Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Propionyl-L-carnitine (PLC) is under development as a therapeutic for the treatment of peripheral artery disease, coronary heart disease and chronic heart failure. Three methods were examined for labelling PLC in its propionyl group with positron-emitting carbon-11 (t12 = 20.3 min), one chemical and two chemoenzymatic. The former was based on the preparation of [11C]propionyl chloride as labelling agent via 11C-carboxylation of ethylmagnesium bromide with cyclotron-produced [11C]carbon dioxide and subsequent chlorination. Reaction of carrier-added [11C]propionyl chloride with L-carnitine in trifluoroacetic acid gave [11C]PLC in 12% radiochemical yield (decay-corrected) from cyclotron-produced [11C]carbon dioxide. However, the radiosynthesis was unsuccessful at the no-carrier-added (NCA) level of specific radioactivity. [11C]Propionate, as a radioactive precursor for chemoenzymatic routes, was prepared via carboxylation of ethylmagnesium bromide with [11C]carbon dioxide and hydrolysis. NCA [11C]PLC was prepared in 68 min in 14% radiochemical yield (decay-corrected) from [11C]propionate via sequential conversions catalysed by acetate kinase, phosphotransacetylase and carnitine acetyltransferase. A superior chemoenzymatic synthesis of NCA [11C]PLC was developed, based on the use of a novel supported Grignard reagent for the synthesis of [11C]propionate and conversions by S-acetyl-CoA synthetase and carnitine acetyltransferase. This gave an overall radiochemical yield of 30-48% (decay-corrected). This synthesis was automated for radiation safety and provides pure NCA [11C]PLC in high radioactivities ready for intravenous administration within 25 min from radionuclide production. The [11C]PLC is suitable for pharmacokinetic studies in human subjects with PET and the elucidation of the fate of the propionyl group of PLC in vivo.
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PMID:Automated chemoenzymatic synthesis of no-carrier-added [carbonyl-11C]propionyl L-carnitine for pharmacokinetic studies. 937 26

The potential of Ca(2+) channel antagonists, particularly nifedipine, to cause apoptotic cell death has been controversial and is of considerable importance for cardiomyocytes as loss of these cells is an important component of the pathophysiology leading to heart failure. To examine the hypothesis that nifedipine induces cell death and modulates calcium-induced apoptosis, cardiomyocytes in culture from embryonic chick hearts, that readily manifest apoptosis, were studied. Apoptosis was evaluated by fluorescent activated cell sorting (FACS) analysis and by quantitative analysis of DNA fragmentation by an enzyme-linked immunosorbent assay (ELISA) specific for histone-associated DNA fragments of mono- and oligonucleosome size. Cell death was evaluated by using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay. Cardiomyocytes were treated with various concentrations of nifedipine over a concentration range relevant to serum concentrations in man. Nifedipine, 1 to 100 microM, did not produce cell death in cardiomyocytes. There was no evidence of apoptosis on FACS analysis of cardiomyocytes stained with fluoresceine diacetate or propidum iodide (PI). Neither was there any evidence of apoptotic nuclei on PI staining of permeabilized cardiomyocytes treated with nifedipine. In contrast, DNA fragmentation consistent with apoptosis was induced in a significant (P<0.05) concentration-dependent manner, by increases in extracellular Ca(2+) concentration ([Ca(2+)](o)). Importantly, nifedipine reduced DNA fragmentation produced by increased [Ca(2+)](o). Furthermore, nifedipine blocked calcium-induced cell death as high [Ca(2+)](o) significantly (P<0. 05) reduced cell viability. These data indicate that nifedipine does not induce apoptosis in cardiomyocytes rather apoptosis in cardiomyocytes is under regulatory control by Ca(2+) and nifedipine can antagonize Ca(2+)-mediated apoptotic cell death.
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PMID:Nifedipine does not induce but rather prevents apoptosis in cardiomyocytes. 1067 28

Twenty-five symptomatic patients of chronic heart failure were subjected to spirometry to detect abnormalities of pulmonary function and to assess the effect of ipratropium bromide in reversing or minimising these abnormalities. All the patients exhibited abnormal pulmonary function manifesting as obstructive (15/25) or restrictive (10/25) ventilatory defect. There was overall improvement in lung functions with ipratropium bromide especially in those with obstructive ventilatory defects and mostly comprised of smokers. Forced expiratory volume in one second increased by 47.7 percent (p < 0.02), forced expiratory volume in one second/forced vital capacity ratio by 14.1 percent (p < 0.001) and maximal voluntary ventilation by 40.6 percent (p < 0.05) in these patients. It is concluded that ipratropium bromide can prove as a promising adjunctive therapeutic intervention in improving quality of life in patients of chronic congestive heart failure who are incapacitated by dyspnoea and have clearly documented ventilatory defects.
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PMID:Pulmonary function profile in chronic congestive heart failure and the effect of ipratropium bromide. 1097 50

