Hyperthyroid Heart Research Articles

Role of nitric oxide in the functional response to ischemia-reperfusion of heart mitochondria from hyperthyroid rats.

We investigated the role of nitric oxide (NO) in the mitochondrial derangement associated with the functional response to ischemia-reperfusion of hyperthyroid rat hearts. Mitochondria were isolated at 3000 g from hearts subjected to ischemia-reperfusion, with or without N(omega)-nitro-L-arginine (L-NNA, an NO synthase inhibitor). During reperfusion, hyperthyroid hearts displayed tachycardia and low functional recovery. Their mitochondria exhibited O(2) consumption similar to euthyroid controls, while H(2)O(2) production, hydroperoxide, protein-bound carbonyl and nitrotyrosine levels, and susceptibility to swelling were higher. L-NNA blocked the reperfusion tachycardic response and increased inotropic recovery in hyperthyroid hearts. L-NNA decreased mitochondrial H(2)O(2) production and oxidative damage, and increased respiration and tolerance to swelling. Such effects were higher in hyperthyroid preparations. These results confirm the role of mitochondria in ischemia-reperfusion damage, and strongly suggest that NO overproduction is involved in the high mitochondrial dysfunction and the low recovery of hyperthyroid hearts from ischemia-reperfusion. L-NNA also decreased protein content and cytochrome oxidase activity of a mitochondrial fraction isolated at 8000 g. This and previous results suggest that the above fraction contains, together with light mitochondria, damaged mitochondria coming from the heaviest fraction, which has the highest cytochrome oxidase activity and capacity to produce H(2)O(2). Therefore, we propose that the high mitochondrial susceptibility to swelling, favoring mitochondrial population purification from H(2)O(2)-overproducing mitochondria, limits hyperthyroid heart oxidative stress.

Analysis of differentially expressed genes in hyperthyroid-induced hypertrophied heart by cDNA microarray.

Experiments were carried out to identify the altered genes in hyperthyroid rat heart and their influence on the functions of cardiac myocytes. Chronic treatment of rats with 3,5,3' triiodo-L-thyronine (T3) resulted in a prominent increase in the size of the left ventricle with increased wall thickness and reduced chamber volume leading to concentric cardiac hypertrophy. The heart weight to body weight ratio (HW/BW) in hyperthyroid rats was increased by about 58% over that of normal rats. Using cDNA microarray comprising 588 genes, we compared the differences in mRNA expression of hyperthyroid and normal rat heart. Based on a threshold of greater than 10% change, about 37 genes were found to be regulated by T3. Further analyses by Western blotting, Northern blotting and real-time quantitative RT-PCR of some of the genes confirmed the microarray results. The T3-altered genes encode various types of proteins related to metabolism, matrix and cytoskeletal structures, growth factors, transcription factors, Ca(2+)-channels etc. The physiological significance of one of these altered proteins in hyperthyroid heart, insulin-responsive glucose transporter (GLUT) type 4 (GLUT4), was studied in detail. The expression of GLUT4 was drastically reduced in the ventricular tissues of hyperthyroid heart. Insulin-induced glucose uptake in hyperthyroid cardiomyocytes was reduced significantly, indicating the impaired glucose transport in cardiac cells. Interestingly, a few genes such as GLUT4, cytochrome P450 isoforms, superoxide dismutase (SOD), collagens, matrix metalloproteinases (MMP), tissue inhibitors of matrix metalloproteinases etc. which had not been reported earlier were found to be altered in hyperthyroid heart. Our results show some new aspects of hyperthyroid heart which will be important in assessing the pathophysiology of hypertrophied cardiomyocytes.

Hyperthyroidism causes mechanical insufficiency of myocardium with possibly increased SR Ca2+-ATPase activity.

