of the analogues showed any appreciable oxytocic activity. When tested together with oxytocin or vasopressin the analogues inhibited the uterine response to the hormones in a dose-dependent and reversible way. Ethyl-analogues were more powerful antagonists than methyl-analogues but further prolongation of the alkyl-chain (butyl) diminished the antagonistic properties of the compounds. The effect on antagonistic potency of deamination at position 1 of the analogues varied among the analogues and depended on the test system used. The possible clinical value of the antagonists is discussed.

scholarly journals The effect of iodothyronines on the conversion of thyroxine into 3,3′-5-tri-iodothyronine in isolated rat renal tubules

1980 ◽  
Vol 190 (2) ◽  
pp. 239-242
Author(s):  
P Heyma ◽  
R G Larkins ◽  
D G Campbell
Keyword(s):  
Dose Response ◽  
Intact Cell ◽  
Cell System ◽  
Renal Tubules ◽  
Reverse T3 ◽  
Naturally Occurring ◽  
Collagenase Digestion ◽  
Isolated Rat

Isolated rat renal tubules prepared by collagenase digestion were used to study the effects of 3,3′,5′-tri-iodothyronine (‘reverse T3’, rT3) and other iodothyronines on the formation of 3,3′,5-tri-iodothyronine (T3) from thyroxine (T4). rT3 inhibited the conversion with a dose response over the concentration range 1.5nM-1.5microM. The inhibition was competitive in nature. Both 3,3′-di-iodothyronine and 3′,5′-di-iodothyronine also inhibited the production of T3 and T4 in isolated rat renal tubules, but tetraiodothyroacetic acid and 3,5-di-iodothyronine were found to have no effect. These experiments demonstrate in an intact cell system that some naturally occurring iodothyronines have significant effects on T4 deiodination.

The Inhibition of Platelet Aggregation by an Aorta Intima Extract

1974 ◽  
Vol 32 (02/03) ◽  
pp. 417-431 ◽  
Author(s):  
A. du P Heyns ◽  
D. J van den Berg ◽  
G. M Potgieter ◽  
F. P Retief
Keyword(s):  
Platelet Aggregation ◽  
Degradation Products ◽  
Adenosine Diphosphate ◽  
Inhibitory Effect ◽  
Protective Role ◽  
Vascular Trauma ◽  
Wear And Tear ◽  
Sequential Addition ◽  
Aggregation Activity

SummaryThe platelet aggregating activity of extracts of different layers of the arterial wall was compared to that of Achilles tendon. Arterial media and tendon extracts, adjusted to equivalent protein content as an index of concentration, aggregated platelets to the same extent but an arterial intima extract did not aggregate platelets. Platelet aggregation induced by collagen could be inhibited by mixing with intima extract, but only to a maximum of about 80%. Pre-mixing adenosine diphosphate (ADP) with intima extracts diminished the platelet aggregation activity of the ADP. Depending on the relationship between ADP and intima extract concentrations aggregating activity could either be completely inhibited or inhibition abolished. Incubation of ADP with intima extract and subsequent separation of degradation products by paper chromatography, demonstrated a time-dependent breakdown of ADP with AMP, adenosine, inosine and hypoxanthine as metabolic products; ADP removal was complete. Collagen, thrombin and adrenaline aggregate platelets mainly by endogenous ADP of the release reaction. Results of experiments comparing inhibition of aggregation caused by premixing aggregating agent with intima extract, before exposure to platelets, and the sequential addition of first the intima extract and then aggregating agent to platelets, suggest that the inhibitory effect of intima extract results from ADP breakdown. It is suggested that this ADP degradation by intima extract may play a protective role in vivo by limiting the size of platelet aggregates forming at the site of minimal “wear and tear” vascular trauma.

Measurement of the Platelet Response to Laser- induced Microvascular Injury

1974 ◽  
Vol 32 (02/03) ◽  
pp. 704-713 ◽  
Author(s):  
F. N McKenzie ◽  
K.-E Arfors ◽  
N. A Matheson
Keyword(s):  
Inhibitory Effect ◽  
Microvascular Blood Flow ◽  
Platelet Response ◽  
High Concentration ◽  
Platelet Activity ◽  
Microvascular Injury ◽  
Arterial Blood ◽  
Proximal Site ◽  
Adenosine Phosphates

SummaryA study has been made of the biochemical factors underlying the platelet response to laser-induced microvascular injury. A platelet aggregating substance is produced at sites of laser-induced injury which markedly stimulates platelet activity at a site of injury inflicted a short distance downstream. Distal sites of injury are not similarly influenced if the distance between the injuries is increased or if the proximal site no longer shows platelet-stimulating activity. The stimulating effect of an adjacent proximal injury on platelet activity at a distal site is inhibited by local intra-arterial infusion of adenosine. Measurements of arterial blood pressure and microvascular blood flow velocity during adenosine infusion showed that its inhibitory effect on platelet activity is largely independent of its vasodilator properties. The effect of infusion of different adenosine phosphates (AMP, ADP, ATP) was also studied. Very small amounts of ADP markedly stimulated platelet activity and the emboli formed were similar to those normally produced at sites of laser injury. At high concentration AMP inhibited while ATP stimulated platelet activity in vivo. The results emphasise the fundamental role of ADP as a mediator of the platelet response at sites of laser- induced microvascular injury.

