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Biomedical subjects

W H Dillmann

Publications and source records attributed to W H Dillmann.

At least 91 records · Page 5Linked to original sources
PubMed1987

Time course of response of individual messenger RNAs in the rat heart to T3.

The time course of response of specific mRNAs following administration of triiodothyronine (T3) to hypothyroid rats was examined. We were particularly interested in identifying mRNAs showing a rapid response. Hypothyroid rats were injected with 0.2 mg of T3/100 g body wt and total cardiac RNA was prepared 0.5, 1, 2, 3, 5, 12 and 24 h later. RNA was translated in vitro in the presence of [35S]-methionine, the labeled peptides separated by two-dimensional electrophoresis and quantitated by digital matrix photometry. Of a total of 427 translational products 13 were identified to be selectively responsive to thyroid hormone. A specific mRNA coding for a protein designated as spot 72b (Mr 81,600, pI 5.34) was observed to show the most rapid response to T3. Administration of T3 to the hypothyroid animal resulted in an increase in the level of spot 72b by 2.6-fold within 1 h. The lag time between injection of T3 and response of other specific mRNA species varied between 5 to 24 h. These results demonstrate the diversity of response of individual cardiac mRNAs. The specific T3 responsive mRNA species described in the heart have not been demonstrated in other tissues indicating that induction of distinctive mRNA species is highly tissue specific. Relatively late responses may represent indirect effects of T3 mediated by interaction with other hormonal or metabolic signals. The rapid induction of spot 72b suggests it may result from the interaction of T3 with the nuclear receptor leading to a direct effect on the expression of this gene in the heart.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Thyroid hormone induced changes in cardiac proteins and mRNAs.

Contraction of the hypothyroid heart is characterized by delayed diastolic relaxation and decreased velocity of systolic contraction. In order to determine if these alterations could be mediated by the changes in the mRNA coding for the Ca++ ATPase of the sarcoplasmic reticulum and alterations of the mRNAs coding for myosin heavy chain (MHC) alpha and beta, the levels of these specific mRNAs were quantitated using a Northern blotting technique. We find that the Ca++ ATPase mRNA was 3-fold lower in hypothyroid hearts. After T3 administration to hypothyroid rats, Ca++ ATPase mRNA increased to 66% of control levels within 2 hrs and to 100% of control levels 5 hrs after T3 administration. In the hypothyroid heart, MHC beta mRNA was the predominant message with MHC alpha mRNA barely detectable. Administration of 2 mg of T3 led to a significant increase in MHC alpha mRNA levels first detectable 2 hrs after T3 administration. Twenty-four hrs after T3 administration, MHC alpha mRNA levels had normalized. The results of these studies indicate that thyroid hormone mediates significant alterations in the level of the mRNA coding for the Ca++ ATPase of the sarcoplasmic reticulum and of the mRNAs coding for MHC alpha and beta. Changes in the level of these specific mRNAs resulting in lower levels of the corresponding proteins may explain the delayed diastolic relaxation and the decreased velocity of contraction of the hypothyroid heart.

Animals↗
PubMed1986

Rapid effects of insulin on in vitro translational activity of specific mRNA in diabetic rat heart.

We studied the time course of response of specific cardiac mRNA after administration of insulin to diabetic rats. The primary aim was to identify specific cardiac mRNA, which show a rapid response to insulin administration. Diabetic rats were injected with 2 U of regular insulin intravenously, and total cardiac RNA was prepared 0.5, 1.5, 3, 5, 12, and 24 h later. RNA was translated in vitro in the presence of [35S]methionine and the translational products separated by two-dimensional electrophoresis and quantitated by digital matrix photometry. A rapid change in the translational activity of five specific mRNA species was observed within 0.5 h after administration of insulin to the diabetic animal. One translational product exhibits a more delayed response at 1.5 h. The predominance of three of these products was increased, while that of three was decreased. Two specific mRNA coding for translation products designated as spots 97 and 106 show the most significant change, with a dramatic decrease of 15-fold and 6.5-fold, respectively, within 0.5 h after insulin administration. The change in levels of these specific mRNA species could result from effects of insulin at various sites of mRNA synthesis or degradation. However, the rapidity of the response is compatible with a direct effect of insulin on gene expression. The very quick response of these specific mRNA species to insulin could thus serve as a useful model system to examine the molecular mechanisms of insulin action in the heart.

