Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.4.1 (myosin ATPase)
 1,140 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increased afterload causes increased cardiac myosin synthesis and ultimately leads to hypertrophy. Since the latter is associated with altered myosin ATPase activity, it was of interest to study the synthesis of myosin subunits in the acute response to this stress. An in vitro guinea pig heart preparation was used which allowed application of afterload to the right ventricle with unaltered coronary flow, and also permitted measurement of synthesis of myosin heavy chains (HC) and combined light chains (LC) by continuous perfusion with labelled amino acids (3H-lysine and/or 3H-phenylalanine) of constant specific activity. Isolation of 3H-labelled HC and LC with heterologous unlabelled carrier was possible because of identical mobilities of HC's and LC's from unlabelled lamb carrier myosin and 3H-labelled guinea pig myosin. This permitted study of comparative synthesis of the HC and LC in small samples as the single guinea pig right ventricle (100--150 mg) and avoided errors inherent in pooling hearts or in measurement of turnover in the nonsteady state. After 3 h or perfusion, the ratio of synthesis of HC/LC was 2 : 1 in controls. This ratio increased significantly to 3 : 1 in after load. It is possible that the disproportionate increase in HC synthesis may lead to stoichiometric problems in myosin assembly which ultimately effect altered myosin ATPase activity.
Cardiovasc Res 1978 Dec
PMID:Synthesis of myosin heavy and light chains in the afterloaded guinea pig right ventricle. 75 24

Male spontaneously hypertensive rats (SHR) and age matched Wistar Kyoto normotensive (WKY) rats of 5 weeks, 16 weeks, and 52 weeks of age were used to determine whether duration of hypertension has any effect on contractile protein ATPase and myosin isoenzyme distribution. Myofibrils, actomyosin, and myosin were isolated from the left ventricles of WKY rats and SHR and assayed for myosin ATPase activity and myosin isoenzyme distribution. Myofibrillar ATPase activity was assayed at various free [Ca++] ranging from 10(-7) to 10(-5) mol X litre-1. Ca++ stimulated actomyosin ATPase activity was determined at several Ca++ concentrations both at low ionic strength, which favours actin-myosin interaction, and at high ionic strength, which diminishes actin interaction with myosin. Purified myosin ATPase activity was assayed in the presence of K+-EDTA and in the presence of several concentrations of Ca++. Actin activated myosin ATPase activity was assayed using 26 mumol X litre-1 skeletal muscle actin. Under all these assay conditions no differences were observed in the contractile protein ATPase activity between SHR and WKY rats in any age group. On the other hand, in both SHR and WKY rats the contractile protein ATPase activity under all assay conditions was significantly decreased in 52 week old rats compared with 5 week old rats. The predominant myosin isoenzyme was Vi in 5 week and 16 week old WKY rats and SHR. In 52 week old WKY rats and SHR, however, significant amounts of isoenzymes V2 and V3 were present along with V1. Percentage distribution of V1, V2, V3 isoenzymes calculated from densitometric scans of gels did not show any differences between WKY rats and SHR in any age group. These results suggest that neither myosin ATPase activity nor myosin isoenzyme distribution is altered in the moderately hypertrophied left ventricles of SHR. Moreover, the data indicate that the myocardium of SHR, despite the persistence of pressure overload, undergoes a similar decrease in myosin ATPase activity and an increase in myosin isoenzyme V3 to age matched normotensive WKY rats.
Cardiovasc Res 1986 Jan
PMID:Age dependent changes in myosin ATPase activity in the myocardium of spontaneously hypertensive rats. 293 54

