Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies in hearts of female rats have demonstrated that ventricular hypertrophy due to systolic overload, when combined with hypertrophy induced by a chronic swimming program, results in increased cardiac performance and enhanced contractile protein activity compared with the effects of hypertension alone. To explore how a chronic running program affects the function of hypertensive hearts, renal hypertension was created in female rats, and the animals were subjected to a program of chronic treadmill running. Running alone caused enhanced cardiac function, an increase in myosin adenosinetriphosphatase (ATPase) activity, and an increase in the percent of the V1 myosin isoenzyme. Hypertension alone caused cardiac hypertrophy with a depression in myosin ATPase activity and a decrease in the percent of the V1 isoenzyme. Running improved cardiac function in hearts of normotensive rats but had no effect in hearts of hypertensive rats. Despite the diminished myosin ATPase activity in hearts of hypertensive runners and the decrease in percent of the V1 isoenzyme, cardiac function was well maintained. The results demonstrate that a chronic running program in hypertensive rats, in contrast to a chronic swimming program, had virtually no effect on cardiac performance or contractile proteins. The dissociation between myocardial performance and the contractile proteins implicates other biochemical mechanisms in the adaptations observed.
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PMID:Combined effects of hypertension and chronic running program on rat heart. 295 51

Streptozocin-diabetic rats were treated with a combination of triiodothyronine and carnitine for 6 weeks. These compounds were used as they are known to correct the diabetes-induced depression of cardiac myosin ATPase and sarcoplasmic reticular (SR) calcium uptake, respectively. Myocardial performance, which was assessed using the working heart preparation, revealed a depression of function in untreated diabetics when compared with controls at most left atrial filling pressures. Hearts from diabetic rats treated with the combination exhibited depression at only the higher filling pressures as compared with untreated or treated controls. The results suggest that functional alterations occurring as a result of diabetes cannot be accounted for by the depression of cardiac myosin ATPase and SR calcium uptake alone.
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PMID:Effects of triiodothyronine and carnitine therapy on myocardial dysfunction in diabetic rats. 375 16

Cardiac hypertrophy, induced by pressure overload, leads to a depression in the rate of force development, velocity of shortening, tension-dependent heat generation, and myosin ATPase activity, whereas cardiac hypertrophy, induced by thyroxine administration, leads to an increase in these parameters. These changes have been attributed, in part, to structural changes in myosin. In this study, we have investigated changes in the relative content of myosin isozymes and differences in primary structure of the isozymes in pressure-overloaded and thyrotoxic cardiac hypertrophy in the rabbit. Three myosin isozymic forms (V1 = fastest, V2 = intermediate, V3 = slowest mobility) were observed in pyrophosphate polyacrylamide gels from normal hearts with the V3 component being the predominant species. In the pressure-overloaded model, the V1 and V2 components disappeared or were present in reduced amounts leaving the V3 more predominant. The most striking difference was the isozymic profile produced in thyrotoxic hearts where the V1 became the predominant component and V2 and V3 the minor components. alpha-Chymotryptic digestion of myosin heavy chains produced characteristic, reproducible peptide patterns for each of the animal models, as did fluorographic analyses of alpha-chymotryptic digests of 14C-iodoacetamide (IAA)-labeled SH1 peptides of myosin. Our results suggest that altered proportions of myosin isozymes may be responsible for altered cardiac performance.
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PMID:Altered myosin isozyme patterns from pressure-overloaded and thyrotoxic hypertrophied rabbit hearts. 621 Dec 93

