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)

Hearts isolated from a guinea pig model of Escherichia coli endotoxemia exhibit decreased systolic contractile function and reduced diastolic compliance of the left ventricle within 4 h after injection of endotoxin. Fluid resuscitation prevented the endotoxin-induced decrease in diastolic compliance without affecting systolic contractile depression. Because intrinsic myocardial dysfunction after endotoxemia may result from alterations in intracellular Ca2+ handling, we tested the hypothesis that in vivo fluid resuscitation improved diastolic function by altering Ca2+ handling of the myocardium. We tested this hypothesis by measuring cell shortening and intracellular Ca2+ of ventricular myocytes isolated from endotoxemic guinea pigs. E. coli endotoxin (LPS, 1 mg/kg)-injected guinea pigs were divided into resuscitated and nonresuscitated groups. Fluid resuscitated animals received a Ringer's infusion (8 mL.kg-1.h-1) intravenously (i.v.) beginning immediately after endotoxin injection. Four hours later, ventricular myocytes were isolated enzymatically and loaded with fura-2/AM. When myocytes were field stimulated at .8 Hz, peak systolic Ca2+ transients of LPS-resuscitated (619 +/- 75 nM) and LPS-nonresuscitated (599 +/- 60 nM) myocytes were not significantly different from each other, but both were significantly less than values from control myocytes (1187 +/- 118 nM, p < .05). The percentage of cell shortening of LPS-resuscitated (6.2 +/- .9%) and LPS-nonresuscitated (6.2 +/- .3%) myocytes were also less than control (11.8 +/- .5%, p < .05). In contrast to improved diastolic compliance of fluid-resuscitated hearts, diastolic [Ca2+]i of myocytes (at .8 Hz) from LPS-resuscitated animals (138 +/- 47 nM) was not statistically different from LPS-nonresuscitated animals (129 +/- 19 nM). Diastolic values of both LPS groups were consistently lower than control value (251 +/- 38 nM, p < .05). These data suggest that improved diastolic compliance of LPS hearts following fluid resuscitation is not associated with improved myocyte contractility or myoplasmic Ca2+ handling.
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PMID:Cytosolic Ca2+ concentration and contraction-relaxation properties of ventricular myocytes from Escherichia coli endotoxemic guinea pigs: effect of fluid resuscitation. 916 75

We have previously demonstrated that chronic alcohol consumption (8 to 10 weeks with ethanol as 36% of the caloric intake) does not exacerbate the effects of ischemia reperfusion injury on the heart. In those same studies, however, Gram-negative sepsis caused myocardial depression in both control and alcoholic rats, but also protected hearts from further damage due to ischemia-reperfusion. In the present study, we determined if preconditioning, a very short ischemia-reperfusion episode that protects the heart from more prolonged ischemia, would have similar effects on hearts from alcoholic and control rats with or without sepsis. Thus, rats were fed a liquid diet supplemented with ethanol or dextrin for 8 to 10 weeks. Some alcoholic and control rats were made septic with Escherichia coli injected into the subcutaneous space, whereas others received an injection of sterile saline. Isolated, isovolumically beating hearts were studied the following day. Hearts were made ischemic for 5 min, reperfused for 5 min, and then made ischemic for 35 min and reperfused for 25 min. Data from similar groups of hearts receiving only 35 min ischemia, and studied at the same time as the present groups, have been previously reported. The 5-min preconditioning episode was more effective in protecting hearts in the alcohol group than in the control group. Postischemic left ventricular developed pressure and +dP/dtmax were not significantly decreased from the preischemic values in the alcohol group, but were significantly decreased in the control group. The time to recovery of spontaneous contractions was decreased by preconditioning in the alcohol group but not in the control group, and the recovery of coronary flow was enhanced in the alcohol group, but not in the control group by pre-conditioning. Thus a single 5-min ischemic procedure was effective in protecting the heart from prolonged ischemia in the alcohol group, whereas it was not sufficient to elicit protection in the control group. Sepsis depressed preischemic function in both groups, but recovery from ischemia was complete.
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PMID:Chronic alcohol consumption causes accelerated myocardial preconditioning to ischemia-reperfusion injury. 926 37