Hyperthyroidism is known to affect multiple organ functions, and thyroid hormone has been known to improve myocardial function in a failing heart. The purpose of this study is to elucidate the functional and metabolic effects of thyroid hormone on myocardium in a rat model exposed to long-term excess thyroid hormone, particularly focusing on the SR Ca(2+)-ATPase (SERCA2) function. 3,5,3'-Triiodo-L-thyronine (T3), or the vehicle, was subcutaneously given for 4 weeks (T3 and control [C] group). Bolus I.V. Thapsigargin (TG) was used to test the SERCA2 function (C-TG and T3-TG) in Langendorff perfused heart. Myocardial functions such as LV-developed pressure (LVDP; mmHg), +/- dP/dt (mmHg/s), tau (ms), and oxygen consumption (MVO(2); ml/min/g wt) were measured. SERCA2 and GLUT4 protein level were also evaluated by Western immunoblotting. Left ventricle to body weight (LV/BW) ratio was significantly higher in the T3 group. Both negative dP/dt and tau were significantly decreased by TG. It is interesting that the decrement of negative dP/dt and tau attained by TG was significantly larger in the hyperthyroid group (T3-TG) than in a normal heart (C-TG). SERCA2 and GLUT4 protein levels were not significantly different between control and the T3 group. We conclude that prolonged exposure to thyroid hormone causes hypertrophy of the myocardium and an augmentation of the SR Ca(2+) ATPase activity. Care must be taken in hyperthyroid heart during the ischemia-reperfusion process where the SRECA2 function is inhibited.

Thyroid hormone regulation of cardiac bioenergetics: role of intracellular creatine.

The effect of thyroid hormone (T(3)) on the content of myocardial creatine (Cr), Cr phosphate (CrP), and high-energy adenine nucleotides and on cardiac function was examined. In the hearts of control and T(3)-treated rats perfused in vitro, while "low" and "high" contractile work was performed, T(3) treatment resulted in a approximately 50% reduction in CrP, Cr, total Cr content (Cr + CrP), and in the CrP-to-Cr ratio. In addition, there was a slight fall in myocardial content of ATP and a large rise in calculated free ADP (fADP), resulting in a significant decrease in the ATP-to-fADP ratio in the hearts of hyperthyroid compared with euthyroid rats. Moreover, there was a substantial decrease in the level of ATP in hearts of T(3)-treated rats under high work conditions. Importantly, the ratio of cardiac work to oxygen consumption was not altered by thyroid status. Treatment with T(3) also resulted in an almost threefold reduction in the content of Na(+)/Cr transporter mRNA in the ventricular myocardium and skeletal muscle but not in the brain. We conclude with the following: 1) changes in the expression of the Na(+)/Cr transporter mRNA correlate with Cr + CrP in the myocardium; 2) hearts of hyperthyroid rats contain lower levels of ATP and higher levels of fADP under both low and high work conditions but no reduction in efficiency of work output; and 3) the reduction in Cr and ATP in hearts of hyperthyroid rats may be the basis for the reduced maximal work capacity of the hyperthyroid heart.

Effect of captopril on vasoactive intestinal peptide levels in the hyperthyroid rat heart atria

Effect of captopril on vasoactive intestinal peptide levels in the hyperthyroid rat heart atria

Hyperthyroid heart disease.

The heart is an organ sensitive to the action of thyroid hormone, and measurable changes in cardiac performance are detected with small variations in thyroid hormone serum concentrations. Most patients with hyperthyroidism experience cardiovascular manifestations, and the most serious complications of hyperthyroidism occur as a result of cardiac involvement. Recent studies provide important insights into the molecular pathways that mediate the action of thyroid hormone on the heart and allow a better understanding of the mechanisms that underlie the hemodynamic and clinical manifestations of hyperthyroidism. Several cardiovascular conditions and drugs can interfere with thyroid hormone levels and may pose a difficulty in interpretation of laboratory data in patients with suspected thyroid heart disease. The focus of this report is a review of the current knowledge of thyroid hormone action on the heart and the clinical and hemodynamic laboratory findings as well as therapeutic management of patients with hyperthyroid heart disease.