Animals↗
PubMed1986

Ischemia of the dog heart induces the appearance of a cardiac mRNA coding for a protein with migration characteristics similar to heat-shock/stress protein 71.

Recent evidence indicates that different forms of stress, including hypoxia, can induce specific proteins called heat-shock or stress proteins in various types of mammalian cells. These studies examined whether myocardial ischemia can result in increased levels of proteins with molecular weight and isoelectric point characteristics similar to those described for heat-shock or stress proteins. The left anterior descending coronary artery of the dog heart was completely occluded; normal and ischemic myocardial samples were obtained 6 hours after occlusion; and total cardiac proteins and RNA were prepared. Ribonucleic acid was translated in vitro in a modified rabbit reticulocyte lysate system, and [35S]-methionine-labelled translational products as well as unlabelled cardiac proteins were separated by two-dimensional gel electrophoresis. Total proteins were visualized by silver staining and in vitro translation products quantified by fluorometry. A translatable mRNA coding for a 71,000 dalton peptide with an isoelectric point of 5.8 was markedly increased in the ischemic myocardium after 6 hours of ischemia. A protein with similar migration characteristics was detected in ischemic myocardium but not in normal myocardium. These results indicate that an mRNA coding for a translational product with similar migration characteristics of heat-shock protein 71 is induced by ischemia in the dog heart.

Animals↗
PubMed1985

Mechanism of action of thyroid hormones.

Thyroid hormones have ubiquitous effects and influence the function of most organs. The influences that thyroid hormones have on these diverse functions are primarily mediated through binding of T3 and T4 to specific nuclear receptor sites. The nuclear action of T3 results in organ-specific increases and decreases of specific mRNAs, leading to alteration in the level of the corresponding proteins. In addition to the well established nuclear action of T3, effects of thyroid hormone on other sites including cell membranes and mitochondria have been documented.

Animals↗
PubMed1985

Methyl palmoxirate increases Ca2+-myosin ATPase activity and changes myosin isoenzyme distribution in the diabetic rat heart.

Previous studies have shown that in rats diabetes mellitus leads to a decrease in cardiac ventricle myosin V1 and an increase in myosin V3 levels. Insulin administration reverts myosin isoenzyme distribution to normal levels. It is currently unclear whether the effects of insulin on myosin isoenzyme distribution are a direct effect of the hormone or are mediated through insulin-induced alterations in cardiac metabolism. To gain further insight into this question diabetic rats received methyl palmoxirate, a potent inhibitor of long-chain fatty acid oxidation. Administration of 25 mg methyl palmoxirate X kg body wt-1 X day-1 to diabetic rats for 4 wk leads to a partial reversal of the effects of diabetes. Myosin V1 predominance is re-established and Ca2+-activated myosin ATPase activity increases by 60% (Ca2+-myosin ATPase normal rats 1.067 +/- 0.13 mumol Pi X mg protein-1 X min-1, diabetic rats 0.609 +/- 0.05 mumol Pi X mg protein-1 X min-1, diabetic + methyl palmoxirate rats 0.912 +/- 0.06 mumol Pi X mg protein-1 X min-1). The methyl palmoxirate-induced increase in myosin V1 levels and Ca2+-activated myosin ATPase activity occurred in the absence of changes in insulin and thyroid hormone levels. Methyl palmoxirate may have acted through its known inhibitory effect on cardiac beta-oxidation and/or the resultant stimulatory effect on glycolytic flux. Our findings may indicate that changes in cardiac substrate consumption can influence myosin isoenzyme predominance.

Adenosine Triphosphatases↗
PubMed1985

Diabetes-induced alterations in the translational activity of specific messenger ribonucleic acids isolated from rat hearts.

