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)

Although cardiac myofibrillar ATPase activity has been shown to be depressed during the development of diabetic heart dysfunction, the mechanisms of this alteration are not fully understood. Since phosphorylation of troponin I (TnI) is known to decrease the myofibrillar ATPase activity, the present study was undertaken to examine the TnI phosphorylation capacity in the diabetic heart homogenate. For this purpose rats were made diabetic by injecting streptozotocin (65 mg/kg; i.v.) and the hearts were removed 8 wk later. Some 6 wk diabetic animals were injected with insulin (3 U/day) for 2 wk. TnI content in the heart homogenate was measured by immunoblot assay, the mRNA abundance for TnI gene was determined by Northern blot analysis and the in vitro phosphorylation level of TnI was estimated by the ratio of phosphorylated TnI and total (phosphorylated and unphosphorylated) TnI. No significant changes in TnI content and gene expression of TnI were observed in right and left ventricles from the diabetic rats. However, the phosphorylation of TnI was higher (approximately 40%) in the diabetic hearts; this change was reversible upon insulin treatment. These results regarding TnI phosphorylation measured under in vitro conditions suggest that increased phosphorylation of TnI may contribute toward the depression in cardiac myofibrillar ATPase activity in chronic diabetes.
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PMID:Troponin I phosphorylation in heart homogenate from diabetic rat. 867 54

Skinned fibers prepared from rabbit fast and slow skeletal and cardiac muscles showed acidotic depression of the Ca2+ sensitivity of force generation, in which the magnitude depends on muscle type in the order of cardiac>fast skeletal>slow skeletal. Using a method that displaces whole troponin-complex in myofibrils with excess troponin T, the roles of Tn subunits in the differential pH dependence of the Ca2+ sensitivity of striated muscle were investigated by exchanging endogenous troponin I and troponin C in rabbit skinned cardiac muscle fibres with all possible combinations of the corresponding isoforms expressed in rabbit fast and slow skeletal and cardiac muscles. In fibers exchanged with fast skeletal or cardiac troponin I, cardiac troponin C confers a higher sensitivity to acidic pH on the Ca2+ sensitive force generation than fast skeletal troponin C independently of the isoform of troponin I present. On the other hand, fibres exchanged with slow skeletal troponin I exhibit the highest resistance to acidic pH in combination with either isoform of troponin C. These results indicate that troponin C is a determinant of the differential pH sensitivity of fast skeletal and cardiac muscles, while troponin I is a determinant of the pH sensitivity of slow skeletal muscle.
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PMID:Roles of troponin isoforms in pH dependence of contraction in rabbit fast and slow skeletal and cardiac muscles. 1039 29

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

The subcellular mechanisms underlying intrinsic myocardial depression during sepsis remain poorly defined, in particular the relative roles of altered intracellular Ca2+ transients versus changes in myofilament properties. We studied contractile function of cardiac myocytes isolated 12 h after induction of endotoxemia (5 mg/kg intravenous E. coli lipopolysaccharide [LPS]) in conscious rats. Cardiomyocytes from LPS-injected rats had depressed twitch shortening compared with control cells (4.10.2% versus 7.80.3%; P2+ transients (peak indo-1 ratio 1.130.02 versus 1.120.02; P = NS). Contractile depression was unaffected by inhibitors of nitric oxide synthase. Steady-state myofilament response to Ca2+, assessed by tetanization of intact cells over a range of [Ca2+], was reduced significantly in the LPS group (P2+ was unaffected by isoproterenol (3 nmol/L) in endotoxemic cells, whereas there was a rightward shift in control cells. A reduction in myofilament response to Ca2+ is the major determinant of intrinsic cardiac depression in systemic endotoxemia. This condition appears to be related to an increase in myocardial troponin I phosphorylation.
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PMID:Cardiac contractile impairment associated with increased phosphorylation of troponin I in endotoxemic rats. 1115 41