3-(2,2,2-trimethylhydrazinium) propionate (MET-88) is an inhibitor of carnitine synthesis. This study was carried out to investigate whether or not reduction of carnitine content could attenuate hypoxic damage in isolated perfused rat hearts. Rats were divided into four groups: 1) vehicle control; 2) pretreatment with MET-88 (MET-88); 3) application of insulin (500 muU/mL) in the perfusate (insulin); and 4) pretreatment with MET-88 and application of insulin (MET-88 + insulin). MET-88 (100 mg/kg) was orally administered once a day for 10 days until the day before the experiments. Hearts were initially perfused for a 10 min period under normoxia, followed by a 30 min period under hypoxia. Hearts were frozen at the end of hypoxia for the measurement of high-energy phosphates, carnitine derivatives, and glycolysis intermediates. In a separate series of untreated and MET-88 treated hearts, exogenous glucose and palmitate oxidation was measured. MET-88 decreased the extent of the depression of cardiac contractility (+dP/dt), and aortic flow during the hypoxic state. Insulin also improved cardiac function, and co-treatment of MET-88 and insulin additionally improved cardiac function during hypoxia. MET-88 prevented the decrease of high-energy phosphate and the increase of long-chain acylcarnitine after 30 min of hypoxic perfusion. In addition, MET-88 increased the steady state of glucose oxidation in hypoxic perfused rat hearts. These results indicate that MET-88 has cardioprotective effects on contractile function and energy metabolism of isolated perfused rat hearts in a hypoxic condition. Preventing the accumulation of long-chain acylcarnitine may serve to protect hypoxic hearts.
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PMID:Cardioprotective profile of MET-88, an inhibitor of carnitine synthesis, and insulin during hypoxia in isolated perfused rat hearts. 956 69

Both preconditioning and inhibition of complement activation have been shown to ameliorate myocardial ischemia-reperfusion injury. The recent demonstration that myocardial tissue expresses complement components led us to investigate whether preconditioning affects complement expression in the isolated heart. Hearts from New Zealand White rabbits were exposed to either two rounds of 5 min global ischemia followed by 10 min reperfusion (ischemic preconditioning) or 10 microM of the ATP-dependent K+ (KATP) channel opener pinacidil for 30 min (chemical preconditioning) before induction of 30 min global ischemia followed by 60 min of reperfusion. Both ischemic and chemical preconditioning significantly (P < 0.05) reduced myocardial C1q, C1r, C3, C8, and C9 mRNA levels. Western blot and immunohistochemistry demonstrated a similar reduction in C3 and membrane attack complex protein expression. The K(ATP) channel blocker glyburide (10 microM) reversed the depression of C1q, C1r, C3, C8, and C9 mRNA expression observed in the pinacidil-treated hearts. The results suggest that reduction of local tissue complement production may be one means by which preconditioning protects the ischemic myocardium.
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PMID:Preconditioning reduces tissue complement gene expression in the rabbit isolated heart. 1060 Aug 58

This study evaluates the effect of aminoguanidine, a preferential inhibitor of inducible nitric oxide synthase (iNOS), on the prevention of cardiac depression in acute endotoxemia. Cardiac performance was evaluated after 4 h of exposure to endotoxin. Rats (n = 5) were selected randomly to receive, by intraperitoneal injection, one of four treatments: saline, LPS (lipopolysaccharide, E. coli, 4 mg/kg, AG (aminoguanidine 100 mg/kg), and LPS + AG at various times. AG and saline treatments were administered 30 min before LPS and at 1 and 3 h after LPS injection. Hearts were perfused using the Langendorff isolated perfusion system and a balloon-tipped catheter was placed into the left ventricle to measure left ventricular developed pressure (LVDP). Myocyte contractile function was assessed with electrical field stimulation and video microscopy. Tissue was immunostained for the expression of iNOS and for nitrotyrosine, a byproduct of protein nitration by peroxynitrite. Perfused hearts from LPS-treated rats exhibited a 57% decrease (P < 0.05) in LVDP compared to saline-treated animals. No improvement in ventricular function was observed with the administration of AG. Similarly, cardiac myocytes prepared from LPS-treated animals demonstrated a significant (P < 0.05) reduction in percent and velocity of shortening and this effect was unaltered with the same dose of AG. AG administration significantly reduced serum nitrite/nitrate levels (P < 0.05) in endotoxemic rats to control levels. Localized expression of iNOS in the myocardium was lessened with AG treatment and was not associated with peroxynitrite formation in this model of endotoxemia. The results indicate that AG given in vivo before and after endotoxin (at a concentration sufficient to decrease NO production) did not reduce cardiac depression. We conclude that selective inhibition of iNOS and the reduction of NO production do not prevent cardiac dysfunction at an early stage in an acute model of endotoxemia.
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PMID:Cardiac response to nitric oxide synthase inhibition using aminoguanidine in a rat model of endotoxemia. 1202 62