It has been reported that at the end stage, apoptosis is involved in the progression of heart failure. It is suggested that cardiac energy metabolism is impaired during the progression of heart failure. Although the mechanism of induction of apoptosis in the failing heart varies according to the model of heart failure, it is not known whether an impairment of energy metabolism in cardiomyocytes is a primary cause of apoptosis. In this study, we applied mitochondrial inhibitors, such as rotenone, cobalt chloride and antimycin A, which inhibit mitochondrial function at different sites of the mitochondrial respiratory chain, to cardiomyocytes. All these reagents markedly decreased 3-(4,5)-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay (MTT) reduction activity, an indicator of mitochondrial function, of cardiomyocytes and greatly increased glucose consumption, suggesting that cardiac energy metabolism is switched from beta-oxidation of fatty acid to glycolysis. It was shown that after 48-72 h of treatment with each reagent, apoptosis was shown to occur by DNA laddering and increase in caspase activity. Interestingly, each reagent with a different action site greatly activated caspase-3, but not caspase-8 activity, suggesting that mitochondria are involved in induction of apoptosis. On the other hand, within 24 h of the treatment, when apoptosis of cardiomyocytes was not observed, the treated cardiomyocytes showed a marked increase in preproendothelin-1 and atrial natriuretic peptide (ANP) gene expressions. In conclusion, the present study suggests that mitochondrial dysfunction with impaired energy metabolism elevates gene expression of cardiac ET-1, an aggravating factor in heart failure, and then finally induces apoptosis in cardiomyocytes. The finding of marked increases in expression of molecular markers (ET-1 mRNA and ANP mRNA) in the failing heart, followed by apoptosis in the treated cardiomyocytes suggests that the inhibition of mitochondrial function of cultured cardiomyocytes provides a possible new in vitro model of heart failure.
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PMID:Mitochondrial dysfunction of cardiomyocytes causing impairment of cellular energy metabolism induces apoptosis, and concomitant increase in cardiac endothelin-1 expression. 1107 77

We previously reported that cardiomyocytes produce endothelin (ET)-1 and that the tissue level of ET-1 markedly increased in failing hearts in rats with chronic heart failure. Because the level of plasma ET-1 also increased progressively in patients with breast cancer who received doxorubicin (Dox; Adriamycin), which possesses cardiotoxicity, we hypothesized that ET-1 plays a role in the pathophysiology of cardiomyocytes injured by Dox. In this study, we investigated the effect of ET-1 on the cytotoxicity of Dox in primary cultured neonatal rat cardiomyocytes. The results showed that ET-1 effectively attenuated Dox-induced acute cardiomyocyte cytotoxicity (24-h incubation with Dox) evaluated by in vitro cell toxicity assay [3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay and lactate dehydrogenase release]. The cytoprotective effect of ET-1 was mediated via ET(A) receptors, because pretreatment with the ET(A)-receptor antagonist BQ123 completely suppressed the cytoprotective effect of ET-1, whereas the ET(B)-receptor antagonist BQ788 did not. The cytoprotective effect of ET-1 was abolished by pretreatment with cycloheximide or staurosporine. These results suggest that a protein molecule(s), which is synthesized de novo by the stimulation of protein kinase pathway, is involved in the cytoprotective effect of ET-1. ET-1 increased the expression of an endogenous antioxidant, manganese superoxide dismutase (Mn-SOD), in the cardiomyocytes, as demonstrated by a Western blotting analysis. Pretreatment with an antisense oligodeoxyribonucleotide of Mn-SOD markedly attenuated the cytoprotective effect of ET-1 on the Dox-induced cytotoxicity. However, under conditions of prolonged incubation with Dox (48 h), ET-1 did not affect Dox-induced cardiomyocyte cytotoxicity in culture. These results suggest that ET-1 prevents the early phase of Dox-induced cytotoxicity via the upregulation of the antioxidant Mn-SOD through ET(A) receptors in cultured cardiomyocytes.
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PMID:A novel pharmacological action of ET-1 to prevent the cytotoxicity of doxorubicin in cardiomyocytes. 1129 60