Antioxidant-sensitive shortening of ventricular action potential in hyperthyroid rats is independent of lipid peroxidation

The effects of substances able to reduce peroxidative processes on thyroid hormone-induced electrophysiological changes in ventricular muscle fibres were examined. For this study, 60 day old euthyroid and hyperthyroid rats were used. One group of hyperthyroid rats was untreated and the others were treated with vitamin E, N-acetylcysteine, and cholesterol, respectively. Hyperthyroidism was elicited by 10 day treatment with daily i.p. injections of triiodothyronine (10 μg/100 g body weight). Vitamin E and N-acetylcysteine were administered for 10 days by daily i.m. injections (20 mg/100 g body weight) and daily i.p. injections (100 mg/100 g body weight), respectively. Cholesterol was administered by cholesterol-supplemented diet (4%) from day 30. Hyperthyroidism induced a decrease in the whole antioxidant capacity and an increase in both lipid peroxidation and susceptibility to oxidative stress. Vitamin E and N-acetylcysteine administration to hyperthyroid rats led to reduction in lipid peroxidation and susceptibility to oxidative stress and to increase in antioxidant level, while the diet addition of cholesterol decreased lipid peroxidation but did not modify the other parameters. The hyperthyroid state was also associated with a decrease in the duration of the ventricular action potential recorded in vitro. The vitamin E and N-acetylcysteine administration attenuated the thyroid hormone-induced changes in action potential duration, which was however, significantly different from that of the euthyroid rats. In contrast, cholesterol supplementation did not modify the electrical activity of hyperthyroid heart. These results demonstrate that the triiodothyronine effects on ventricular electrophysiological properties are mediated, at least in part, through a membrane modification involving a free radical mechanism. Moreover, they indicate that the antioxidant-sensitive shortening of action potential duration induced by thyroid hormone is likely independent of enhanced peroxidative processes in sarcolemmal membrane.

Vitamin E administration attenuates the tri-iodothyronine-induced modification of heart electrical activity in the rat.

This work was designed to determine whether the thyroid-hormone-induced modifications of heart electrical activity are, at least in part, due to increased free radical production. For this study, 60-day-old euthyroid, hyperthyroid and hyperthyroid vitamin-E-treated rats were used. Hyperthyroidism, elicited by a 10 day treatment with tri-iodothyronine, induced an increase in lipid peroxidation without changing the level of antioxidants. Intraperitoneal vitamin administration to hyperthyroid rats led to a reduction in lipid peroxidation and a non-significant increase in antioxidant level. The hyperthyroid state was also associated with an increase in heart rate measured in vivo and a decrease in the duration of the ventricular action potential recorded in vitro. Administration of vitamin E attenuated the thyroid-hormone-induced changes in heart rate and action potential duration, which were, however, significantly different from those of the control euthyroid rats. These results suggest that vitamin E protects hyperthyroid heart against lipid peroxidation by mechanisms that may be independent of the changes in antioxidant systems. Moreover, the reduction in the tri-iodothyronine effects on heart electrophysiological properties indicates that such effects are mediated, at least in part, through a membrane modification, probably related to increased lipid peroxidation, involving a free radical mechanism.

Hyperthyroidism increases adenosine transport and metabolism in the rat heart.

Hyperthyroidism induces a number of metabolic and physiological changes in the heart including hypertrophy, increase in inotropic status, and alterations of myocardial energy metabolism. The effects of hyperthyroidism on adenosine metabolism which is intimately involved in the control of many aspects of myocardial energetics, have not been clarified. The aim of this study was thus to evaluate the potential role of adenosine in the altered physiology of the hyperthyroid heart. Transport of adenosine was studied in cardiomyocytes isolated from hyperthyroid and euthyroid rats. Activities of different enzymes of purine metabolism were studied in heart homogenates and concentrations of nucleotide and creatine metabolites were determined in hearts freeze-clamped in situ. Both transport of adenosine into cardiomyocytes and the rate of intracellular phosphorylation were higher in the hyperthyroid rat. At 10 microM concentration, adenosine transport rates were 275 and 197 pmol/min/mg protein in hyperthyroid and euthyroid cardiomyocytes respectively whilst rates of adenosine phosphorylation were 250 and 180 pmol/min/mg prot. An even more pronounced difference was observed if values were expressed per number of cells due to cardiomyocyte enlargement. Hyperthyroidism was associated with a 20% increase in adenosine kinase, 30% decrease in membrane 5'-nucleotidase and 15% decrease in adenosine deaminase activities measured in heart homogenates. In addition there was a substantial depletion in the total creatine pool from 63.7 to 41.6 mumol/g dry wt, a small decrease in the adenylate pool (from 27.2 to 24.3 mumol/g dry wt) and an elevation of the guanylate pool (from 1.22 to 1.36). These results show that adenosine transport and phosphorylation capacity is enhanced in hyperthyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophysiological properties of the hyperthyroid rat heart.

