Hypothyroid Rat Heart Research Articles

Impaired Cardiovascular Function in Male Rats with Hypo- and Hyperthyroidism: Involvement of Imbalanced Nitric Oxide Synthase Levels.

All three isoforms of nitric oxide (NO) synthase (NOS) are targets for thyroid hormones in the cardiovascular system. The aim of this study was to assess the effects of hypo- and hyperthyroidism on inducible (iNOS), endothelial (eNOS), and neural (nNOS) NOS levels in aorta and heart tissues of male rats. Rats were divided into control, hypothyroid, and hyperthyroid groups; hypo- and hyperthyroidism were induced by adding propylthiouracil (500 mg/L) and L-thyroxine (12 mg/L) to drinking water for a period of 21 days. On day 21, systolic blood pressure, heart rate, left ventricular developed pressure (LVDP), peak rate of positive and negative (±dp/dt) changes in left ventricular pressure as well as NO metabolites (NOx) and iNOS, eNOS, and nNOS protein levels in aorta and heart, were all measured. Compared to controls, LVDP and ±dp/dt were lower in both hypo- and hyperthyroid rats. Compared to controls, heart rate and systolic blood pressure were lower in hypothyroid and higher in hyperthyroid rats. NOx levels in the heart of hypothyroid rats were lower (53%), whereas that in hyperthyroid rats were higher (56% and 40%) than controls. Compared to controls, hypothyroid rats had lower levels of eNOS, iNOS, and nNOS in the aorta (16%, 34%, and 15%, respectively) and lower iNOS and higher nNOS in heart tissue (27% and 46%). In hyperthyroid rats, eNOS levels were lower (54% and 30%) and iNOS were higher (63%, and 35%) in the aorta and heart while nNOS was lower in the aorta (18%). Hypothyroidism increased while hyperthyroidism decreased the ratio of eNOS/iNOS in aorta and heart; these changes of NOS levels were associated with impaired cardiovascular function.

Light and ultrastructural study in the propylthiouracil-induced hypothyroid rat heart ventricles and the ameliorating role of folic acid

Thyroid hormones have marked effects on the growth, development, and metabolic function of virtually all organs and tissues. Thyroid status is an important determinant of cardiovascular function. The present work studied the histopathological and ultrastructural changes in the hypothyroid rat left ventricle at post-pubertal stage, in addition to the ameliorating role of folic acid. A total of 50 male albino rats were randomly divided into 5 groups (group I, control; group II, folic acid; group III, propylthiouracil-induced hypothyroid rats; group IV, co-treatment with folic acid; group V, post-treatment). In order to ensure the hypothyroid state, the level of serum triiodothyronine (T(3)) and thyroid stimulating hormone (TSH) through the dose period was regularly determined. The TSH levels were significantly higher while T(3) levels were significantly lower in hypothyroid rats when compared to control group. The high-performance liquid chromatography analysis showed an increase in homocysteine (Hcy) in the hypothyroid rats group when compared to the control group. The histopathological studies of the ventricle in hypothyroid rats revealed hydrophobic changes in myofibrillar structure with striations, myocardial atrophy, nuclear pyknosis, cytoplasmic vacuoles, and cytoplasmic eosinophilia. Transmission electron micrographs in the myocardium of hypothyroid rats revealed a marked reduction in muscle fibre mass, a marked degeneration of muscle fibres, swollen mitochondria, dilated sarcoplasmic reticulum and more prominent perinuclear oedema observed in the cardiac myocytes. In co-treated hypothyroid rats with folic acid, a regular arrangement of muscle fibres, mild swelling of myofibrillar structure with striations and no continuity with adjacent myofibrils were observed while the post-treated hypothyroid rat with folic acid showed normal architecture of myofibrillar structure with striations and continuity with adjacent myofibrils. In conclusion, our results indicated that folic acid had ameliorative effect against cardiac damage induced by 6-n-propyl-2-thiouracil and the best results were found in case of using the folic acid as an adjuvant therapy after returning to the euthyroid state.