Physiological hypertrophy is present when the increase in myocardial mass resulting from chronic mechanical loading is associated with normal or enhanced myocardial function and myosin ATPase activity. Morphological alterations occurring during the formation of hypertrophy are fully reversible in physiological hypertrophy. In pathological hypertrophy myocardial function and myosin ATPase activity are depressed and morphological changes do not or only incompletely regress following the elimination of the stimulus of hypertrophy. In the experimental animal myocardial hypertrophy resulting from exercise conditioning or slight to moderate ventricular pressure overload fulfills the criteria of physiological hypertrophy. More severe sudden pressure overload is accompanied by depression of contractile function. These pressure overload models have however, little analogy to the more progressive development of pressure loading in humans. In young dogs and in cats with a gradually increasing pressure load, in vivo ventricular ejection fraction remained within normal limits 37 to 60 weeks after banding of the ventricular outflow vessel. In vitro myocardial function evaluated in the hypertrophied papillary muscle was, however, at least in part depressed, notably when hydroxyproline concentration was augmented. Following debanding in rats with aortic constriction hydroxyproline content did not regress suggesting that fibrosis once established is not reversible. In man myocardial hypertrophy from exercise conditioning is associated with normal ventricular function except in older athletes, who may show a subtle reduction in ventricular shortening. Patients with chronic pressure overload from aortic stenosis or volume overload from aortic insufficiency in whom the angiographic muscle mass is severely increased (greater than or equal to 180 g/m2) elicit a depressed left ventricular contractile function. Preserved left ventricular ejection performance in aortic valve disease is however not associated with normal myocardial structure because interstitial fibrosis evaluated from endomyocardial biopsies or biopsies obtained at surgery was found to be increased. Patients with depressed left ventricular contractility were characterized by having an abnormally high muscle fibre diameter. Normal function after surgery was not accompanied by normalization of myocardial structure: Interstitial fibrosis increased, fibrous content remained the same and cellular hypertrophy regressed incompletely regardless whether angiographic muscle mass had regressed to normal or remained still increased after surgery. In summary, the bulk of available functional and morphological data suggests that the occurrence of true physiological hypertrophy is probably limited to exercise conditioning and eventually to mild chronic mechanical overload. The more severe secondary hypertrophy such as in patients with aortic valve disease who undergo valve replacement, is not a physiological adaptation, but must be considered as a pathological process.
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PMID:[Is secondary myocardial hypertrophy a physiological or pathological adaptive mechanism?]. 621 76

In this paper we review our previous work on the myothermic economy of isometric force production in compensated cardiac hypertrophy secondary to pulmonary artery constriction (pressure overload) and/or thyrotoxicosis (volume overload). Hypertrophy-induced changes in isotonic and isometric twitch mechanics are correlated with accompanying changes in actin-activated myosin ATPase and heat liberation. Heat measurements were made with rapid, high-sensitivity thermopiles on right ventricular papillary muscles from normal and hypertrophied rabbit hearts. Total activity-related heat was separated into initial and recovery heat. Initial heat was separated into a tension-dependent component (TDH) relating to cross-bridge activity, and a tension-independent component (TIH) relating to excitation-contraction coupling. There were oppositely directed changes in most parameters studied in pressure overload hypertrophy (P) as compared with thyrotoxic hypertrophy (T). Thus, in P there was depression (30-50% in the rate of isometric force production, mechanical Vmax, TDH and TDH rate, myosin ATPase, TIH, and prolongation in time-to-peak twitch tension, whereas in T all parameters were oppositely changed except for no change in TIH. Thyrotoxicosis following pressure overload reversed the P-induced changes in all parameters. There was a direct, linear relation between in vitro actin-activated myosin ATPase and in vivo TDH. However, TDH per unit twitch tension or tension-time integral varied inversely with ATPase, making force production more economical than normal in P muscles and less economical than normal in T muscles. These cellular changes beneficially equip P hearts for slow, high-pressure, economical pumping the T hearts for fast, high-volume, uneconomical pumping. The differences are similar to those between slow and fast skeletal muscle and between neonatal and adult skeletal muscle. The mechanism of these changes is discussed in terms of an enzyme kinetic scheme of chemomechanical coupling in actomyosin interaction.
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PMID:Heat, mechanics, and myosin ATPase in normal and hypertrophied heart muscle. 646 Jun 50