We have studied the effects of in vivo administration of different T3 doses to thyroidectomized rats on electrophysiological properties, measured in vitro, of papillary muscle fibers. The treatment with increasing T3 doses was associated with a significant reduction of the action potential duration up to a dose as large as 25 micrograms/100 g body weight every second day. The treatment with larger doses of T3 tended to restore the values of the action potential duration present in animals treated with physiological doses (5 micrograms/100 g body weight every second day). Action potential duration is frequency dependent. As the stimulation rate was increased from 1 to 5 Hz, this duration increased in all groups. However the difference between the rat groups remained significant. The cardiac frequency measured in unanaesthetized rats increased as the T3 doses. Furthermore the intrinsic frequency showed a similar increase, indicating a direct effect of T3 on the pacemaker cells in all thyroid states. The mechanism of this action of the thyroid hormone is not, however clear.

Control of intracellular creatine concentration in a mouse myoblast cell line.

The muscle cell creatine concentration is an important bioenergetic parameter. Pathological alterations in muscle [creatine] have been found in e.g. muscular dystrophy, and dietary creatine supplementation has been shown to raise the muscle [creatine] and increase the strength of maximal contraction [ l ] . We studied factors influencing intracellular [creatine] in the mouse muscle cell line G8. G8 cells (passage 8-16) were cultured to confluence in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal calf serum, 10% horse serum and 2mM glutamine. Myoblast cells were also fused to myotubes using DMEM containing 1% fetal calf serum and 1% horse serum. Total intracellular [creatine] (i.e. creatine plus phosphocreatine) was measured in NaOH cell extracts using a ninhydrin based fluorimetric technique, and expressed relative to total cell protein determined by the Lowry method. In addition, cell water volume was determined by incubating the cells with Vitiated methylglucose for 90 minutes. In 48h incubations at altered creatine concentrations, intracellular [creatine] was relatively independent of extracellular [creatine], the relationship between them being steepest over the physiological range of extracellular [creatine] (Figure 1). This would be partly consistent with a simple model in which intracellular [creatine] is determined by the balance between active carrier-mediated influx and passive efflux [2]. In accordance with this, Na-creatine cotransport has been described in the rat muscle cell line L6 [3]. However, this model would predict that complete creatine depletion should be possible during prolonged incubation without creatine. In fact, cellular (creatine] decreased slowly by only 30% over 6 days (Figure 2). This suggests either that passive efflux permeability is very low, or that a large component of total cell creatine is not available for efflux under these conditions. Furthermore, the effects of creatine-free incubation may be complicated by an upregulation in the synthesis of Na-creatine carrier protein, such as is seen in L6 [3]; this should reduce further the dependence of cell [creatine] on extracellular [creatine] [2]. Following differentiation of myotubes to myoblasts the creatine content of the cells (expressed per microgram of cell protein) increased by 50-100%. However, as the cell water content of myoblasts was approximately 1.9 pllmg cell protein, while that of the fused cells was approximately 3.9 pl/mg cell protein, it is possible to interpret this as an attempt to maintain myoblast [creatine] levels in cytosolic water. In the hyperthyroid heart. both active uptake and passive efflux of creatine are enhanced [4]. We exposed myoblasts to triiodothyronine (T3) in the presence of 0.5mM creatine simultaneously for 48 h. As Figure 3 shows, this increased cellular [creatine] by up to 200%. suggesting that active creatine uptake was increased. Interestingly, it has been shown that thyroid hormones increase the amount and activity of the Na,K-ATPase in rat myotubes and make the membrane potential more negative [5]. The effect on creatine uptake that we describe here may be related to this in several ways: first, an increased negative membrane potential would be expected to enhance the (presumably) electrogenic cotransport of neutral creatine and Na cations; second, Na/K pump-mediated local increases in cytosolic [Na] might enhance Na-creatine cotransport; thirdly, a primary effect on Na-creatine cotransport might tend to increase cell [Na] and so contribute to a secondary increase in the Na,KATPase. The decreasing effect at higher T3 concentration is consistent with an decreased stability in the membrane leading to increased passive efflux.