Decreased cardiac SERCA2 expression, SR Ca uptake, and contractile function in hypothyroidism are attenuated in SERCA2 overexpressing transgenic rats

The sarco/endoplasmic reticulum (SR) Ca(2+)-ATPase SERCA2a has a key role in controlling cardiac contraction and relaxation. In hypothyroidism, decreased expression of the thyroid hormone (TH)-responsive SERCA2 gene contributes to slowed SR Ca(2+) reuptake and relaxation. We investigated whether cardiac expression of a TH-insensitive SERCA2a cDNA minigene can rescue SR Ca(2+) handling and contractile function in female SERCA2a-transgenic rats (TG) with experimental hypothyroidism. Wild-type rats (WT) and TG were rendered hypothyroid by 6-N-propyl-2-thiouracil treatment for 6 wk; control rats received no treatment. In vivo measured left ventricular (LV) hemodynamic parameters were compared with SERCA2a expression and function in LV tissue. Hypothyroidism decreased LV peak systolic pressure, dP/dt(max), and dP/dt(min) in both WT and TG. However, loss of function was less in TG. Thus slowed relaxation in hypothyroidism was found to be 1.5-fold faster in TG compared with WT (P < 0.05). In parallel, a 1.4-fold higher V(max) value of homogenate SR Ca(2+) uptake was observed in hypothyroid TG (P < 0.05 vs. hypothyroid WT), and the hypothyroidism-caused decline of LV SERCA2a mRNA expression in TG by -24% was markedly less than the decrease of -49% in WT (P < 0.05). A linear relationship was observed between the SERCA2a/PLB mRNA ratio values and the V(max) values of SR Ca(2+) uptake when the respective data of all experimental groups were plotted together (r = 0.90). The data show that expression of the TH-insensitive SERCA2a minigene compensates for loss of expressional activity of the TH-responsive native SERCA2a gene in the female hypothyroid rat heart. However, SR Ca(2+) uptake and in vivo heart function were only partially rescued.

The changes in β-adrenoceptor-mediated cardiac function in experimental hypothyroidism: the possible contribution of cardiac β3-adrenoceptors

Thyroid hormone deficiency has been reported to decrease expression and function of both beta(1)- and beta(2)-adrenoceptor in different tissues including heart. The purpose of this study was to examine the possible contribution of beta(3)-adrenoceptors to cardiac dysfunction in hypothyroidism. In addition, effect of this pathology on beta(1)- and beta(2)-adrenoceptor was investigated. Hypothyroidism was induced by adding methimazole (300 mg/l) to drinking water of rats for 8 weeks. Cardiac hemodynamic parameters were measured in anesthetised rats in vivo. Responses to beta-adrenoceptor agonists were examined in rat papillary muscle in vitro. We also studied the effect of hypotyroidism on mRNA expression of beta-adrenoceptors, Gialpha, GRK, and eNOS in rat heart. All of the hemodynamic parameters (systolic, diastolic and mean arterial pressure, left ventricular pressure, heart rate, +dp/dt, and -dp/dt) were significantly reduced by the methimazole treatment. The negative inotropic effect elicited by BRL 37344 (a beta(3)-adrenoceptor preferential agonist) and positive inotropic effects produced by isoprenaline and noradrenaline, respectively, were significantly decreased in papillary muscle of hypothyroid rats as compared to those of controls. On the other hand, hypothyroidism resulted in increased cardiac beta(2)- and beta(3)-adrenoceptor, Gialpha(2), Gialpha(3), GRK3, and eNOS mRNA expressions. However, beta(1)-adrenoceptor and GRK2 mRNA expressions were not changed significantly in this pathology. These results show that mRNA expression of beta(3)-adrenoceptors as well as the signalling pathway components mediated through beta(3)-adrenoceptors are significantly increased in hypothyroid rat heart. Since we could not correlate these alternates with the decreased negative inotropic response mediated by this receptor subtype, it is not clear whether these changes are important for hypothyroid induced reduction in cardiac function.