Ca2+-activation of cardiac muscle myofilaments is more sensitive to depression by acidic pH than is the case with skeletal myofilaments. We tested the hypothesis that this difference is related to specific regions of the TnI (troponin I) isoforms in these muscles. We exchanged native Tn complex in detergent-extracted fiber bundles from mouse ventricles with Tn containing various combinations of fast (fsTnI) or slow skeletal (ssTnI) complexed with either cardiac TnC (cTnC) or fsTnC, and with cTnC complexed with the following chimeras: (1) fsTnI N-terminal region (fN) plus cTnI inhibitory peptide (cIp) and cTnI C-terminal region (cC); and (2) cTnI N-terminal region (cN)-cIp-fsTnI C-terminal region (fC). We determined the change in half maximal Ca2+(DeltaEC50) for tension activation at pH 7.0 and pH 6.5. Similar DeltaEC50 values were obtained for unextracted controls (5.53+/-0.30 microm), for preparations containing cTnI-cTnC (5.74+/-0.40 microm), and preparations exchanged with cTnI-fsTnC (5.63+/-0.40 microm). However, replacement of cTnI with fsTnI significantly decreased DeltaEC50 to 3.95+/-0.17 microm. Replacement of cTnI with ssTnI also significantly depressed DeltaEC50 to 2.07+/-0.15 microm. Results of studies using the chimeras demonstrated that the C-terminal domains of cTnI and fsTnI are responsible for these differences. This conclusion also fits with data from experiments in which we measured Ca2+-binding to the regulatory site of cTnC in binary complexes containing cTnC with cTnI, fsTnI, or the chimeras. Our results localize a region of TnI important in effects of acidosis on cardiac myofilaments and extend our earlier data indicating that C-terminal regions of cTnI outside the Ip are critical for activation by Ca2+.
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PMID:Localization of regions of troponin I important in deactivation of cardiac myofilaments by acidic pH. 1143 35

The present study investigated whether genistein, a broad-spectrum tyrosine kinase inhibitor, could increase the myofilament Ca(2+) sensitivity and partially reverse postischemic depressed myocardial function. Left ventricular papillary muscles were isolated from adult Wistar rats and loaded with the Ca2+ indicator, aequorin. The use of fluorocarbon immersion with hypoxia simulated a model of ischemia. Myofilament responsiveness to Ca2+ was evaluated from force-[Ca2+]i relationship recorded during tetani in papillary muscles. Protein levels of troponin I (TnI) were measured in postischemic papillary muscles with the Western blot technique. Isometric contraction was depressed during the period of ischemia and remained low after 60 min of reoxygenation without a corresponding significant change of peak [Ca2+]i in the control group (n = 7). In contrast, the depression of isometric contraction was ameliorated during ischemia in muscle preparations in the presence of genistein (2 micro M; n = 8), and postischemic depressed myocardial contractility partially recovered after a 60-min reperfusion. The myofilament Ca2+ responsiveness was significantly increased in papillary muscles in the presence of genistein. Protein levels of TnI were reduced in postischemic papillary muscles, whereas genistein partially restored decreased protein levels of TnI. Our results reveal that genistein produces an effective attenuation of postischemic depressed myocardial function and improves myofibrillar Ca2+ responsiveness in rat myocardium.
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PMID:Genistein attenuates postischemic depressed myocardial function by increasing myofilament Ca2+ sensitivity in rat myocardium. 1219 6