During diabetes mellitus, total proteins and ribonucleic acids are significantly decreased in the rat heart, and these parameters can be increased by insulin administration. To determine whether all ribonucleic acids are equally sensitive to insulin, we examined the influence of this hormone on individual translatable ribonucleic acids. Cardiac ribonucleic acid prepared from control, untreated, and insulin-treated diabetic animals was translated in vitro in the presence of [35S]methionine. The radiolabeled peptides were separated by two-dimensional gel electrophoresis and were analyzed by fluorometry. We found that diabetes induces both qualitative and quantitative changes in the predominance of a few specific translatable messenger ribonucleic acid species. The translation of 11 messenger ribonucleic acid species was significantly decreased and that of eight messenger ribonucleic acid species was significantly increased in diabetic preparation. Twelve of the 19 translation products were quantified by digital matrix photometry: three labeled peptides were observed only when cardiac ribonucleic acid from diabetic animals was added to the cell-free translation system, four new peptides appeared when cardiac ribonucleic acid from control animals was added, and although the remaining five peptides were translated in vitro after either control or diabetic ribonucleic acid was added, their relative predominance was altered 2- to 200-fold. When translation products coded for by messenger ribonucleic acids prepared from either diabetic or hypothyroid hearts were compared, we found that most of the alterations induced by diabetes were also induced by hypothyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Myosin isoenzyme distribution and Ca+2-activated myosin ATPase activity in the rat heart is influenced by fructose feeding and triiodothyronine.

Studies were conducted to determine if the level of cardiac Ca+2-activated myosin ATPase activity and ventricular myosin isoenzyme distribution are influenced by both T3 administration and fructose feeding. Previous studies have shown that in the cardiac ventricle of hypothyroid rats, only myosin V3 is present, and the Ca+2-activated myosin ATPase activity is markedly decreased. Hypothyroid [thyroidectomized (Tx)] rats were fed a diet containing 60% fructose or a regular diet (47% complex carbohydrates) for 4 weeks. Fructose feeding of hypothyroid rats led to a significant increase in Ca+2-activated myosin ATPase activity (Tx regular diet, 0.33 +/- 0.02 mumol Pi/mg protein X min; Tx fructose diet, 0.54 +/- 0.04 mumol Pi/mg protein X min). In addition, myosin V1 was detectable in the heart of fructose-fed Tx rats, but was absent in Tx rats on the regular diet. To determine if fructose had an effect of similar magnitude in animals of different thyroid states, Tx rats were injected with 0.075, 0.150, 0.225, and 0.300 micrograms T3/100 g BW daily and placed on fructose or regular diets. The fructose-induced increase in Ca+2-myosin ATPase activity was between 24-27% in Tx rats receiving 0-0.15 micrograms T3/100 g BW daily. In animals receiving 0.225 and 0.300 micrograms T3/100 g BW daily, fructose feeding did not induce a significant increase in myosin ATPase activity. This is due to the fact that the Ca+2-activated myosin ATPase activities of euthyroid and hyperthyroid animals are not significantly different from each other. In hypothyroid rats receiving a 60% glucose diet, Ca+2-myosin ATPase activity showed a significant 20% increase above the value in regular diet-fed Tx rats. Fructose- and glucose-induced changes in Ca+2-myosin ATPase activity occurred in the absence of changes in thyroid hormone or insulin levels. Our findings may indicate that cardiac carbohydrate consumption influences the predominance of ventricular myosin isoenzymes in the rat heart.

Animals↗
PubMed1984

Effect of diabetes and hypothyroidism on the predominance of cardiac myosin heavy chains synthesized in vivo or in a cell-free system.

Rat cardiac ventricular myosins and RNA were prepared from normal, diabetic, insulin-treated diabetic, hypothyroid, and 3,3',5-triiodo-L-thyronine-treated hypothyroid rats. Myosin heavy chains isolated from purified myosin or synthesized in vitro from cardiac RNAs were subjected to partial protease digestion during sodium dodecyl sulfate-polyacrylamide gel electrophoresis. It was found that peptide maps obtained from cardiac myosin heavy chains of hypothyroid and diabetic rats were identical but differed from the maps of myosin heavy chain from control and hormone-treated animals. The same results were obtained, whether the heavy chains were isolated from purified myosin synthesized in the intact heart or from translation products coded for by cardiac RNAs added to the modified reticulocyte lysate. These results indicate that the myosin heavy chain RNA species present in the hypothyroid heart is also expressed during insulin deficiency but differs from the species expressed in normal animals. The expression of the two myosin heavy chain RNA species found in the rat cardiac ventricle appears to be independently regulated by these two hormones.