Ischemic preconditioning fails to confer additional protection against ischemia-reperfusion injury in the hypothyroid rat heart

There is accumulating evidence showing that ischemic preconditioning (PC) may lose its cardioprotective effect in the diseased states. The present study investigated whether PC can be effective in hypothyroidism, a clinical condition which is common and often accompanies cardiac diseases such as heart failure and myocardial infarction. Hypothyroidism was induced in rats by 3-week administration of 6n-propyl-2-thiouracil in water (0.05 %). Normal and hypothyroid hearts (HYPO) were perfused in Langendorff mode and subjected to 20 min of zero-flow global ischemia and 45 min of reperfusion. A preconditioning protocol (PC) was also applied prior to ischemia. HYPO hearts had significantly improved post-ischemic recovery of left ventricular developed pressure, end-diastolic pressure and reduced lactate dehydrogenase release. Furthermore, phospho-JNK and p38 MAPK levels after ischemia and reperfusion were 4.0 and 3.0 fold lower in HYPO as compared to normal hearts (P<0.05). A different response to PC was observed in normal than in HYPO hearts. PC improved the post-ischemic recovery of function and reduced the extent of injury in normal hearts but had no additional effect on the hypothyroid hearts. This response, in the preconditioned normal hearts, resulted in 2.5 and 1.8 fold smaller expression of the phospho-JNK and phospho-p38 MAPK levels at the end of reperfusion, as compared to non-PC hearts (P<0.05), while in HYPO hearts, no additional reduction in the phosphorylation of these kinases was observed after PC. Hypothyroid hearts appear to be tolerant to ischemia-reperfusion injury. This response may be, at least in part, due to the down-regulation of ischemia-reperfusion induced activation of JNKs and p38 MAPK kinases. PC is not associated with further reduction in the activation of these kinases in the hypothyroid hearts and fails to confer added protection in those hearts.

Differential Regulation of the Myosin Heavy Chain Genes α and β in Rat Atria and Ventricles: Role of Antisense RNA

The myosin heavy chain (MHC) genes are regulated by triiodothyronine (T3) in a reciprocal and chamber-specific manner. To further our understanding of the potential mechanisms involved, we determined the T3 responsiveness of the MHC genes, alpha and beta, and the beta-MHC antisense (AS) gene in the rat ventricles and atria. Hypothyroid rats were administered a single physiologic (1 microg) or pharmacologic (20 microg) dose of T3, and sequential measurements of beta-MHC hn- and AS RNA and alpha-MHC heterogeneous nuclear RNA from rat ventricular and atrial myocardium were performed with reverse transcription PCR. We have demonstrated that T3 treatment increases the myocyte content of an AS beta-MHC RNA in atria and ventricles that includes sequences complementary to both the first 5' and last 3' introns of the beta-MHC sense transcript. In the hypothyroid rat ventricle, beta-MHC sense RNA expression is maximal, while in the euthyroid rat ventricle, beta-MHC AS RNA is maximal. beta-MHC AS expression increased by 52 +/- 9.8% at the peak, 24 hours after injection of a physiologic dose of T3 (1 microg/animal), while beta-MHC sense RNA decreased by 41 +/- 2.2% at 36 hours, the nadir. In hypothyroid atria, beta-MHC AS RNA was induced by threefold within 6 hours of administration of 1 microg T3, demonstrating that in the atria, beta-MHC AS expression is regulated by T3, while alpha-MHC expression is not. In the hypothyroid rat heart ventricle, beta-MHC AS RNA expression increases in response to T3 similar to that of alpha-MHC. Simultaneous measures of beta-MHC sense RNA are decreased, suggesting a possible mechanism for AS to regulate sense expression. In atria, while alpha-MHC is not influenced by thyroid state, beta-MHC sense and AS RNA were simultaneously and inversely altered in response to T3. This confirms a close positive relationship between T3 and beta-MHC AS RNA in both the atria and ventricles, while demonstrating for the first time that alpha- and beta-MHC expression is not coupled in the atria.

Upregulation of the α1-adrenoceptor-induced phosphoinositide and inotropic response in hypothyroid rat heart

