Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0599766 (functional recovery)
 13,441 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The importance of the Na+/K+/Cl- co-transport system of the rat myocardial sarcolemma was studied under hypothermic ischemia by investigating the effect of the co-transport blockers furosemide and bumetanide on the sodium influx into the myocardium. The intracellular Na+ accumulation during hypothermic ischemia was followed by 23Na-NMR. For this purpose the shift reagent [Dy(TTHA)3-] (SR) was added to the Krebs-Henseleit (KH) perfusion solution. The same solution was also present during the hypothermic preservation. A significant reduction in the intracellular Na+ accumulation after 12 h was found when 100 microM furosemide was present during the perfusion and preservation periods. The intracellular Na+ levels returned to the pre-ischemic values after 1 h of reperfusion with KH in both the treated and control groups. Dose-response studies have indicated that 1-100 microM furosemide or 0.1 microM bumetanide added to the KH-SR solution reduced the Na+ influx significantly over 4 h of hypothermic ischemia. No statistically significant effect was found with furosemide concentration of 0.1 microM or with bumetanide concentrations higher or lower than 0.1 microM. 31P-NMR measurements showed no effect of the 100 microM furosemide on the intracellular ATP, the sum of inorganic phosphate and phosphomonoester, or pH levels over 4 h or after 12 h of hypothermic ischemia. Hearts treated with KH containing 100 microM furosemide showed, significantly higher functional recovery after 12 h of hypothermic ischemia than hearts treated only with KH. This study strongly indicates the existence of the Na+/K+/Cl- co-transport system in the intact rat heart sarcolemma, and its major role in sodium influx during hypothermic ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of sodium influx and improved preservation of rat hearts during hypothermic ischemia by furosemide and bumetanide: a 23Na- and 31P-NMR study. 815 60

Preconditioning with brief intermittent periods of ischemia has been shown to lessen the detrimental effects of a subsequent sustained (30-60 min) period of ischemia. Because adenosine has been suggested to be the mediator of preconditioning, we were interested in investigating whether adenosine antagonists would block the effect of preconditioning on ionic changes during ischemia. We found that 10 microM of the adenosine antagonist BW-A1433U did not reverse the effect of preconditioning on intracellular pH (pHi). Hearts preconditioned with BW-A1433U had virtually no decrease in pHi during the 30-min sustained period of ischemia; after 30 min of ischemia, the pH in untreated hearts was 5.97 +/- 0.16 compared with 6.52 +/- 0.10 in preconditioned hearts and 6.90 +/- 0.08 in hearts preconditioned plus BW-A1433U. Because anaerobic glycolysis is largely responsible for the fall in pHi during ischemia, we examined the effect of BW-A1433U [and other adenosine antagonists, such as PD-115,199 and 8-cyclopentyl-1,3-dipropylxanthine (CPDPX)] on glucose uptake and phosphorylation during aerobic perfusion using 31P-nuclear magnetic resonance to monitor uptake and phosphorylation of 2-deoxyglucose (2-DG) to 2-deoxyglucose 6-phosphate (2-DG-6-P) when one-half of the glucose in the perfusate was replaced with 2-DG. Uptake of 2-DG-6-P after 15 min was reduced by 66% in the presence of BW-A1433U and 82% in the presence of PD-115,199 as compared with untreated hearts, but was not reduced in the presence of CPDPX. Thus CPDPX was the only adenosine antagonist tested that did not block accumulation of 2-DG-6-P. We also found that CPDPX did not block the beneficial effect of preconditioning on ionic alterations during a sustained 30-min period of ischemia or the improved recovery of function on reflow.
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PMID:Effects of adenosine antagonists on hexose uptake and preconditioning in perfused rat heart. 823 5