Animals↗
PubMed1984

Hormonal influences on cardiac myosin ATPase activity and myosin isoenzyme distribution.

It has been recognized for a long time that changes in hormone secretion can influence cardiac function; however, the biochemical basis for these changes has only recently been clarified. In this review the influences of hormonal status on the contractile protein myosin is discussed. Myosin has a rod-like portion and a globular head and consists of two myosin heavy chains (MHC) and four light chains (LC), two of which are identical. The globular head is the site of an ATP-splitting enzyme, the myosin ATPase, and increases in myosin ATPase activity are closely related to an increased velocity of contraction of the heart. Myosin ATPase activity shows marked response to alterations in thyroid hormone, insulin, glucocorticoid, testosterone and catecholamine levels, but marked animal species differences in this response occur. Thyroid hormone administration to normal rabbits, for example, increases myosin ATPase activity markedly, but the myosin ATPase activity of hyperthyroid rats remains unchanged. In contrast, in hypothyroid rats myosin ATPase activity is markedly decreased but the hypothyroid rabbit shows no such response. These species-related differences in the hormonal response of myosin ATPase activity result from the predominance pattern of specific myosin isoenzymes. In the normal rat heart three myosin isoenzymes, V1, V2 and V3, can be separated electrophoretically. Myosin V1 predominates (70% of total myosin), and has the highest myosin ATPase activity, whereas in rabbits myosin V3, which has a lower myosin ATPase activity, is the predominant isomyosin. Thyroid hormone administration to rabbits induces myosin V1 predominance and therefore increases myosin ATPase activity, whereas in hyperthyroid rats only a small further increase in V1 predominance can occur. The alterations in myosin isoenzyme predominance and myosin ATPase activity are closely correlated to changes in cardiac contractility. Hormone-induced alterations in myosin isoenzyme predominance are mediated through changes in the formation of two isoforms of myosin heavy chain. Changes in the expression of different myosin heavy chain genes are most likely responsible for the thyroid hormone and insulin-induced alterations in myosin isoenzyme predominance. Investigation of the control of myosin heavy chain formation can provide further insights into the hormonal control of a multigene family as well as broaden our understanding of the molecular events which result in altered cardiac contractility.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Triphosphatases↗
PubMed1984

Fructose feeding increases Ca++-activated myosin ATPase activity and changes myosin isoenzyme distribution in the diabetic rat heart.

Previous studies have shown that in rats, diabetes mellitus induces a 45% decrease in cardiac Ca++-activated myosin ATPase activity which is accompanied by a decrease in myosin isoenzyme V1 and an increase in myosin isoenzyme V3 levels. Insulin administration reverts Ca++-activated myosin ATPase activity and myosin isoenzyme distribution to normal levels. It is currently unclear whether the effects of insulin on Ca++-myosin ATPase activity and myosin isoenzyme distribution are direct effects of the hormone or are mediated through insulin-induced alterations in cardiac metabolism. To determine if insulin may exert part of its effects by the latter route, diabetic rats were fed a normal, glucose, or fructose diet. Unlike glucose, fructose can enter the initial steps of the glycolytic pathway in the absence of insulin. Placing diabetic rats on different forms of 60% fructose diets for 4 weeks led to a 20-35% increase in Ca++-activated myosin ATPase activity, which was highly significant (normal Ca++-activated myosin ATPase activity, 0.917 mumol Pi/mg protein X min; diabetic, 0.553 mumol Pi/mg protein X min; diabetic + fructose, 0.661 mumol Pi/mg protein X min). The increase in Ca++-activated myosin ATPase activity was accompanied by increased myosin isoenzyme V1 and decreased myosin isoenzyme V3 levels. Feeding animals a 60% glucose diet did not lead to changes in Ca++-activated myosin ATPase activity or myosin isoenzyme distribution. The fructose-induced increase in Ca++-activated myosin ATPase activity and alteration in myosin isoenzyme distribution occurred in the absence of changes in insulin and thyroid hormone levels or improvement in the general metabolic status of fructose-fed diabetic rats.