Chronic (8 weeks) coronary artery ligation caused marked left-ventricular dysfunction (LVD) in rabbits. The positive inotropic effect observed in vivo with intraventricular injection of saline in sham-operated (control) animals was reversed in rabbits with LVD. In vitro, a step increase in filling pressure from 10 to 15 cm H(2)O caused an immediate increase, followed by a slow increase, in left-ventricular peak systolic pressure (LVP(max)) and cardiac output (CO) over 5-7 min in sham-operated hearts. No significant slow positive inotropic effect was observed in hearts with LVD in response to a standard increase in filling pressure. Progressive increases in filling pressure increased (LVP(max)) and CO to a maximum value at 20 cm H(2)O in control hearts. In the LVD group, progressive increases in filling pressure caused a negative inotropic response and reduced CO. Hearts from the LVD group were significantly dilated compared with control hearts but no significant changes in myocardial compliance were observed in beating or quiescent hearts. These studies reveal an impaired inotropic response to increased ventricular filling in LVD rabbit hearts; this defect included the depression of the slow inotropic response to an increased end-diastolic volume. These changes appear not to be accompanied by altered passive mechanical properties.
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PMID:Depressed inotropic response to increased preload in rabbit hearts with left-ventricular dysfunction induced by chronic myocardial infarction. 1213 71

Striated muscle tropomyosin (TM) interacts with actin and the troponin complex to regulate calcium-mediated muscle contraction. Previous work by our laboratory established that alpha- and beta-TM isoforms elicit physiological differences in sarcomeric performance. Heart myofilaments containing beta-TM exhibit an increased sensitivity to calcium that is associated with a decrease in the rate of relaxation and a prolonged time of relaxation. To address whether the carboxyl-terminal, troponin T binding domain of beta-TM is responsible for these physiological alterations, we exchanged the 27 terminal amino acids of alpha-TM (amino acids 258 -284) for the corresponding region in beta-TM. Hearts of transgenic mice that express this chimeric TM protein exhibit significant decreases in their rates of contraction and relaxation when assessed by ex vivo work-performing cardiac analyses. There are increases in the time to peak pressure and a dramatic increase in end diastolic pressure. In myofilaments, this chimeric protein induces depression of maximum tension and ATPase rate, together with a significant decrease in sensitivity to calcium. Our data are the first to demonstrate that the TM isoform-specific carboxyl terminus is a critical determinant of sarcomere performance and calcium sensitivity in both the whole heart and in isolated myofilaments.
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PMID:Functional importance of the carboxyl-terminal region of striated muscle tropomyosin. 1269 96

The efficacy of Withania somnifera (Ws) to limit myocardial injury after ischemia and reperfusion was explored and compared to that of Vit E, a reference standard known to reduce mortality and infarct size due to myocardial infarction. Wistar rats (150-200 g) were divided into six groups and received orally saline (sham, control group), Ws-50/kg (Ws control and treated group) and Vit E-100 mg/kg (Vit E control and treated group) respectively for 1 month. On the 31st day, rats of the control, Vit E and Ws treated groups were anesthetized and subjected to 45 min occlusion of the LAD coronary artery followed by 60 min reperfusion. Hemodynamic parameters: systolic, diastolic and mean arterial pressure (SAP, DAP, MAP), heart rate (HR), left ventricular end diastolic pressure (LVEDP), left ventricular peak (+)LVdP/dt and (-)LVdP/dt were monitored. Hearts were removed and processed for histopathological and biochemical studies: Myocardial enzyme viz, creatin phosphokinase (CPK), and antioxidant parameters: malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSHPx) were estimated. Postischemic reperfusion produced significant cardiac necrosis, depression of left ventricular functions (MAP, LVEDP, (+) and (-)LVdP/dt) and a significant fall in GSH (p < 0.01), SOD, CAT (p < 0.05), LDH and CPK (p < 0.01) as well as an increase in MDA level (p < 0.05) in the control group rats as compared to sham group. The changes in levels of protein and GPx was however, not significant. Ws and Vit E favorably modulated most of the hemodynamic, biochemical and histopathological parameters though no significant restoration in GSH, MAP (with Vit E) were observed. Ws on chronic administration markedly augmented antioxidants (GSH, GSHPx, SOD, CAT) while Vit E did not stimulate the synthesis of endogenous antioxidants compared to sham. Results indicate that Ws significantly reduced myocardial injury and emphasize the beneficial action of Ws as a cardioprotective agent.
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PMID:Cardioprotection from ischemia and reperfusion injury by Withania somnifera: a hemodynamic, biochemical and histopathological assessment. 1522 84