In this study, we examined changes in the biochemical and inotropic events of the alpha(1)-adrenoceptor signaling pathway in hypothyroid rat hearts. Hypothyroidism was induced by treating experimental animals with 0.05% 6-n-propyl-2-thiouracil (PTU) in drinking water for 7 weeks. A significant decrease of beta- and an increase in alpha(1)-adrenoceptor density as well as an increase in the basal activity of the phosphoinositide (4,5) bisphosphate hydrolyzing phospholipase C was observed in sarcolemmal membranes purified from hypothyroid hearts as compared to age-matched euthyroid controls. Following stimulation with 10 microM phenylephrine (in the presence of 10 microM atenolol), the increase of contractile parameters over baseline values was significantly higher in hypo- than euthyroid hearts, while the opposite occurred under beta-stimulation with 0.1 microM isoproterenol. Interestingly, the increase in phenylephrine-mediated positive inotropy was accompanied by a significant increase in the sarcolemmal phospholipase C activity and in the inositol 1,4,5-trisphosphate content in hypothyroid as compared to euthyroid controls. Our results suggest that cardiac alpha(1)-adrenoceptor and its associated phosphoinositide signaling pathway may act as a reserve for catecholamine inotropic response in hypothyroidism, where the beta-adrenoceptors are compromised.

Slowing effects of Mg2+ on contractile kinetics of skinned preparations of rat hearts depending on myosin heavy chain isoform content.

The effects of changes in Mg2+ concentration on the kinetics of stretch activation were investigated on skinned rat heart preparations under maximal Ca2+ activation. Muscle strips of hyper- and hypothyroid rat hearts were investigated at 0.5 and 1 mM free Mg2+; the total ATP concentration was 8 mM which resulted in saturating MgATP2- concentrations above 5 mM. Preparations containing exclusively the cardiac alpha-myosin heavy chain (hyper- and hypothyroid atria, hyperthyroid ventricles) showed an acceleration of the kinetics of stretch activation by a factor of about 1.5 (P<0.01, paired t-test) when free Mg2+ was decreased from 1 to 0.5 mM. Conversely, preparations containing exclusively the beta-myosin heavy chain isoform showed only a small acceleration by a factor of 1.05 (P<0.05, paired t-test) under the same conditions. The fact that the Mg2+ sensitivity was dependent on the myosin heavy chain isoform excludes the possibility that Mg2+ exhibits only unspecific effects on contractile proteins. Several hypotheses for explaining the observed Mg2+ effects are discussed. The conditions used in our experiments might be close to the physiological situation and, thus, changes of Mg2+ concentration must be considered as possible factors modulating the contractile kinetics especially of atrial muscle tissue.

2535 Hypothyroid rat hearts display increased tolerance to ischaemia-reperfusion; investigation of possible mechanisms

2535 Hypothyroid rat hearts display increased tolerance to ischaemia-reperfusion; investigation of possible mechanisms

Heat acclimation induces changes in cardiac mechanical performance: the role of thyroid hormone.

The involvement of reduced thyroxine level in the emergence of heat acclimation-induced negative lusitropic effect was examined. Experiments were carried out on 1) control rat hearts maintained at 24 +/- 1 degreesC (C); 2) rat hearts acclimated at 34 degreesC for 1 mo (AC); 3) AC-euthyroid rat hearts, via administration of thyroxine in the drinking water (AT); and 4) hypothyroid rat hearts, maintained at 24 +/- 1 degreesC, via administration of thiouracil in the drinking water (CP). Systolic pressure and velocities of contraction (dP/dt. P) and relaxation (-dP/dt. P) were measured using the Langendorff perfusion system. The steady-state levels of Ca2+-ATPase and phospholamban mRNAs and the expression of the encoded proteins Ca2+-ATPase (SERCA) and phospholamban (PLB) were measured, using semi-quantitative RT-PCR and Western immunoblotting, respectively. Rat thyroxine levels were measured using RIA. Heat acclimation, which brought about a reduced thyroxine level, led to downregulation of Ca2+-ATPase mRNA expression and translation and upregulation of phospholamban mRNA and PLB. Consequently, the PLB-to-SERCA ratio (PLB/SERCA) of the AC hearts showed a significant increase. These changes, as well as the greater pressure generation and the reduced dP/dt. P and -dP/dt. P observed in AC hearts were blunted in the AT hearts. Our data suggest that sustained heat acclimation-induced low thyroxine level has a decisive effect on the contractile machinery of the AC heart. Elevated PLB/SERCA apparently explains the negative lusitropic effect observed in these hearts.

Alterations of cardiac alpha 1-adrenoceptor subtypes in hypothyroid rats.