Adenosine Triphosphatases↗
PubMed1983

Influence of thyroid hormone on the in vitro translational activity of specific mRNAs in the rat heart.

The influence of thyroid hormone on the translational activity of specific cardiac mRNA was determined by in vitro translation of RNA isolated from the heart of normal, hypothyroid, and 3,3',5-triiodo-L-thyronine-injected hypothyroid rats. Proteins synthesized in vitro in the presence of [35S]methionine were separated by two-dimensional gel electrophoresis and quantitated by a novel scanning procedure using digital matrix photometry. A total of 421 translational products were detected by fluorography and changes in the predominance of 12 of these were influenced by the thyroid state of the animals. The relative predominance of 8 species was increased in euthyroid animals, whereas 4 translational products were increased in hypothyroid animals. The majority of these thyroid hormone-related alterations occurred in spot pairs of similar molecular weights, but slightly different isoelectric points. In contrast, the relative predominance of mRNAs coding for the major contractile proteins, light chain 1, light chain 2, tropomyosin, actin, and myosin heavy chain was not altered by the thyroid status of the animals. The relative levels of these abundant mRNA species remained unaltered in spite of a thyroid hormone-related increase in total RNA levels. In vivo effects of thyroid hormone on cardiac RNA levels are complex. In addition to a general increase in total RNA and mRNA levels, increases or attenuations in the predominance of a small number of specific mRNA species are observed when euthyroid and hypothyroid animals are compared.

Animals↗
PubMed1983

A physiological dose of triiodothyronine normalizes cardiac myosin adenosine triphosphatase activity and changes myosin isoenzyme distribution in semistarved rats.

The possibility that the lowering of thyroid hormone levels which occurs in the nonthyroidal illness syndrome results in a hypothyroid state at the cardiac tissue level was examined in semistarved rats. Rats were fed 50% of their normal food intake in the form of a regular diet (R. diet) or low carbohydrate diet (L.C. diet) for 8 weeks. Animals semistarved for 8 weeks on the R. diet lost 42% of their body weight, while plasma T3 and T4 levels decreased by 45-50%. Semistarvation on the L.C. diet resulted in a 19% weight loss and a similar 46-49% decrease in plasma T3 and T4 levels. Ca++-activated myosin ATPase activity declined by 28% and 48% with the R. and L.C. diets, respectively [normal rats myosin ATPase, 1.30 +/- 0.18 mumol Pi/(mg protein . min) (mean +/- SD); semistarvation R diet, 0.93 +/- 0.15; semistarvation L.C. diet, 0.67 +/- 0.15]. The administration of physiological amounts of T3 (0.3 micrograms T3/100 g BW daily) restored the cardiac myosin ATPase activity in both groups. To confirm that the T3 effect was due to a normalization of the thyroid status at the tissue level, hypothyroid animals on a normal diet were injected with 0.3 micrograms T3 for 4 weeks, which resulted in normalization of myosin ATPase activity levels. Thyroidectomized rats receiving daily T3 injections, and when placed on a 50% reduction of food intake for 4 weeks still maintained normal myosin ATPase activity even though they lost 36% of their body weight. Distribution of cardiac myosin isoenzymes was determined by pyrophosphate polyacrylamide gel electrophoresis. In normal cardiac ventricles, myosin isoenzyme V1 predominates and represents 68 +/- 7% (+/- SD) of the total myosin. Semistarvation resulted in a redistribution of myosin isoenzymes so that V3 myosin was the predominant species (53 +/- 3% of the total myosin). The administration of 0.3 microgram T3/100 g BW daily for 4 weeks to semistarved rats reverted myosin isoenzyme distribution to V1 predominance (V1 myosin, 54 +/- 3% of the total myosin). These results indicate that the semistarvation-induced lowering plasma T3 and T4 levels is an important determinant of myosin ATPase activity and myosin isoenzyme distribution. Restoration of myosin ATPase activity to its normal level and return to myosin V1 predominance after T3 administration make it likely that these changes are related to the lowering of thyroid hormone levels.