Diabetes appears to cause a cardiomyopathy independent of atherosclerotic coronary artery disease and hypertension. Left ventricular papillary muscle function studies in rats made severely diabetic with streptozotocin have shown a slowing of relaxation and a depression of shortening velocity. However, the effects of insulin therapy on the myocardial mechanics of diabetic rats have not been studied. Therefore, rats diabetic for 6-10 weeks were treated with PZI insulin for 2, 6, 10, or 28 days and the mechanical performance of their left ventricular papillary muscles was compared to that of untreated diabetics and age-matched controls; cardiac contractile protein enzymatic activity was also measured. Neither 2 nor 6 days of therapy had any effects on the depressed cardiac muscle performance of diabetic animals, although plasma glucose concentration was restored to normal. By 10 days of therapy, recovery of mechanical performance was nearly complete, and by 28 days of therapy, complete reversal of the altered myocardial mechanics was observed. Crystalline insulin added to the bath (9 mU/ml) had no effect on myocardial mechanics in either diabetics or controls. A gradual recovery of actomyosin and myosin ATPase activity in the hearts of insulin-treated diabetic animals was also found, complementing the mechanical studies. In addition to demonstrating a gradual but complete reversibility of the abnormalities in papillary muscle function in diabetic rats (although control of hyperglycemia was less than ideal), this study confirms that this model of a cardiomyopathy is not a result of streptozotocin-induced cardiac toxicity. Additional data are provided indicating that depressed thyroid hormone levels in diabetic rats are not responsible for the mechanical changes observed.
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PMID:Reversibility of diabetic cardiomyopathy with insulin in rats. 703 May 13

The incidence of mortality from cardiovascular diseases in higher in diabetic patients. The cause of this accelerated cardiovascular disease is multifactorial and, although atherosclerotic cardiovascular disease in association with well-defined risk factors has an influence on morbidity and mortality in diabetics, myocardial cell dysfunction independent of vascular defects have also been defined. We postulate that these adverse cardiac effects could presumably result as a consequence of the following sequence of events. Major abnormalities in myocardial carbohydrate and lipid metabolism occur as a result of insulin deficiency. These changes are closely linked to the accumulation of various acylcarnitine and coenzyme derivatives. Abnormally high amounts of metabolic intermediates could cause disturbances in calcium homeostasis either directly or indirectly through structural and functional subcellular membrane alterations. Over time, chronic abnormalities such as reduced myosin ATPase activity, decreased ability of the sarcoplasmic reticulum to take up calcium as well as depression of other membrane enzymes such as Na(+)-K+ ATPase and Ca(2+)-ATPase leads to changes in calcium homeostasis and eventually to cardiac dysfunction. More importantly from the point of view of pharmacological intervention, during the initial stages, acute disturbances in both the glucose and FFA oxidative pathways may provide the initial biochemical lesion from which further events ensue. Thus therapies which target these metabolic aberrations in the heart during the early stages of diabetes, in effect, can potentially delay or impede the progression of more permanent sequelae which could ensue from otherwise uncontrolled derangements in cardiac metabolism. There is little dispute that an attempt should be made to lower raised plasma triglyceride and FFA levels. This would decrease the heart's reliance on fatty acids and, hence, overcome the fatty acid inhibition of myocardial glucose utilization. In this regard, the likely application of fatty acid oxidation inhibitors (CPT inhibitors, beta-oxidation inhibitors, sequestration of mitochondrial CoA) is also apparent.
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PMID:Myocardial substrate metabolism: implications for diabetic cardiomyopathy. 776 Mar 40

The heart is a major target organ for thyroid hormone action, and marked changes occur in cardiac function in patients with hypothyroidism or hyperthyroidism. Triiodothyronine (T3)-induced changes in cardiac function can result from direct or indirect T3 effects. Direct T3 effects result from T3 action in the heart itself and are mediated by nuclear or extranuclear mechanisms. Extranuclear T3 effects, which occur independently of nuclear T3 receptor binding and increases in protein synthesis, influence primarily the transport of amino acids, sugars, and calcium across the cell membrane. Nuclear T3 effects are mediated by the binding of T3 to specific nuclear receptor proteins, which results in increased transcription of T3-responsive cardiac genes. The T3 receptor is a member of the ligand-activated transcription factor family and is encoded by cellular erythroblastosis A (c-erb A) genes. T3 increases the heart transcription of the myosin heavy chain (MHC) alpha gene and decreases the transcription of the MHC beta gene, leading to an increase of myosin V1 and a decrease in myosin V3 isoenzymes. Myosin V1, which is composed of two MHC alpha, has a higher myosin ATPase activity than myosin V3, which contains two MHC beta. The globular head of myosin V1, 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. T3 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 T3 effect results from T3-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, T3 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 pathophysiologic basis for myxedema is the opposite of that discussed for the hyperthyroid heart. In addition to decreased direct effects of thyroid hormone in cardiac myocytes, indirect effects occur through decreases in peripheral oxygen consumption and changes in hemodynamic parameters. Myofibrillar swelling with loss of striation and interstitial fibrosis occurs on histologic examination of hypothyroid hearts. In addition, accumulation of mucopolysaccharide substances (Glycosaminoglycans) can be demonstrated. On electron microscopic examination, mitochondria show disruption and lipid inclusion. Cardiac papillary muscle obtained from animals with hypothyroidism shows a depression of the force velocity curve and reduced rate of tension development, indicating significant contractile abnormalities. In patients with hypothyroidism, a true enhanced incidence of hypertension (increased peripheral vascular resistance) has been found. In addition, hypercholesterolemia and impairment of fatty acid mobilization are associated with myxedema and present additional risk factors for the development of atherosclerotic cardiovascular disease.
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PMID:[Cardiovascular effects of thyroid hormones]. 906 69