Levosimendan is a novel positive inotropic drug targeted to increase contraction force of the heart through its calcium-dependent binding to troponin C (cTnC). We investigated the calcium-sensitizing effect of levosimendan on contractile proteins as well as its positive inotropic and lusitropic effects in paced guinea pig papillary muscle. We also studied the effect on energy consumption of myosin-actin crossbridges in a myosin ATPase assay. The calcium sensitization induced by levosimendan in fibers skinned with saponin was dependent on the perforation velocity of cell membranes. Levosimendan was almost ineffective in slowly perforated fibers, but was the most potent calcium sensitizer in fibers with rapidly perforated cells. The perforation-dependent calcium sensitization was probably due to changes in phosphorylation state of contractile proteins during the slow dissection of fibers. It is noteworthy that the calcium-sensitizing effect of levosimendan was not affected by acidic pH. Levosimendan at therapeutically relevant (0.3-10 microM) concentrations markedly increased calcium sensitivity both at pH 6.7 and 7.0, being more potent than EMD 53998, pimobendan, and MCI-154. The lack of effect of levosimendan on maximum tension supports the hypothesis that levosimendan increases calcium sensitivity through its action on cTnC. Unlike EMD 53998, levosimendan did not increase myosin ATPase activity, indicating that it did not increase the cycling rate of myosinactin crossbridges. In paced papillary muscles, levosimendan induced positive inotropic effect without changing relaxation time. Thus, levosimendan was devoid of the main negative factors described for calcium sensitizers.
J Cardiovasc Pharmacol 1995 May
PMID:Troponin C-mediated calcium sensitization induced by levosimendan does not impair relaxation. 763 Jan 57

Diabetic cardiomyopathy as a distinct entity was first recognized by Rubler et al. in diabetics with congestive heart failure (CHF), who had no evidence of coronary atherosclerosis. The Framingham study showed a 2.4-fold increased incidence of CHF in diabetic men and a 5.1-fold increase in diabetic women over 18 years. Pathological studies show left ventricular hypertrophy and fibrosis with varying degrees of small vessel disease, the functional significance of which is uncertain. Hypertension was recognized as an important cofactor in the development of fatal congestive heart failure in diabetics. On cardiac catheterization, in patients symptomatic of heart failure, either congestive or restrictive patterns have been observed. In contrast, asymptomatic diabetics had decreased left ventricular compliance but normal systolic function on hemodynamic study. Noninvasive studies show alterations in systolic and especially diastolic function, particularly in diabetics with microvascular complications and/or coexistent hypertension. Using load-independent measures of contractility, however, systolic function was generally found to be normal in asymptomatic normotensive diabetics. Experimental studies have focused on the mildly diabetic dog and the severely diabetic rat. Decreased left ventricular compliance and increased interstitial connective tissue were observed in chronically diabetic dogs. In contrast, ventricular myocardium from diabetic rats exhibits a reversible decrease in the speed of contraction, prolongation of contraction, and a delay in relaxation. These mechanical changes are associated with a decreased myosin ATPase, a shift in myosin isoenzyme distribution, alterations in a variety of Ca2+ fluxes, and changes in responses to alpha- and beta-adrenergic and cholinergic stimulation. These biochemical changes may be secondary to alterations in carbohydrate, lipid, and adenine nucleotide metabolism in the diabetic heart.(ABSTRACT TRUNCATED AT 250 WORDS)
Cardiovasc Drugs Ther 1994 Feb
PMID:Diabetic cardiomyopathy. 808 30

Before the application of skeletal muscle in a cardiac-assist device, a preconditioning procedure is required in order to overcome the easy fatigability of this muscle. We evaluated the effect of preconditioning muscles while keeping their collateral blood supply. In 15 male rabbits, a skeletal muscle ventricle (SMV) was constructed from silicone and pectoralis major muscle with minimal dissection. In six rabbits, the muscle was electrically preconditioned. The pressure generated by the SMV was measured under various conditions. Histochemical fiber grouping was performed using myosin ATPase staining. The pressure rose with preconditioning despite an increase in slow-twitch fibers. The cross-sectional area of both slow-twitch and fast-twitch fibers increased significantly. The rise in pressure is attributable to muscle hypertrophy. The use of muscles with minimal dissection may avoid or shorten the vascular delay because of a well maintained blood supply and nearly isometric preconditioning.
Thorac Cardiovasc Surg 1993 Dec
PMID:Force and histochemical changes in rabbit pectoral muscle induced by chronic electrical stimulation for use in cardiac assistance. 812 62