The effects of propranolol and verapamil on hyperthyroid heart symptoms and function, assessed by systolic time intervals.

The effects of acute and chronic administration of propranolol and verapamil on heart rate and systolic time intervals were studied in 10 hyperthyroid patients and 10 normal subjects, both groups without signs of cardiovascular or pulmonary disease. In normal subjects iv propranolol reduced heart rate significantly, and both drugs increased the total electromechanical systole significantly without difference between the drugs. This effect was insignificant when the drugs were given orally. In hyperthyroid patients both drugs reduced heart rate significantly in acute and chronic administration, and no difference between the two drugs was found. Neither drug altered cardiac contractility as assessed by systolic time intervals. These results indicate that the metabolic effects of thyroid hormone on contractility were unaltered and unblocked by the drugs. None of the participants developed signs of heart failure. Verapamil can thus be used as an alternative to propranolol in the treatment of tachycardia in hyperthyroidism.

Thyroid control over membrane processes in rat heart

We have studied the effects of hypo- and hyperthyroidism on sarcolemmal (SL) and sarcoplasmic reticular (SR) ion transport processes and mitochondrial energy production in rat heart. The following conclusions were derived. 1) Compared with euthyroid state, hyperthyroidism led to increased SR Ca2+-accumulation. In SL, the activities of Ca2+-stimulated adenosine triphosphatase (ATPase), ATP-dependent Ca2+ pumping, and Na+-Ca2+ exchanger were not affected; but ouabain-sensitive Na+-K+-ATPase activity was enhanced. 2) Hypothyroidism resulted in depressed activities of Ca2+ pumps both in SL and SR. In SL, the Na+-K+-ATPase activity was decreased, but Na+-Ca2+ exchange was unaltered. 3) Thus slower relaxation of the hypothyroid myocardium may be attributed to depressed functioning of Ca2+ pumps in SR and SL, whereas faster relaxation of the hyperthyroid heart may be based on increased Ca2+-pumping activity of SR. 4) Hyperthyroidism and hypothyroidism, respectively, led to enhanced and decreased rates of mitochondrial phosphocreatine synthesis. The thyroid state appears to control the functional coupling between mitochondrial creatine kinase and ATP-ADP translocase: the energy of oxidative phosphorylation was transformed into phosphocreatine more effectively in mitochondria from hypothyroid hearts than in those from hyperthyroid hearts. euthyroid; hyperthyroid; hypothyroid; mitochondrial creatine kinase; myocardium; oxidative phosphorylation; phosphocreatine synthesis; sarcolemma; sarcoplasmic reticulum

Thyroid control over membrane processes in rat heart.

We have studied the effects of hypo- and hyperthyroidism on sarcolemmal (SL) and sarcoplasmic reticular (SR) ion transport processes and mitochondrial energy production in rat heart. The following conclusions were derived. 1) Compared with euthyroid state, hyperthyroidism led to increased SR Ca(2+)-accumulation. In SL, the activities of Ca(2+)-stimulated adenosine triphosphatase (ATPase), ATP-dependent Ca2+ pumping, and Na(+)-Ca2+ exchanger were not affected; but ouabain-sensitive Na(+)-K(+)-ATPase activity was enhanced. 2) Hypothyroidism resulted in depressed activities of Ca2+ pumps both in SL and SR. In SL, the Na(+)-K(+)-ATPase activity was decreased, but Na(+)-Ca2+ exchange was unaltered. 3) Thus slower relaxation of the hypothyroid myocardium may be attributed to depressed functioning of Ca2+ pumps in SR and SL, whereas faster relaxation of the hyperthyroid heart may be based on increased Ca(2+)-pumping activity of SR. 4) Hyperthyroidism and hypothyroidism, respectively, led to enhanced and decreased rates of mitochondrial phosphocreatine synthesis. The thyroid state appears to control the functional coupling between mitochondrial creatine kinase and ATP-ADP translocase: the energy of oxidative phosphorylation was transformed into phosphocreatine more effectively in mitochondria from hypothyroid hearts than in those from hyperthyroid hearts.