The isolated working rat heart model was use to define the cardioprotective effects (function, metabolic and ultrastructure) of the oxygenated St. Thomas' Hospital No. 2 cardioplegic solution (STH) during lengthy, hypothermic ischaemia (20 degrees C, 4 hours and 5 hours). Hearts (n = 9 for each group) were arrested with and exposed to multidose reinfusion (2 min every 40 min interval) throughout the ischaemic period with the cold (4 degrees C) STH or oxygenated (95% O2:5% CO2) STH. Oxygenated STH significantly (p < 0.01) improved the postischaemic recovery of cardiac output from 49.5 +/- 11.1% to 96.8 +/- 1.5% (in 4 hours) and from 20.3 +/- 7.2% to 72.2 +/- 5% (in 5 hours). Other indices of functional recovery showed similar improved performance with the significant decrease in time from the onset of reperfusion to the return of regular sinus rhythm (57 +/- 8 v 495 +/- 150 s). The efflux of lactate during 5 hr ischaemic arrest was decreased (20.62 +/- 1.3 v 26.18 +/- 1.73 mumol/heart for oxygenated STH and STH, respectively, p < 0.05) and the progressive increase in the coronary vascular resistance was abolished in the oxygenated STH treated hearts. These improvements were associated with the reduction in the decline of the myocardial adenosine triphosphate (14.49 +/- 2 v 3.3 +/- 0.19 mumol/g dry wt), creatine phosphate (24.61 +/- 3.47 v 7.48 +/- 1.34 mumol/g dry wt) and guanosine triphosphate (1.69 +/- 0.2 v 0.84 +/- 0.08 mumol/g dry wt) during ischaemia, total resynthesis after reperfusion (ATP: 103% v 36%, CP: 105% v 69% and GTP: 203% v 61% of control) and the total absence of myocardial cells and microvasculature injuries in ischaemic (non-reperfused) hearts. These results confirm that the provision of additional oxygen to the St. Thomas' Hospital solution (with 95% O2:5% CO2) can meet the metabolic demand of the ischaemic myocardium and thus increase the safe duration of cardiac arrest.
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PMID:Protective effects of oxygenated St. Thomas' Hospital cardioplegic solution during ischaemic cardiac arrest: improved function, metabolism and ultrastructure. 828 49

Age-related differences in the activity of 5'-nucleotidase, an enzyme responsible for conversion of high-energy phosphates to their the diffusible precursors, may help to explain age-related differences in tolerance of global myocardial ischemia. Postischemic function and high-energy phosphate content were measured in the hearts of rabbits 7 to 10 days old (neonate), 30 to 40 days old (1 month), and 6 to 12 months old (adult). Hearts in each age group were subjected to 60 minutes of ischemia at 34 degrees C either with no cardioplegia, with unmodified St. Thomas' Hospital cardioplegic solution, or with St. Thomas' Hospital cardioplegic solution with pentoxifylline, a 5'-nucleotidase inhibitor. These groups were compared with one another and with control hearts that were continuously perfused for 1 hour. In adults, addition of pentoxifylline to St. Thomas' Hospital cardioplegic solution restored adenosine triphosphate and total nondiffusible nucleotide levels to control values and improved recovery of cardiac output and developed pressure compared with results with unmodified St. Thomas' Hospital cardioplegic solution. In contrast, biochemical and functional parameters in neonatal hearts were not affected by either unmodified St. Thomas' Hospital cardioplegic solution cardioplegia or St. Thomas' Hospital cardioplegic solution with pentoxifylline. Functional recovery in neonatal hearts subjected to unprotected ischemia was superior to that in the older age groups. In 1-month-old hearts, St. Thomas' Hospital cardioplegia improved recovery compared with recovery after unprotected ischemia, but no incremental improvement in function or high-energy stores was seen with addition of pentoxifylline. The lack of effect of pentoxifylline on neonatal hearts suggest that there is a relative deficiency of 5'-nucleotidase in this age group. This may contribute to the improved functional recovery observed in unprotected hearts. Furthermore, addition of pentoxifylline to adult hearts appears to confer the benefits of low 5'-nucleotidase activity occurring naturally in the neonate.
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PMID:Developmental differences in myocardial protection in response to 5'-nucleotidase inhibition. 830 72

Cardiopulmonary bypass causes a "euthyroid-sick" state characterized by low levels of circulating triiodothyronine. Triiodothyronine supplementation in this setting has been postulated to improve postischemic left ventricular function by increasing the availability of myocardial high-energy phosphates. These postulates have not been substantiated, however, using load-independent parameters of left ventricular function and analysis of high-energy phosphate metabolism. To test these hypotheses, 14 healthy pigs (30 to 40 kg) were placed on cardiopulmonary bypass and instrumented with left ventricular minor-axis ultrasonic crystals and micromanometer-tipped pressure catheters. Hearts were subjected to 30 minutes of global, normothermic ischemia. Triiodothyronine (0.1 mg/kg; n = 7) or placebo (n = 7) was administered in a random, investigator-blinded fashion at the removal of the aortic cross-clamp and after 60 minutes of reperfusion. Hemodynamic, metabolic, and ultrastructural data were obtained before ischemia and after 30, 60, 90, and 120 minutes of reperfusion. By 90 minutes of reperfusion left ventricular contractility had returned to preischemic levels in hearts supplemented with triiodothyronine, despite postischemic myocardial adenosine triphosphate levels of 50% to 60% of baseline in both groups. Ultrastructurally, the sarcoplasmic reticulum and mitochondria were significantly better preserved in the group treated with triiodothyronine. This study suggests that triiodothyronine supplementation significantly enhances postischemic left ventricular functional recovery and that this recovery is due to mechanisms other than enhanced availability of myocardial high-energy phosphates.
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PMID:Effects of triiodothyronine supplementation after myocardial ischemia. 834 1