The definition of myocardial contractility remains complex and its exact measurement remains difficult, especially in the intact heart. Measurement of load-independent effects requires sophisticated equipment and preparations that are not applicable to clinical practice. At present, the more attractive concept is to think in terms of the calcium-contractile protein interaction, especially at the level of calcium-troponin-C. Either an increased supply of calcium is required to bind to the regulatory site on troponin-C, or modifications in troponin-C are required to promote interaction with the contractile system at the same level of cytosolic calcium. In other words, contractility can best be conceived of as the calcium-contractile protein interaction. There are, in addition, other sites at which calcium can act, such as by enhancing the myosin ATPase activity. Calcium-dependent phosphorylation of myosin light chains can also occur but is probably of much greater importance in vascular smooth muscle. Once calcium has interacted with troponin-C to promote the strong binding state, the crossbridge interaction has a cooperative effect whereby any attachment of crossbridges enhances binding of calcium to troponin-C. Hypothetically, even those troponin-C molecules not being activated by calcium can by this mechanism participate in the contractile process.
J Cardiovasc Pharmacol 1995
PMID:Regulation of myocardial contractility. 890 26

This review compares the mechanisms of action of the calcium-sensitizing agents levosimendan, pimobendan, MCI-154, and EMD 53998. By using purified human recombinant troponin-C (cTnC), the role of cTnC as a target protein for these compounds was investigated. Accordingly, the calcium-dependent binding to cTnC in a cTnC-high-performance liquid affinity chromatography (HPLAC) column and the stabilizing effects of the compounds on the calcium-induced conformation of dansylated cTnC were studied. Only levosimendan showed calcium-dependent action on cTnC. Of the studied compounds, levosimendan was the most potent calcium sensitizer in skinned fiber experiments. Furthermore, EMD 53998 and MCI-154, but not levosimendan and pimobendan, increased myosin ATPase activity, indicating that they may enhance the cycling rate of myosin-actin crossbridges. By analyzing the velocity (dT/dt) of isometric tension development in paced papillary muscles, it was shown that levosimendan probably enhances the association rate but decreases the dissociation rate of myosin-actin crossbridges. These effects occurred before the peak twitch tension was achieved. Therefore, levosimendan does not seem to affect the actual relaxation phase. The other calcium sensitizers, however, appear to act mainly by decreasing the dissociation rate of crossbridges. The weak calcium-sensitizing effect of pimobendan may be based on indirectly mediated increase in affinity of cTnC for calcium. MCI-154 might act in a similar way but, like EMD 53998, MCI-154 also acts on myosin-actin crossbridges. We suggest that levosimendan binds in a calcium-dependent manner to the N-terminal domain of cTnC, which magnifies the extent of the contraction produced by cTnC when it is calcium-activated.
J Cardiovasc Pharmacol 1995
PMID:Mechanisms of action of calcium-sensitizing drugs. 890 27