Adenosine Triphosphatases↗
PubMed1983

The effects of amiodarone on serum thyroid hormones and hepatic thyroxine 5'-monodeiodination in rats.

Amiodarone (2-n-butyl-3,4'-diethylaminoethoxy-3', 5'-diiodobenzoyl-benzofurane) is an antiarrhythmic drug which increases serum T4 and rT3 levels in patients and lowers serum T3 levels. To investigate its effects on T4 metabolism and its cardiac action, we fed amiodarone to male Fisher rats at doses of 5, 15, and 45 mg/kg BW X day; controls received potassium iodide for 4-7 weeks, and another group received sodium ipodate. At 4 weeks, amiodarone caused a dose-dependent increase in the serum T4 concentration and a slight reduction of serum TSH without a change in the serum T3 concentration. These changes were not present at 7 weeks. Sodium ipodate raised serum T4 concentrations at both times. Rats treated with T4 (150 micrograms/kg BW X day) to suppress thyroidal secretion of hormone and with amiodarone (15 mg/kg) had marked reduction of serum T3 concentrations compared with controls receiving T4 without amiodarone. Liver homogenates from rats treated with amiodarone showed marked reduction on T4 5'-monodeiodinase activity in a dose-related manner. Amiodarone added to liver homogenates in vitro at concentrations of 0.001-1 mM did not inhibit T3 production from T4, whereas ipodate added in vitro (0.01-1 mM) did inhibit T3 production. Rats treated with amiodarone showed a lowering of the resting heart rate and a reduction of the increment in heart rate after iv isoproterenol administration. The cardiac Ca++ myosin ATPase activity was reduced in rats receiving amiodarone (45 mg/kg) compared with that in controls. The data indicate that rats treated with amiodarone have reduced peripheral conversion of T4 to T3 owing to impaired hepatic T4 5'-monodeiodinase activity. In addition, these rats have slowing of heart rate and reduction of cardiac Ca++ myosin ATPase activity. These findings are consistent with the hypothesis that amiodarone blocks some effects of thyroid hormone on the heart, but additional studies are needed to test this hypothesis.

Amiodarone↗
PubMed1982

Influence of thyroid hormone administration on myosin ATPase activity and myosin isoenzyme distribution in the heart of diabetic rats.

Previous studies have shown that diabetes mellitus leads in rats to a 45% decrease in cardiac Ca++ activated myosin ATPase, a change in myosin isoenzyme distribution and a lowering of plasma T4 and T3 levels. Hypothyroidism causes similar changes in myosin ATPase and myosin isoenzyme distribution. We determined if thyroid hormone administration in physiological replacement dose (0.3 microgram T3/100 g BW) or pharmacological doses (3 micrograms T3/100 g BW and 10 micrograms T4/100 g BW) can normalize myosin ATPase and isoenzyme distribution in diabetic rats. Control animals have a Ca++ myosin ATPase activity of 1.23 +/- 0.14 mumol Pi/mg protein/min and myosin V1 represented 70% and myosin V3 15% of total myosin. Four weeks after streptozotocin administration myosin ATPase was 0.61 +/- 0.14, and myosin V3 represented 67% of total myosin. Administration of 0.3 microgram T3/100 g BW/day for four weeks to diabetic animals resulted in no significant increase in myosin ATPase (0.69 +/- 0.07 mumol Pi/mg protein/min) or in myosin isoenzyme distribution. In contrast, administration of 3 micrograms T3/100 g BW/day or 10 micrograms T4/100 g BW/day for 4 wk led to a normalization of myosin ATPase activity (for T3 1.03 +/- 0.18, for T4 1.06 +/- 0.15). In addition the myosin isoenzyme distribution pattern normalized. These findings may point to a diminished thyroid hormone responsiveness in diabetic rats or could result from diabetes related disturbances of cellular metabolism, which are normalized by pharmacologic doses of thyroid hormone.

Adenosine Triphosphatases↗