The mechanism responsible for cardiac depression in septic shock remains unknown. The present study examined whether nitric oxide (NO) overproduced by inducible NO synthase (iNOS) can inhibit aerobic energy metabolism and impair the myocardial function in endotoxin-treated rat hearts. Lipopolysaccharide (LPS) significantly decreased systolic blood pressure (BP) to 44% of control during the 48 h treatment. Hearts from control and LPS-treated rats were perfused in a Langendorff apparatus. After LPS injection, left ventricular (LV) developed pressure (LVDP) was significantly depressed, plasma NO2-/NO3- (NO(x)) concentration was markedly increased, and myocardial adenosine 5'-triphosphate (ATP), creatine phosphate (CrP), and the ratio of ATP/adenosine 5'-diphosphate were progressively decreased with time. Immunological examination showed a significant expression of iNOS protein in the LPS-treated myocytes. Aminoguanidine, an inhibitor of iNOS, significantly attenuated these LPS-induced functional and metabolic changes. Myocardial cyclic guanosine 3',5'-monophosphate (cGMP) content was significantly increased after LPS injection. Methylene blue, an inhibitor of soluble guanylate cyclase, blunted this increase in cGMP and significantly restored the LPS-induced contractile dysfunction 6 h after LPS injection. In addition, there was a significant negative correlation between LVDP and myocardial cGMP levels as well as a significant negative correlation between LVDP and plasma NO(x) levels. In contrast, 48 h after LPS injection, methylene blue no longer affected cardiac performance, and there was a significant positive correlation between LVDP and myocardial ATP content. Furthermore, the normalized activities (as a ratio of the citrate synthase activity) of mitochondrial NADH-CoQ reductase, succinate-CoQ reductase, and ATPase, were significantly inhibited, and the swelling or disruption of mitochondria cristae was seen in the 48 h LPS treatment. These LPS-induced functional and morphological disorders in the mitochondria were significantly improved by aminoguanidine. The findings suggest that sustained production of NO by iNOS leads to contractile dysfunction via cGMP in the early stage, but that it can directly impair the mitochondrial function, lower myocardial energy production, and contribute significantly to the myocardial dysfunction in the later stage of septic shock.
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PMID:Cytokine-induced nitric oxide inhibits mitochondrial energy production and induces myocardial dysfunction in endotoxin-treated rat hearts. 1535 Aug 50

Hearts from severely Cu-deficient rats show a variety of pathological defects, including hypertrophy and, in intact hearts, depression of contractile function. Paradoxically, isolated cardiomyocytes from these rats exhibit enhanced contractile properties. Because hypertrophy and enhanced contractility observed with other pathologies are associated with elevation of insulin-like growth factor-I (IGF)-I, this mechanism was examined for the case of dietary Cu deficiency. Male, weanling Sprague-Dawley rats were provided diets that were deficient (approximately 0.5 mg Cu/kg diet) or adequate (approximately 6 mg Cu/kg diet) in Cu for 5 wk. IGF-I was measured in serum and hearts by an ELISA method, cardiac IGF-I and IGF-II receptors and IGFBP-3 were measured by Western blotting analysis, and mRNAs for cardiac IGF-I and IGF-II were measured by RT-PCR. Contractility of isolated cardiomyocytes was assessed by a video-based edge-detection system. Cu deficiency depressed serum and heart IGF-I and heart IGFBP-3 protein levels and increased cardiac IGF-I receptor protein. Cardiac IGF-II protein and mRNA for cardiac IGF-I and IGF-II were unaffected by Cu deficiency. A Cu deficiency-induced increase in cardiomyocyte contractility, as indicated by increases in maximal velocities of shortening (-dL/dt) and relengthening (+dL/dt) and decrease in time to peak shortening (TPS), was confirmed. These changes were largely inhibited by use of H-1356, an IGF-I receptor blocker. We conclude that enhanced sensitivity to IGF-I, as indicated by an increase in IGF-I receptor protein, accounts for the increased contractility of Cu-deficient cardiomyocytes and may presage cardiac failure.
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PMID:Increased contractility of cardiomyocytes from copper-deficient rats is associated with upregulation of cardiac IGF-I receptor. 1573 78


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