1. Alterations in the cardiac alpha 1-adrenoceptor and its subtypes in hypothyroid rats were studied by radioligand binding assays and reverse transcription-polymerase chain reaction (RT-PCR). Hypothyroidism was created by feeding rats with 0.2% 2-thiouracil solution instead of daily drinking water for 20 days. 2. The density of cardiac alpha 1-adrenoceptors (Bmax) was increased from 67.5 +/- 4.3 fmol/mg in control rats to 81.1 +/- 7.2 fmol/mg (P < 0.05) in hypothyroid rats. 3. Compared with control rats, in hypothyroid rats the percentages of high-affinity sites for (+)-niguldipine and 5-methylurapidil were increased from 13.8 +/- 5.6 and 31.9 +/- 6.3%, respectively, to 24.9 +/- 7.3 and 45.5 +/- 2.4%, respectively (both P < 0.05), while those for BMY7378 were decreased from 37.2 +/- 8.9 to 23.8 +/- 8.4% (P < 0.05), respectively. The percentage of high-affinity sites for WB4101 was not significantly different in control and hypothyroid rats (43.3 +/- 9.1 and 39.4 +/- 3.6%, respectively). 4. Reverse transcription-PCR experiments revealed that the steady state levels of mRNA for alpha 1A- and alpha 1B-adrenoceptors were increased, while those for alpha 1D-adrenoceptor were decreased in the hearts of hypothyroid rats. 5. The concentration-contraction response curves for noradrenaline in the presence of a beta-adrenoceptor antagonist in control and hypothyroid rats showed that the maximal response was reduced from 344 +/- 58 to 200 +/- 23 mg, respectively (P < 0.05). 6. The data suggest that in hypothyroid rats the total number of cardiac alpha 1-adrenoceptors is increased. The change is subtype-selective, with levels of alpha 1A- and alpha 1B-adrenoceptors being increased and levels of alpha 1D-adrenoceptors being reduced. Furthermore, the positive inotropic response mediated by alpha 1-adrenoceptors is reduced in hypothyroid rats.

Geometry of coronary capillaries in hyperthyroid and hypothyroid rat heart.

Coronary capillary geometry was studied in male rats treated with 3,3',5-triiodo-L-thyronine (T3; Hyper), 6-N-propyl-2-thiouracil (PTU; Hypo), or a sequence of PTU and T3 (Hypo/Hyper). Ventricular mass and heart-to-body mass ratios revealed myocardial hypertrophy in Hyper, atrophy in Hypo, and a return of ventricular mass to control (Con) values in Hypo/Hyper rats. From cross-sectional analysis, capillary densities for Hyper and Hypo/Hyper were comparable with Con, despite increased left ventricular mass. Hypo rats demonstrated increased capillary density. In Hyper and Hypo rats, tissue area surrounding individual capillaries (capillary domain) decreased, compared with Con, for capillaries close to the feeding arteriole. In Hyper and Hypo/Hyper, capillaries distal to the feeding arteriole had similar domain areas as Con; in Hypo, this area was smaller. From longitudinal analysis, capillary segment lengths were significantly shorter in all groups compared with Con. Our data suggest that while hypothyroidism induced myocardial atrophy and hyperthyroidism induced myocardial hypertrophy, both thyroid states stimulated capillary proliferation.

In vivo regulation of recombinant cardiac myosin heavy chain gene expression by thyroid hormone.

Cardiac myocytes have the unique ability to express exogenous genes that have been injected directly into the heart tissue in vivo. This technique makes it possible to identify cis-acting DNA sequences responsible for the regulation of myocyte-specific genes in a working heart. In these studies we introduced recombinant plasmids containing 5'-flanking sequences of the alpha-myosin heavy chain (alpha MHC) gene into the rat myocardium in order to identify sufficient promoter/enhancer sequences that faithfully reproduced the activity of the endogenous gene. The transcriptional activity of the alpha MHC promoter sequence was measured by the level of activity of the firefly luciferase reporter gene and was reported as the activity relative to a coinjected constitutively active viral promoter construct (pRSVCAT) which corrected for variations in DNA uptake and posttranscriptional events. We report that a recombinant plasmid containing 5'-flanking sequences -2560 to +421 basepairs of the transcriptional start site of the alpha MHC gene was appropriately inactive in the hypothyroid rat heart, in which expression of the endogenous gene was also inhibited. The activity of this promoter sequence was increased 44-fold by thyroid hormone in the hearts of thyroidectomized rats. In contrast, although this recombinant plasmid was appropriately active in the euthyroid myocardium, its activity could not be further stimulated by thyroid hormone. The observation that regulation of the transcriptional activity of the alpha MHC promoter by thyroid hormone was different in euthyroid and hypothyroid hearts suggests that the participation of nuclear regulatory factors, including the thyroid hormone/retinoid family of receptors, may differ according to thyroid status.