To evaluate the supplemental value of serial troponin I (Trp) measurements when combined with a clinical model composed of six clinical parameters in predicting in-hospital adverse event rates, a total of 118 consecutive patients admitted over a 23-month period with intermediate- or high-risk unstable angina or non-Q wave myocardial infarction (MI) as defined by AHCPR criteria who had coronary angiography within 72 hours of hospitalization were studied. Presenting clinical characteristics were graded using a previously validated variation of the Braunwald criteria (RUSH model). The RUSH model clinical score includes six clinical parameters: age, diabetes, intravenous nitroglycerin, pre-admission calcium-channel and beta-blocker, ST depression and post-MI angina (< 2 weeks), and creates an estimated probability of MI or death. The RUSH model was compared to serial Trp levels drawn at 6-hour intervals (0, 6 and 12 hours). An abnormal Trp value was defined as > 2.0 mg/dl. Outcome measures included death, MI, recurrent chest pain and new ST or T changes and enzyme elevation. One death, 23 MIs and 24 other adverse clinical events occurred. The event group had a RUSH score predictive of 12.7 12.4% risk and the no-event group had a score of 13.2 10.2% risk (p = 0.64). The Trp positive group had a clinical score predicting 14.2 13.2% risk and the Trp negative group had a score of 11.7 9.3% risk (p = 0.21). Patients with elevated Trp had an adverse event rate of 32/50 (64%) vs. 21/68 (31%) in patients with normal Trp (p < 0.0004). Elevated Trp had 60.4% sensitivity and 72.3% specificity, odds ratio of 3.97 (1.71 9.33), as well as 64% positive and 69.1% negative predictive values for predicting adverse events. Thus, there was significant incremental value to adding Trp to the clinical score when predicting outcomes in patients with intermediate- and high-risk clinical scores. When Trp was abnormal, it was useful when predicting higher risk; if Trp was normal, it was useful predicting lower but still elevated risk. Consequently, in a population selected for intermediate and high risk, the presence or absence of elevated Trp I is a sensitive and specific additive predictor to clinical score to predict need for revascularization and adverse in-hospital outcomes, as suggested in current guidelines.
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PMID:Supplemental value of troponin I combined with a clinical risk model to predict in-hospital events in intermediate and high risk patients with acute coronary syndromes. 1236 14

Chest pain (CP) patients presenting to the ED may manifest electrocardiographic ST segment elevation (STE). AMI (acute myocardial infarction) is a less frequent cause of such abnormality and one of many patterns responsible for ST segment elevation in ED CP patients. We performed a retrospective comparative review of the electrocardiographic features of various STE syndromes, focusing on differences between AMI and non-AMI syndromes. The electrocardiograms (ECGs) of consecutive ED adult CP patients (with 3 serial troponin I determinations) were interpreted by 3 attending emergency physicians. These ECGs with STE represented the study population used for analysis. Various electrocardiographic features such as STE, ST segment depression (STD), STE morphology, anatomic distribution of STE, and the number of leads with STE were recorded; derived values such as total STE, total ST segment deviation, and average STE per lead were calculated. Interobserver reliability concerning STE morphology was determined. AMI was diagnosed by abnormal serum troponin I values (>0.1 mg/dL) followed by a rise and fall of the serum marker; STE diagnoses of non-AMI causes were determined by medical record review. Five hundred ninety-nine CP patients were entered in the study with 212 (35%) individuals showing STE, 55 (26%) with electrocardiographic AMI and 157 (74%) with non-AMI electrocardiographic syndromes. Anatomic location within the AMI group included 32 inferior and inferior variants, 18 anterior and anterior variants, and 5 lateral; non-AMI anatomic locations included 56 inferior and inferior variants, 98 anterior and anterior variants, and 3 lateral; anterior STE occurred significantly more often in non-AMI syndromes. Total STE was 15.3 mm in AMI patients and 7.4 mm in non-AMI patients (P =.0004). The number of leads with STE was not significantly different between the two groups, 3.4 mm in AMI and 4.1 in non-AMI syndromes. ST segment elevation per lead was not significantly different in the 2 groups, 4.4 mm in AMI versus 1.8 mm in non-AMI syndromes. Total ST segment deviation (sum of STE and STD) was significantly greater in AMI syndromes, 17.8 mm in AMI compared with 10.5 mm in non-AMI syndromes (P =.00009). The presence of STD occurred at statistically similar rates in both groups. The morphology of the STE occurred in significantly different rates between AMI and non-AMI patterns, concave more often in non-AMI patterns (P <.00001) and nonconcave more often in AMI (P <.00001). Non-AMI causes of STE account for the majority of electrocardiographic syndromes encountered in ED chest pain patients. These findings alone are not adequate to determine the electrocardiographic cause of the ST segment elevation in chest pain patients. When determining AMI versus non-AMI with the ECG, these various findings should be used in the consideration of the overall clinical picture (history, examination, and electrocardiogram) in chest pain patients with ST segment elevation.
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PMID:Electrocardiographic ST segment elevation: a comparison of AMI and non-AMI ECG syndromes. 1244 39