Distribution of myosin heavy chain mRNA in normal and hyperthyroid heart

Hyperthyroid treatment produces rapid cardiac cell hypertrophy with all subcellular components increasing in an orderly manner. We compare normal and hyperthyroid tissue in order to relate changes in distribution of myosin mRNA during rapid assembly of myofibrils. At the light microscopic level, in situ hybridization of the ventricular cells shows myosin heavy chain mRNA to be distributed in a spoke-like pattern radiating from the nucleus. Electron microscopy provides the higher resolution necessary to determine mRNA distribution with respect to adjacent sarcomeric and cytoskeletal structures. Papillary muscles were removed from hyperthyroid and normal rabbits, aldehyde fixed, and embedded in LR white. Biotinated riboprobe transcribed from 0.5 kb in the coding region of terminal portion of the rod of α-myosin was hybridized and detected by immunocytochemical methods using 5 nm immunoglobulin G gold conjugates. Electron microscopy in situ hybridization runs with same-sense and antisense riboprobes were processed and ten micrographs randomly taken from each. Specific cytoplasmic densities of myosin mRNA were calculated by counting clusters of five or more gold particles over respective tissue components after subtraction of background counts. For both normal myocytes and hyperthyroid myocytes, the density of myosin mRNA was about 15 times higher in the cytoskeletal-rich inter-myofibrillar space than in the myofibrils. About half of the myosin mRNA in this inter-myofibrillar region is found within 10 nm of the peripheral filament, but no excess sarcomeric accumulation was seen beside the A-Band. It appears that most of the myosin is translated from mRNA within the inter-myofibrillar space along the entire length of the myofibril periphery. The emerging myosin heavy chain is not directly anchored to the thick filaments in either normal or rapidly growing cardiac cells.

Influence of external calcium on cyclic AMP and on the contractility in the hyperthyroid rat heart

Influence of external calcium on cyclic AMP and on the contractility in the hyperthyroid rat heart

Biochemical basis of thyroid hormone action in the heart

Thyroid hormone-induced changes in cardiac function have been recognized for over 150 years; however, the biochemical basis of triiodothyronine (T 3) action in the heart has been intensely investigated only during the last two decades. T 3-induced changes in cardiac function can result from direct or indirect T 3 effects. Direct T 3 effects result from T 3 action in the heart itself and are mediated by nuclear or extranuclear mechanisms. Extranuclear T 3 effects, which occur independent of nuclear T 3 receptor binding and increases in protein synthesis, influence primarily the transport of amino acids, sugars, and calcium across the cell membrane. Nuclear T 3 effects are mediated by the binding of T 3 to specific nuclear receptor proteins, which results in increased transcription of T 3-responsive cardiac genes. The T 3 receptor is a member of the ligand-activated transcription factor family and is encoded by cellular erythroblastosis A (c- erb A) genes. The c- erb A protein is the cellular homologue of the viral erythroblastosis A (v- erb A) protein, which causes red cell leukemia in chickens. Currently, three T 3-binding isoforms of the c- erb protein and two non-T 3-binding nuclear proteins that exert positive and negative effects on T 3-responsive cardiac genes have been identified. T 3 increases the heart transcription of the myosin heavy chain (MHC) α gene and decreases the transcription of the MHC β gene, leading to an increase of myosin V 1 and a decrease in myosin V 3 isoenzymes. Myosin V 1, which is composed of two MHC α, has a higher myosin ATPase activity than myosin V 3, which contains two MHC β. The globular head of myosin V 1, with its higher ATPase activity, leads to a more rapid movement of the globular head of myosin along the thin filament, resulting in an increased velocity of contraction. T 3 also leads to an increase in the speed of diastolic relaxation, which is caused by the more efficient pumping of the calcium ATPase of the sarcoplasmic reticulum (SR). This T 3 effect results from T 3-induced increases in the level of the mRNA coding for the SR calcium ATPase protein, leading to an increased number of calcium ATPase pump units in the SR. Overall, thyroid hormone leads to an increase in ATP consumption in the heart. In addition, less chemical energy of ATP is used for contractile purposes and more of it goes toward heat production, which causes a decreased efficiency of the contractile process in the hyperthyroid heart.