The appropriate choice of anesthesia for patients (pts) undergoing renal transplantation (Ktx) requires minimal toxicity and accurate monitoring for pts at high risk for metabolic, cardiovascular, and respiratory perioperative complications. We evaluated the anesthetic management and postoperative follow-up in pediatric Ktx performed in the last 12 years in our institution. From 1988 to 1999, 75 ASA class II-III pts (45 males, 22 females) younger than 18 years scheduled for Ktx were studied: 49 received a graft from a cadaveric donor (CD) and 26 from a living donor (LD). All pts were treated with dialysis within 24 h before the procedure. Standard monitoring consisted of an electrocardiogram, central venous pressure, non-invasive arterial pressure, pulse oximetry, and inspiratory and expiratory gas analysis. If necessary, an arterial cannula and pediatric pulmonary catheter were introduced. Anesthesia was induced with sodium thiopental, propofol, halothane, or sevoflurane and maintained with isoflurane and/or fentanyl and droperidol in O2:N2O (FiO2 0.4%). As muscle relaxants atracurium or cisatracurium besilate were used, except in allergic pts, in whom vecuronium or rocuronium bromide was administered. Dopamine, 20% mannitol, and furosemide were used to increase diuresis. Continuous morphine and ketoralac infusions were used for postoperative pain relief. The surgical technique was the same in all cases. Complications and renal-function (RF) recovery were evaluated relating to CD and LD using the chi-square test; differences in mean anesthesia and surgical time were evaluated by Student's t-test; survival curves were calculated from the day of Ktx to death or last follow-up and estimated by the Kaplan-Meier method. Values of P below 0.05 were considered significant. Postoperative immunosuppressive therapy was based on cyclosporine together with other conventional drugs. Mean anesthesia time was 228 +/- 65 min. Mean kidney ischemia time for CD was 16.5 +/- 4 h. Four pts (3 CD, 1 LD) died within 72 h postoperatively: 3 due to cardiac failure and 1 to metabolic coma. Six pts showed cardiovascular and 3 had infective complications, all successfully treated. Three pts (2 CD, 1 LD) died within 2 to 12 months after, surgery; 10 (6 CD, 4 LD) had graft failure and are still alive on dialysis; 58 (38 CD, 20 LD) are alive in good health after a mean follow-up of 57.6 +/- 36.6 months (range 12-120 months). Fifteen of 26 pts younger than 12 years (21 CD and 5 LD) recovered RF intraoperatively (10 CD, 5 LD); 1 with CD and 1 with LD showed postoperative graft failure and 2 with CD died within 72 h postoperatively, 22 (18 CD and 4 LD) are alive in good health. This group showed no statistical difference compared to pts older than 12 years. Of 16 pts (15 CD and 1 LD) with body weight (BW) less than 25 kg, 6 showed intraoperative (5 CD, 1 LD) recovery of RF. The 3 deaths were all in CD pts, 2 within 72 h and one 2 months after surgery; only 1 LD had postoperative graft failure. Twelve pts (75%) (12 CD, 80%) are alive in good health. Compared to pts with BW of 25 kg or more, this group showed lower intraoperative recovery of RF (P < or = 0.05). No peri- and postoperative complications occurred in all 26 LD pts (100%). Recent advances in surgery, anesthesia, immunosuppression, and antimicrobial prophylaxis have made Ktx a more predictable procedure even in pediatric pts. For high-risk pts, mortality and morbidity can be controlled by accurate surgical, anesthetic, and postoperative management. Pts younger than 12 years and with BW less than 25 kg are more likely to develop peri- and postoperative complications.
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PMID:Pediatric renal transplantation: anesthesia and perioperative complications. 1131 82

The aim of the work is to study the influence of a long-term ipratropium bromide on the character of the functional heart indices changes in patients with chronic obstructive bronchitis. Positive effects on the myocardial reserve are reported under a 2-week atrovent monotherapy. Atrovent favoured a positive trend in clinical symptoms, that determined the myocardial reserve. With the above drug, the frequency of the reduced myocardial reserve has come to be lowered by 34.5%. Based on the data presented recommendations are given for use of ipratropium bromide in chronic obstructive bronchitis patients with the incipient form of heart failure.
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PMID:[Effect of anticholinergic therapy on myocardial reserve dynamics in patients with chronic obstructive bronchitis]. 1188 64