The objective of this study was to determine the safety of the glycoprotein IIb/IIIa receptor inhibitor eptifibatide in patients at high risk for adverse clinical outcomes and to determine risk factors for eptifibatide-associated bleeding. Consecutive patients (n = 175) who presented with an acute coronary syndrome and who were at high risk for adverse clinical outcomes were prospectively observed for eptifibatide-associated bleeding, which was classified according to Thrombolysis in Myocardial Infarction (TIMI) and Global Use of Strategies to Open Occluded arteries (GUSTO) criteria. High risk was defined as unstable angina or non-Q-wave myocardial infarction with at least one of the following: left ventricular ejection fraction < 40%, diabetes mellitus, ST segment depression or transient ST segment elevation, serum [troponin I] > 2.5 ng/mL, and recurrent angina symptoms after initiation of conventional antianginal therapy. Bleeding incidences in the patients in this study were compared with those in the 4722 eptifibatide-treated patients in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial. Compared to PURSUIT patients, the population in this study was similar in age but had a higher proportion of females, African Americans, hypertension, diabetes, prior myocardial infarction, heart failure, and revascularization. Bleeding incidences in this study's patients were similar to or lower than those in the PURSUIT population: TIMI major 1.1% versus 10.8%, TAMI minor 12.6% versus 13.1%, GUSTO severe 1.7% versus 1.5%, GUSTO moderate 3.9% versus 11.3%, and GUSTO mild 19.7% versus 26.1%. Renal dysfunction was an independent risk factor for TIMI (odds ratio = 9.1 ([95% CI= 1.6-52.5]) and GUSTO (odds ratio = 6.1 [95% CI = 1.2-30.0]) bleeding. In conclusion, despite being at higher risk for adverse outcomes, patients administered eptifibatide according to this study's institutional guidelines had comparable or lower bleeding rates than in the PURSUIT trial. Renal dysfunction is an independent risk factor for eptifibatide-induced bleeding.
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PMID:Bleeding associated with eptifibatide targeting higher risk patients with acute coronary syndromes: incidence and multivariate risk factors. 1246 32

Myocardial stunning is a form of acute reversible cardiac dysfunction that occurs after brief periods of ischemia and reperfusion. In several animal models, stunning is associated with proteolytic truncation of troponin I (TnI). Mice expressing the same proteolytic TnI fragment [TnI-(1-193)] demonstrate cardiac depression with a decreased maximal calcium-activated tension. We therefore hypothesized preferential improvement in mice expressing TnI-(1-193) treated with the calcium-sensitizing drug EMD-57033. TnI-(1-193) and nontransgenic myofibrils exhibited significant sensitization to calcium in Mg-ATPase assays after EMD-57033 exposure. However, only transgenic myofibrils exhibited an increase in maximal activity (P = 0.023). EMD-57033 also increased maximal calcium-activated force in TnI-(1-193) muscle, such that it was comparable to nontransgenic cardiac muscle. EMD-57033 enhanced in vivo systolic function modestly in controls but had a marked effect in transgenic mice, with an almost threefold greater leftward shift of the end-systolic pressure-volume relation (P = 0.0005). These data indicate a targeted efficacy of EMD-57033 in offsetting the contractile defect in TnI-(1-193) mice, and this may have therapeutic implications in models displaying this myofilament defect.
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PMID:Augmented systolic response to the calcium sensitizer EMD-57033 in a transgenic model with troponin I truncation. 1469 78


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