Diabetes is one of the most prevalent chronic conditions that has a high association with death from cardiovascular disease(s). An impaired cardiac function independent of vascular disease suggests the existence of a primary myocardial defect in diabetes mellitus. We and others have documented that myocardial performance is impaired in the hearts of chronically diabetic rats and rabbits. Abnormalities in the contractile proteins and regulatory proteins could be responsible for the mechanical defects in streptozotocin (STZ)-diabetic hearts. The major focus of research on contractile proteins in the diabetic state has been on myosin ATPase and its isoenzymes. However, in the contractile protein system, this could be only one of the mechanisms that might be a controlling factor in myofilament contraction in diabetes. To define the role of cardiac contractile as well as regulatory proteins (troponin-tropomyosin) as a whole in the regulation of actomyosin system in diabetic cardiomyopathy, individual proteins of the cardiac system were reconstituted under controlled conditions. Enzymatic data confirmed a diminished calcium sensitivity in the regulation of the cardiac actomyosin system when regulatory protein(s) complex was recombined from diabetic hearts. This diminished calcium sensitivity along with shifts in cardiac myosin heavy chain (V1-->V3) could contribute to the impaired cardiac function in the hearts of chronic diabetic rats. It has also been reported that sarcomeric proteins such as myosin light chain-2 (MLC-2) and troponin I (TnI) could be involved in regulating muscle contraction and in calcium sensitivity. Since phosphorylation of cardiac TnI is associated with altered maximum enzymatic activity and calcium force relationship in isolated muscle preparations. TnI phosphorylation could contribute to depressed myocardial contractility in experimental diabetes. While we have yet to understand the exact function of each component in cardiac muscle and their behavior in concert where all of them act in tandem, we have focussed on the role of contractile proteins and their regulation in diabetes in this review. We have also included a brief discussions on other relevant intracellular components. In summary, there is substantial evidence to suggest that there are independent processes associated with diabetes which effect cardiac performance in experimental animals and in man. The focus of this review has been the explication of a biochemical defect which underlies cardiac contractile dysfunction in experimental models of diabetes.
Cardiovasc Res 1997 Apr
PMID:Regulation of contractile proteins in diabetic heart. 921 70

Various protocols for the isolation and cultivation of adult rat cardiomyocytes were compared, and the cytoprotective potential of the reversible myosin ATPase inhibitor butanedione monoxime (BDM) was evaluated based on cell yield, cell vitality, lactate dehydrogenase (LDH) and creatine kinase (CK) release, and the mRNA expression of atrial natriuretic peptide (ANP). Overall, a yield of 11.9 x 10(6)cells with >92% cell vitality was obtained when BDM was added to the isolation and cultivation buffers. In contrast, cell vitality ranged from 30% to 70% and cell yield was (4-10) x 10(6) when standard methods for the isolation of cardiomyocytes were used. Butanedione monoxime, at a 15 mM concentration, was cytoprotective during the isolation and cultivation of heart muscle cells, as judged by the morphological appearance (rod shape, lack of bleb formation, and other cytoskeleton defects) and the mRNA expression of the ANP gene. The activities of LDH and CK were also significantly reduced (p < 0.05%) when BDM was added to the isolation and cultivation buffer. The results obtained with BDM warrant further investigation into its cytoprotective potential during ischemia and damage to the cytoskeleton.
Cardiovasc Toxicol 2001
PMID:Butanedione monoxime increases the viability and yield of adult cardiomyocytes in primary cultures. 1221 98

Eugenol (EUG) acts as a calcium antagonist but effects on the contractile proteins could also occur. We investigated inotropic effects of EUG in rat left ventricular papillary muscles, measuring isometric force, time variables, and post rest potentiation and EUG actions on the effects of Ca2+ (0.62 to 2.5 mM) and isoproterenol (5 ng/ml), on myosin ATPase activity and on the calcium currents in single ventricular myocytes. EUG reduced tension and time variables without altering the sarcoplasmic reticulum activity increasing post-pause relative potentiation. Isoproterenol and Ca2+ counteract these negative inotropic effects. Tetanic tension diminished, but not the myosin ATPase activity suggesting an isolated sarcolemmal effect. EUG 0.1 mM decreased the Ca2+ current amplitude in the entire potential range tested and 0.5 mM almost completely blocked this inward current. Results suggested that EUG depresses force without affecting the contractile machinery and its action is the only dependent blockade of the calcium inward current.
J Cardiovasc Pharmacol 2004 Dec
PMID:Effects of eugenol, an essential oil, on the mechanical and electrical activities of cardiac muscle. 1555 Jul 89


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