We have studied the effects of adding 0.5 mmol/L CaCl2 to University of Wisconsin solution (0.08 mmol/L free Ca++) on hypothermic heart preservation. Isolated pig hearts were subjected to 8 hours of preservation at 12 degrees C; eight hearts were arrested with Ca++ free University of Wisconsin solution, and seven hearts were arrested with Ca(++)-containing University of Wisconsin solution. The recovery of contractile function was evaluated by measuring isovolumic ventricular pressure development. 31P nuclear magnetic resonance spectroscopy was used to monitor the changes in high-energy phosphates. Compared to the hearts arrested with the Ca(++)-free University of Wisconsin solution, the heart arrested with the Ca(++)-containing University of Wisconsin solution showed significantly improved (p < 0.001) contractile functional recovery. No "stone heart" or loss of high-energy phosphates was observed on reperfusion. The hearts showed an increase in diastolic pressure during infusion of the Ca(++)-containing University of Wisconsin solution, however, to show the relationship between the addition of calcium and the increase in diastolic pressure, a second protocol was performed. A 30-minute period of ischemia was induced in thirteen hearts that were arrested at 12 degrees C with either Ca(++)-containing University of Wisconsin solution (n = 8) or Ca(++)-free University of Wisconsin solution (n = 5). Diastolic pressure was monitored during ischemia while ventricular volume was maintained constant with a balloon. The hearts arrested with the Ca(++)-containing University of Wisconsin solution showed a mean rise of 5 mm Hg in diastolic pressure and a rapid decline of phosphocreatine (p < 0.001). Our results suggest that, although 0.08 mmol/L free Ca++ improves functional recovery after 8 hours of heart preservation with University of Wisconsin solution at 12 degrees C, it can increase diastolic pressure during ischemia and accelerate breakdown of the high-energy phosphate stores in the myocardium, suggesting that use of University of Wisconsin solution containing 0.5 mmol/L CaCl2 may result in a significant increase in the intracellular calcium level.
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PMID:The effects of Ca++ on the preservation of myocardial energy and function with University of Wisconsin solution. A 31P nuclear magnetic resonance study of isolated blood perfused Langendorff pig hearts. 844 6

Increased concentrations of intracellular H+, Na+, and Ca2+ have been observed during ischemia, and these ionic alterations have been correlated with several indexes of cell injury in a number of studies. Recently, adenosine was proposed to play a role in ischemic preconditioning, since adenosine antagonists block the protective effects of these brief intermittent periods of ischemia and reflow. In this study we evaluated the protective effects of adenosine (20 microM) on high-energy phosphate metabolism, H+ and Ca2+ accumulation, and glycolytic rate during 30 min of no-flow ischemia. Adenosine was observed to slow the onset of contracture (7.0 +/- 0.9 min) and to improve left ventricular developed pressure (62 +/- 7% of initial) during reperfusion compared with untreated hearts (5.0 +/- 0.6 min and 18 +/- 5%, respectively). Intracellular Ca accumulation at the end of 30 min of ischemia was higher in the untreated (2,835 +/- 465 nM) than in the adenosine-treated (2,064 +/- 533 nM) hearts, while intracellular pH fell more in the untreated (5.85 +/- 0.17) than in the adenosine-treated hearts (6.27 +/- 0.16). Glycolytic rate and the rate of ATP decline were significantly attenuated in the adenosine-treated hearts during ischemia. Thus adenosine treatment slowed the rate of metabolism and delayed the accumulation of H+ and Ca2+ during ischemia, resulting in better recovery of function upon reflow.
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PMID:Protective effects of adenosine in the perfused rat heart: changes in metabolism and intracellular ion homeostasis. 847 25

Effect of verapamil post-treatment (0.2 mg/kg bolus, followed by 0.01 mg/kg/min infusion) on the functional and metabolic changes of the heart after a brief regional ischemia (20 min) followed by 1 hr of reperfusion was studied in open-chest pentobarbitone anaesthetized dogs. In control dogs 1 hr of reperfusion failed to cause any improvement of depressed myocardial contractility (LVdP/dtmax and LVEDP) caused by 20 min of ischemia, which confirmed the earlier reported phenomenon of 'Stunned Myocardium'. Myocardial ischemia caused a significant loss of high-energy phosphate (HEP) content of the affected myocardium (ATP decreased by 60% and CP decreased by 75% of non-ischemic level). Following 1 hr of reperfusion, myocardial ATP was not replenished, though creatine phosphate became near normal. When verapamil was administered just before reperfusion, it showed a profound beneficial effect on the incidence of fatal reperfusion arrhythmias. At the end of 1 hr of reperfusion in this group, the recovery of the myocardial contractility was incomplete, but a significant replenishment of the myocardial HEP content was observed. Thus verapamil post-treatment can prevent reperfusion-induced myocardial injury but functional recovery may be delayed due to the drug's inherent direct myocardial depressant effect.
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PMID:Effect of verapamil post-treatment in myocardial reperfusion injury. 850 Aug 27