The role of calcium in the enhanced myocardial contractility of the hyperthyroid rat heart

The hyperthyroid rat myocardium exhibits enhanced contractility. There is evidence that altered calcium handling by the myocardium may be responsible for this enhanced state. To investigate this, isolated hyperthyroid and euthyroid hearts were perfused in the working mode and exposed to alterations in external calcium concentration. Heart rate was not significantly different in either group of hearts, nor was it altered by the change in calcium. The concentration of calcium needed to elicit half-maximal contractility (dP/dtmax) was lower in the hyperthyroid (0.81 +/- 0.07 mM) than in the euthyroid hearts (1.12 +/- 0.09 mM, p less than 0.05). This increase in calcium sensitivity was unlikely to be at the site of the sarcolemma as verapamil exerted equal negative inotropic effects on both groups of hearts. Dantrolene, which blocks calcium release from the sarcoplasmic reticulum, exerted a significantly greater (p less than 0.01) depression in dP/dtmax after 12 min in the hyperthyroid (50 +/- 7%) than in the euthyroid heart (15 +/- 2%). We conclude from our results that the enhanced contractile state of the hyperthyroid rat heart is likely to involve an altered mechanical response to calcium which is possibly at the level of enhanced calcium release from the sarcoplasmic reticulum.

The effect of propranolol, verapamil and dantrolene treatment on cardiac hypertrophy, enhanced myocardial contractility and tachycardia in the hyperthyroid rat

Experimentally induced hyperthyroidism is associated with cardiac hypertrophy, tachycardia and elevated myocardial contractility. To investigate the possibility of ameliorating the cardiac changes pharmacologically, hyperthyroid rats were treated with propranolol, verapamil or dantrolene. Cardiac hypertrophy was assessed from the heart mass: body mass ratio and cardiac function was measured in vitro. Both verapamil and propranolol reversed the cardiac hypertrophy of the hyperthyroid animals from 0·92 ± 0·02 mg·g −1 to 0·70±0·01 mg·g −1 ( P<0·001) and 0·72 ± 0·02 mg·g −1 ( P<0·001) respectively. Verapamil was effective in reducing the spontaneous heart rate from 331±8 beats·min −1 to 273±7 beats·min −1 ( P<0·001) while propranolol reduced the d P/d t max of the hyperthyroid hearts from 4089±87 mmHg·s −1 to 3497±97 mmHg·s −1 ( P<0·001). Dantrolene had no effect on any parameter. We conclude from our results that cardiac hypertrophy of the hyperthyroid heart can be reversed by treatment with propranolol and verapamil probably via their inotropic and chronotropic properties.

The hyperthyroid heart. An analysis of systolic and diastolic properties in single rat ventricular myocytes.

Single ventricular myocytes were isolated by collagenase digestion from the hearts of 6-8-month-old male Wistar rats in either the control (euthyroid) state or after 7 days of daily injection of 0.64 mg/kg thyroxine (hyperthyroid). Myocytes were field-stimulated from slack length, and contraction was measured with an inverted microscope-photodiode array-computer apparatus. The effect of pacing rate and ouabain administration on systolic and diastolic function was examined. Single myocytes isolated from hyperthyroid hearts maintain the properties of bulk muscle, because maximal twitch velocity is augmented 98% and the time course of contraction as measured by the time to peak shortening, relaxation time, or contraction duration is abbreviated 39%. Spontaneous sarcoplasmic reticulum calcium release, as measured by the occurrence of contractile waves, is increased in the hyperthyroid myocytes. This increased frequency of spontaneous sarcoplasmic reticulum calcium release is most marked under conditions known to be associated with high intracellular calcium, such as low pacing rates or digitalis glycoside administration. It can account for the hypoperformance of the hyperthyroid myocytes noted under these conditions because it is associated with depletion of sarcoplasmic reticulum calcium stores and diminution of subsequent twitch amplitude. These observations may help explain, in part, the cellular basis of the altered cardiac performance in the hyperthyroid state.