The Effects of Heparin and Annexin V on Fibrin Accretion after Injury in the Jugular Veins of Rabbits

1993 ◽  
Vol 69 (03) ◽  
pp. 227-230 ◽  
Author(s):  
J Van Ryn-McKenna ◽  
H Merk ◽  
T H Müller ◽  
M R Buchanan ◽  
W G Eisert
Keyword(s):  
Vessel Wall ◽  
Thrombin Generation ◽  
Antithrombin Iii ◽  
Specific Effect ◽  
Annexin V ◽  
Inhibitory Effect ◽  
Jugular Veins ◽  
Prothrombinase Complex ◽  
Wall Injury

SummaryWe compared the relative abilities of unfractionated heparin and annexin V to prevent fibrin accretion onto injured jugular veins in vivo. Heparin was used to accelerate the inhibition of thrombin by antithrombin III, and annexin V was used to inhibit the assembly of the prothrombinase complex on phospholipid surfaces, thereby blocking thrombin generation. Rabbit jugular veins were isolated in situ, a 2 cm segment was injured by perfusing it with air, and then blood flow was re-established. Five minutes later, each rabbit was injected with heparin (20 U/kg) or annexin V (0.3 mg/kg) and then with 125I-fibrinogen. The amount of 125I-fibrin accumulation onto each injured vessel wall segment was measured 4 h later. Each injured vessel was completely deendothelialized as a result of the air perfusion as demonstrated by electron microscopy. 125I-fibrin accretion onto the injured jugular veins was enhanced 2.4-fold as compared to the uninjured veins in sham-operated animals. Heparin treatment did not reduce fibrin accretion, whereas, annexin V treatment decreased fibrin accretion by 60%, p <0.05. This latter effect was achieved without sustained circulating anticoagulation. Additional experiments confirmed that the inhibitory effect of annexin V on fibrin accretion was associated with a surface specific effect, since more annexin V bound to the injured jugular vein segments as compared to the non-injured jugular veins. We conclude that, i) mild vessel wall injury (selective de-endothelialization) in veins results in a thrombogenic vessel wall; ii) the thrombogenecity of which is not inhibited by prophylactic doses of heparin; but iii) is inhibited by annexin V, which binds to injured vessel wall surface, and inhibits thrombin generation independently of antithrombin III.

The Effect of Barbituric Acid Derivatives on Platelet Function in Vitro and in Vivo

1973 ◽  
Vol 30 (02) ◽  
pp. 315-326
Author(s):  
J. Heinz Joist ◽  
Jean-Pierre Cazenave ◽  
J. Fraser Mustard
Keyword(s):  
Platelet Aggregation ◽  
Platelet Function ◽  
Barbituric Acid ◽  
Platelet Rich Plasma ◽  
Inhibitory Effect ◽  
Primary Response ◽  
Sodium Pentobarbital ◽  
Barbituric Acid Derivatives

SummarySodium pentobarbital (SPB) and three other barbituric acid derivatives were found to inhibit platelet function in vitro. SPB had no effect on the primary response to ADP of platelets in platelet-rich plasma (PRP) or washed platelets but inhibited secondary aggregation induced by ADP in human PRP. The drug inhibited both phases of aggregation induced by epinephrine. SPB suppressed aggregation and the release reaction induced by collagen or low concentrations of thrombin, and platelet adherence to collagen-coated glass tubes. The inhibition by SPB of platelet aggregation was readily reversible and isotopically labeled SPB did not become firmly bound to platelets. No inhibitory effect on platelet aggregation induced by ADP, collagen, or thrombin could be detected in PRP obtained from rabbits after induction of SPB-anesthesia.

Inhibition of Human and Animal Platelet Adhesiveness to Glass Bead Columns by Adenosine, Dipyridamole, Chlorpromazine and Acetylsalicylic Acid

1976 ◽  
Vol 36 (02) ◽  
pp. 401-410 ◽  
Author(s):  
Buichi Fujttani ◽  
Toshimichi Tsuboi ◽  
Kazuko Takeno ◽  
Kouichi Yoshida ◽  
Masanao Shimizu
Keyword(s):  
Guinea Pig ◽  
Acetylsalicylic Acid ◽  
Guinea Pigs ◽  
Glass Bead ◽  
Animal Species ◽  
Inhibitory Effect ◽  
Rabbit Platelet ◽  
Platelet Adhesiveness

SummaryThe differences among human, rabbit and guinea-pig platelet adhesiveness as for inhibitions by adenosine, dipyridamole, chlorpromazine and acetylsalicylic acid are described, and the influence of measurement conditions on platelet adhesiveness is also reported. Platelet adhesiveness of human and animal species decreased with an increase of heparin concentrations and an increase of flow rate of blood passing through a glass bead column. Human and rabbit platelet adhesiveness was inhibited in vitro by adenosine, dipyridamole and chlorpromazine, but not by acetylsalicylic acid. On the other hand, guinea-pig platelet adhesiveness was inhibited by the four drugs including acetylsalicylic acid. In in vivo study, adenosine, dipyridamole and chlorpromazine inhibited platelet adhesiveness in rabbits and guinea-pigs. Acetylsalicylic acid showed the inhibitory effect in guinea-pigs, but not in rabbits.

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