Changes in beta 1- and beta 2-adrenergic receptor mRNA levels in brown adipose tissue and heart of hypothyroid rats.

The aim of the present work was to study the effect of hypothyroidism on the expression of the beta-adrenergic receptor (beta-AR) in interscapular brown adipose tissue and heart. The total density of plasma membrane beta-AR per tissue is decreased by 44% in hypothyroid rat interscapular brown adipose tissue and by 55% in hypothyroid rat heart compared with euthyroid controls. The effects of hypothyroidism on the density of both beta 1- and beta 2-AR subtypes were also determined in competition displacement experiments. The densities of beta 1- and beta 2-AR per tissue are decreased by 50% and 48% respectively in interscapular brown adipose tissue and by 52% and 54% in the heart. Northern blot analysis of poly(A)+ RNA from hypothyroid rat interscapular brown adipose tissue demonstrated that the levels of beta 1- and beta 2-AR mRNA per tissue are decreased by 73% and 58% respectively, whereas in hypothyroid heart, only the beta 1-AR mRNA is decreased, by 43%. The effect of hypothyroidism on the beta 1-AR mRNA is significantly more marked in the interscapular brown adipose tissue than in the heart. These results indicate that beta-AR mRNA levels are differentially regulated in rat interscapular brown adipose tissue and heart, and suggest that the decrease in beta-AR number in interscapular brown adipose tissue and heart of hypothyroid animals may in part be explained by a decreased steady-state level of beta-AR mRNA.

Effect of L‐thyroxine (LT4) and D‐thyroxine (DT4) on cardiac function and high‐energy phosphate metabolism: A 31P NMR study

31P NMR spectroscopy was used to monitor the cardiac energy metabolism in hypothyroid rat hearts. Differential alterations in phosphocreatine and inorganic phosphate levels were observed upon treatment of hypothyroid animals with DT4 and LT4, while both agents were equipotent in reducing cholesterol. These results show potential for NMR spectroscopy as a technique to determine therapeutic selectivity.

Thyroid hormone markedly increases the mRNA coding for sarcoplasmic reticulum Ca2+-ATPase in the rat heart.

Previous findings have shown that thyroid hormone markedly increases the speed of diastolic relaxation in the heart. This thyroid hormone-dependent change is also accompanied by an increased Ca2+ pumping ability in the sarcoplasmic reticulum. In an effort to determine the underlying cause of improved Ca2+ transport, mRNA levels of the slow Ca2+-ATPase of the sarcoplasmic reticulum were quantified on Northern blots. In hypothyroid rat hearts, the steady state level of Ca2+-ATPase mRNA was only 36% of control levels, whereas hyperthyroid rat heart mRNA levels were 136% of control. Ca2+-ATPase mRNA responded rapidly to T3, as the mRNA level was significantly increased by 2 h and normalized by 5 h after T3 injection into hypothyroid rats. The well established effect of thyroid hormone on improved myocardial contractility and increased speed of diastolic relaxation may in part relate to specific alterations in the level of the mRNA coding for Ca2+-ATPase, resulting in increased pump units.

The effect of experimental hypothyroidism on phosphofructokinase activity and fructose 2,6-bisphosphate concentrations in rat heart.