In view of the activation of renin-angiotensin system under conditions associated with pressure overload on the heart, we examined the effects of captopril, an angiotensin converting enzyme inhibitor, and losartan, an angiotensin II receptor antagonist, on cardiac function, myofibrillar ATPase and sarcoplasmic reticular (SR) Ca2+-pump (SERCA2) activities, as well as myosin and SERCA2 gene expression in hypertrophied hearts. Cardiac hypertrophy was induced in rats treated with or without captopril or losartan by banding the abdominal aorta for 8 weeks; sham operated animals served as control. Decrease in left ventricular developed pressure, +dP/dt and -dP/dt as well as increase in left ventricular end diastolic pressure and increased muscle mass due to pressure overload were prevented by captopril or losartan. Treatment of animals with captopril or losartan also attenuated the pressure overload-induced depression in myofibrillar Ca2+-stimulated ATPase, myosin ATPase, SR Ca2+-uptake and SR Ca2+-release activities. An increase in beta-myosin heavy chain mRNA and a decrease in alpha-myosin heavy chain mRNA as well as depressed SERCA2 protein and SERCA2 mRNA levels were prevented by captopril or losartan. These results suggest that both captopril and losartan improve myocardial function in cardiac hypertrophy by preventing changes in gene expression and subsequent subcellular remodeling due to pressure overload.
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PMID:Modification of cardiac subcellular remodeling due to pressure overload by captopril and losartan. 1005 50

Ca(2+) sensitizers may be advantageous for treatment in human heart failure by increasing cardiac force without increasing the Ca(2+) transient or energy consumption. To study the mode of action of the Ca(2+) sensitizers EMD 57033 (EMD) and CGP 48506 (CGP), their influence on butanedione monoxime (BDM)-mediated depression of cross-bridge cycling was analyzed in human myocardium (explanted hearts, dilated cardiomyopathy, n = 19). In Triton X (1%)-skinned fiber preparations of left ventricular myocardium from patients suffering from dilated cardiomyopathy, troponin I was extracted by vanadate (10 mM) treatment, resulting in a Ca(2+)-independent contraction. In troponin I-depleted fibers BDM (5-50 mM) was applied in the absence and presence of EMD (10 microM) or CGP (10 microM). To analyze the influence on cross-bridge kinetics, tension cost (ratio of ATPase activity and tension development) was studied. BDM exerted a dose-dependent force inhibition in troponin I-depleted fibers (IC(50) = 7.22 mM), which was antagonized by EMD (IC(50) of BDM + EMD = 19.97 mM) and CGP (IC(50) of BDM + CGP = 15.30 mM). EMD increased Ca(2+) sensitivity of force and maximal force in Triton X-skinned fibers. The Ca(2+)-sensitizing effect of CGP was accompanied by an increased Ca(2+) sensitivity of myosin-ATPase activity, an increased slope of the Ca(2+) force and Ca(2+) ATPase curve, as well as a reduced maximal myosin ATPase activity. CGP and EMD reduced tension cost. In conclusion, EMD and CGP antagonize the BDM-mediated relaxation in troponin I-depleted cardiac muscle fibers. The Ca(2+)-sensitizing effect of CGP seems to be dependent on an improvement of the myofilament cooperativity, whereas EMD seems to operate by increasing the force per cross-bridge.
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PMID:Different effect of the Ca(2+) sensitizers EMD 57033 and CGP 48506 on cross-bridge cycling in human myocardium. 1108 66


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