Human cardiac valves are increasingly used in the reconstruction of ventricular outflow tracts and offer performance advantages over porcine and mechanical prostheses; the durability of these replacements has been associated with leaflet interstitial cell viability and a presumed sustained function after implantation. Preimplantation tissue preparation entails sequential steps that are potentially cytotoxic and may therefore affect functional cell survival at thaw. We defined the metabolic consequences of each interval using semilunar cusps from 118 porcine valves to model a homograft preparation with 40 minutes of fixed cadaveric (harvest) ischemia. Fifty-eight valves served as controls and were first processed according to standard cryopreservation protocol; nucleosides were extracted at the end of each step to differentiate independent contributions to high-energy phosphate depletion. Sixty simultaneously harvested leaflets were administered the nucleoside transport inhibitor p-nitrobenzy-thionosine (NBMPR) and the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) at procurement, to attempt adenosine salvage and restitution of processing-incurred adenine nucleotide losses. High-performance liquid chromatography was used to compare adenosine triphosphate, diphosphate, and monophosphate and diffusible nucleopurines of the control and EHNA/NBMPR-treated groups. Control results indicate that disruption of the adenosine triphosphate-diphosphate cycle occurs independently with antibiotic disinfection and cryopreservation. However, throughout all preparation steps, adenine nucleotides were maintained at harvest (baseline) concentrations in the EHNA/NBMPR valves. This suggests that salvage therapy may protect a significant number of cells from net high-energy phosphate catabolism. If, with further study, the durability of transplanted valves is concluded to benefit from retained leaflet interstitial cell viability, such enhancement of metabolic tolerance to the obligatory processing may facilitate functional recovery.
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PMID:Inhibition of adenosine deaminase and nucleoside transport. Utility in a model of homograft cardiac valve preimplantation processing. 850 37

Myocardial ischemia has traditionally been viewed as an imbalance between energy supply and demand. Within the first few seconds following an acute reduction of myocardial blood flow, energy demand of the hypoperfused myocardium clearly exceeds the reduced energy supply. However, this imbalance between energy supply and demand is an inherently unstable condition since ischemia induces mechanisms which are not yet understood, but reduce contractile function and thus energy demand. In the subsequent steady-state condition, the amount of contractile dysfunction is in proportion to the reduction of myocardial blood flow. A situation of persistent ischemic contractile dysfunction in viable myocardium which normalizes upon reperfusion has been termed myocardial hibernation. The metabolic status of such hibernating myocardium improves over the first few hours as myocardial lactate production is attenuated and creatine phosphate, after an initial reduction, returns towards control values. The hibernating myocardium can respond to an inotropic stimulation by dobutamine with increased contractile function, however, at the expense of a renewed worsening of the metabolic status. This situation of an increased regional contractile function at the expense of metabolic recovery during inotropic stimulation can be used to identify hibernating myocardium. The development of such delicate balance between regional myocardial blood flow and function during early ischemia is disturbed by unfavorable alterations in supply and demand. When after 5 min of ischemia, at a blood flow reduction compatible with the development of myocardial hibernation over 90 min, energy supply is further reduced by a further reduction of myocardial blood flow, necroses develop. Likewise, increasing energy demand by continuous inotropic stimulation with dobutamine induces necroses. Thus, both the further reduction in energy supply by an increasing severity of ischemia and an enhanced energy expenditure by continuous inotropic stimulation impair the development of myocardial hibernation and precipitate myocardial infarction. Hibernation over the first few hours of ischemia (short-term hibernation) is well characterized in animal experiments. Increased release of endogenous adenosine and activation of ATP-dependent potassium channels as the underlying mechanisms have been ruled out. The existence of hibernation over weeks or months (long-term hibernation) can only be inferred from clinical studies. In long-term hibernating myocardium morphological alterations occur. In myocardial biopsies from patients with prolonged contractile dysfunction which was reversible after bypass surgery, myofibrils are reduced in number and disorganized. Myocardial glycogen content as well as the extracellular collagen network are increased. Thus, despite the fact that the myocardium remains viable during persistent ischemia and contractile dysfunction is reversible upon reperfusion, there are severe morphological alterations. Understandably, full functional recovery following reperfusion can therefore require weeks or even months.
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PMID:[Pathophysiology of the "hibernating" myocardium]. 858 79


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