Experimental hypothyroidism was induced in rats by the administration of NaClO4. Hearts from normal and hypothyroid rats were homogenized, and the extracts were assayed for phosphofructokinase-1 and phosphofructokinase-2 activity and fructose 2,6-bisphosphate concentrations. Hypothyroidism was associated with a drastic loss of phosphofructokinase-1 activity. A hyperbolic relationship between plasma thyroxine concentrations and phosphofructokinase-1 activity was found. As treatment with NaClO4 progressed, the decrease in blood thyroxine was faster than the decrease in enzyme activity. After prolonged hypothyroidism (a decrease in thyroxine of more than 10-fold), a 4-fold decrease in phosphofructokinase-1 activity was observed. In this metabolic condition 2-fold decreases in phosphofructokinase-2 activity and in fructose 2,6-bisphosphate were observed. A similar decrease in phosphofructokinase-1 activity in a partially purified preparation was found. The addition of L-thyroxine in the diet had little effect on phosphofructokinase-1 activity. However, exposure of minced pieces of hearts of hypothyroid rats to tri-iodothyronine for 5 h resulted in a clear increase in phosphofructokinase-1 activity, which was partially prevented by the simultaneous addition of cycloheximide. These results could account for the decrease in carbohydrate metabolism in heart from hypothyroid rats.

Hypothyroidism delays ischemia-induced contracture and adenine nucleotide depletion in rat myocardium.

Isolated perfused paced hearts from rats rendered hypothyroid by chronic administration of propylthiouracil have a delayed onset of ischemia-induced myocardial contracture in contrast to hearts from control rats. In addition, the time to reach maximum contracture is delayed, and the magnitude of the contracture pressure is reduced. Preischemia myocardial adenosine triphosphate (ATP) values in the hypothyroid rat hearts are similar to those of control, but the rate of decrease in ATP is slower in the hearts of hypothyroid rats. Thus, it appears that in the hypothyroid state the development of ischemic contracture is associated with a slower fall of ATP.

A myothermal analysis of the myosin crossbridge cycling rate during isometric tetanus in normal and hypothyroid rat hearts.

Hypertrophied rabbit heart papillary muscles (thyrotoxicosis), with a high V1/V3 myosin isoenzyme ratio and contractile protein ATPase activity, have a high velocity of unloaded shortening and a decrease in the myothermal economy of isometric twitch force development and dissipation; in hypertrophied hearts (pressure overload) with a low V1/V3 isoenzyme ratio and ATPase activity, the converse was found to be true (Am J Cardiol 1979; 44:947-953; Fed Proc 1982; 41:192-198). In the present study the confounding problem of internal shortening, which takes place during force development and dissipation in the isometric twitch, is minimized by carrying out measurements of the rate of heat liberation during the plateau phase of tetanic force maintenance. The studies are further extended to another species (rat) where the V1/V3 myosin isoenzyme ratio is altered by treating the animal with propyl thiouracil added to the drinking water (PTU); here the contractile protein alteration occurs with myocardial atrophy rather than hypertrophy. High resolution, rapid temperature measurements are made in tetanically stimulated isometrically contracting rat heart papillary muscles from normal (high V1/V3 ratio) and PTU treated (low V1/V3 ratio) rats to assess the relationship between contractile protein performance (crossbridge cycling rate) in the intact muscle and that under controlled conditions in isolated myofibrils. In papillary muscles from the normal heart the crossbridge cycling rate (+/- SEM) during force maintenance was 6.53 (+/- 1.73) cycles/second compared with 3.13 (+/- 0.24) and 0.53 (+/- 0.17) cycles s-1 in the myofibril at high and low ionic strength, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of hypothyroid status on adenosine 3',5'-mono-phosphate-dependent protein kinase of skeletal, heart and diaphragm muscle of rats.

Properties of cyclic AMP-dependent protein kinases from skeletal, heart and diaphragm muscles of hypothyroid rats were compared. Increased enzyme activity was observed in skeletal muscle from hypothyroid rats after DEAE-cellulose chromatography. Changes in isozyme distribution were also shown in the hypothyroid status. The elution profile on DEAE-cellulose suggested a possible translocation of the enzyme from the particulate to the soluble fraction in the heart of hypothyroid rats. The turnover rate of the enzyme protein decreased in the skeletal muscle of hypothyroid rats, but the other two organs showed no change even in the hypothyroid status. The activity of heat-stable protein kinase inhibitor increased in the skeletal and the diaphragm muscles in hypothyroid rats, whereas the activity in the heart decreased in the hypothyroid status. These data suggested the possibility that changes in enzyme properties, modification of isozyme distribution, and changes in modulator activity might account for the modulation of muscle function in hypothyroid rats.