Conventional pharmacotherapy of severe asthma and status asthmaticus includes beta2-sympathomimetics, theophylline, corticosteroids and occasionally topical anticholinergics (ipratropium bromide). Since hypoxemia is the most severe phenomenon in status asthmaticus the administration of oxygen is mandatory. However, if the bronchodilating therapy fails and hypoxemia continues, usually respiratory failure develops due to progressive respiratory muscle failure. An increasing PaCO(2) and respiratory acidosis are indications for mechanical ventilatory support to unload the failing respiratory pump. Nowadays, there is increasing consensus that ventilatory support should be administered primarily as non-invasive ventilation (NIV) via a face mask1. However, in a significant number of patients with severe asthma NIV is either contraindicated or insufficient. In this case usually the patient must be endotracheally intubated and mechanically ventilated "invasively". Intubation and ventilation of patients with severe asthma or status asthmaticus is associated with a high incidence of complications compared to patients ventilated for other causes of respiratory failure2,3. Therefore the risks of invasive mechanical ventilation have to be weighted carefully to ongoing conservative therapy and NIV. Cardiopulmonary arrest and severe hypoxemia in spite of O2 supplement and NIV are absolute criteria for intubation and ventilation. Mostly deterioration in mental status and exhaustion are the clinical findings leading to mechanical ventilation. Decision is guided rather by the course of the deterioration (how fast the patient's condition is worsening) than by pathological values alone. An increased PaCO(2) with moderate respiratory acidosis alone is not per se an indication for mechanical ventilation. However, a continuously rising PaCO(2) or the development of a severe metabolic acidosis after 1 hour of NIV is a strong argument for invasive mechanical ventilation. Other criteria are evidence of cardiac failure with fall in pulse volume and dysrhythmias, pneumomediastinum or pneumothorax (which has to be drained before mechanical ventilation!).
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PMID:Ventilating the patient with severe asthma: nonconventional therapy. 1276 62

The detection of doxorubicin-induced apoptosis in individual cardiomyocytes was performed on a microfluidic device. Microstructures integrated on a CD-like plastic disk were adapted for the selection of individual cells their lysis in an alkaline environment and the separation of released apoptotic DNA fragments. The fragments with typical 180 base pairs ladder pattern were electrophoretically resolved in a 2% solution of linear polyacrylamide with 0.1 M NaOH on a migration distance of 6 mm. The laser-induced fluorescence of fragments labeled by ethidium bromide was monitored by a photomultiplier tube mounted on a confocal microscope. The causal relation between the enhanced doxorubicin concentration and the extent of DNA fragmentation in a single cell was confirmed. The results show that the extent of DNA fragmentation is proportional to the time of a cell treatment. Onset of necrosis was evident in cardiomyocytes treated by doxorubicin for more than 24 h. The adverse effect of doxorubicin, an important cytostatics used for the treatment of many solid tumors, leads to the destruction of cardiomyocytes and, consequently, may result in the heart failure of treated individuals. Therefore, the monitoring of the extent of apoptotic DNA damage of cardiac myocytes represents critical step toward understanding of the development of chronic doxorubicin-induced cardiomyopathy.
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PMID:Detection of DNA fragmentation in a single apoptotic cardiomyocyte by electrophoresis on a microfluidic device. 1461 5

Loss of cardiomyocytes by apoptosis is proposed to cause heart failure. Angiotensin II (ANG II), an important neurohormonal factor during heart failure, can induce cardiomyocyte apoptosis. Inasmuch as hexarelin has been reported to have protective effects in this process, we examined whether hexarelin can prevent cardiomyocytes from ANG II-induced cell death. Cultured cardiomyocytes from neonatal rats were stimulated with ANG II. Apoptosis was evaluated using fluorescence microscopy, TdT-mediated dUTP nick-end labeling (TUNEL) method, flow cytometry, DNA laddering, and analysis of cell viability by (3,4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). It was found that incubation with 0.1 micromol/l ANG II for 48 h increased cardiomyocyte apoptosis. Administration of 0.1 micromol/l hexarelin significantly decreased this ANG II-induced apoptosis and DNA fragmentation and increased myocyte viability. To further investigate the underlying mechanisms, caspase-3 activity assay and mRNA expression of Bax, Bcl-2, and growth hormone secretagogue receptor (GHS-R; the supposed hexarelin binding site) were examined. GHS-R mRNA was abundantly expressed in cardiomyocytes and was upregulated after administration of hexarelin. These results suggest that hexarelin abates cardiomyocytes from ANG II-induced apoptosis possibly via inhibiting the increased caspase-3 activity and Bax expression induced by ANG II and by increasing the expression of Bcl-2, which is depressed by ANG II. Whether the upregulated expression of GHS-R induced by hexarelin is associated with this antiapoptotic effect deserves further investigation.
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PMID:Hexarelin protects rat cardiomyocytes from angiotensin II-induced apoptosis in vitro. 1461 77


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