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 cardioprotective effects of mioflazine, a recently developed cardiovascular drug, were investigated in 41 anaesthetised open chest Beagle dogs subjected to 1 h normothermic global myocardial ischaemia. The severity of the model is evidenced by the finding that only one out of 20 control dogs could be weaned from extracorporeal bypass. Oral pretreatment with mioflazine (2.5 mg X kg-1) resulted in complete functional recovery in 17 out of 20 animals. Biochemical analysis of left ventricular biopsies taken before, during and after aortic cross clamping showed a preservation of purines and a better recovery of ATP, ATP/ADP X Pi ratio and energy charge (p less than 0.05) in the pretreated animals. Morphological and cytochemical assessment of the myocardium demonstrated that the ultrastructure of the sarcolemma and its calcium binding capacity is remarkably well preserved in the drug treated animals. These results indicate a strong cardioprotective effect of mioflazine. The biochemical, cytochemical and ultrastructural findings suggest an interaction of the drug with the sarcolemma.
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PMID:Cardioprotective effects of mioflazine during 1 h normothermic global ischaemia in the canine heart. 646 70

The degradation of adenine nucleotide levels and impairment of functional recovery associated with exposure to hypothermic (20 degrees C) cardioplegia was studied in 84 isolated working rat hearts. After a 1-hour control period, hearts were exposed to 1 hour of cardioplegia that consisted of increasingly longer periods of cardioplegic solution (CPS) infusion (30 seconds and 10, 30 and 60 minutes), followed by increasingly shorter periods of global ischemia (591/2 minutes and 50, 30 and 0 minutes). Hearts were then reperfused for 1 hour with control perfusate, during which recovery of cardiac output was monitored. Additional hearts were freeze-clamped at various points in the protocols to determine adenine nucleotide levels (ATP, ADP, AMP and their sum TAN). Exposure to increasingly longer periods of CPS perfusion resulted in proportionally greater degradation of nucleotides and poorer recovery of cardiac output. Addition of inosine to the recovery perfusate as well as the CPS further improved nucleotide levels and recovery of cardiac output. These results suggest that washout of nucleotide degradation products in the CPS or reperfusion prevents their salvage for nucleotide resynthesis and impairs functional recovery from cardioplegia.
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PMID:Nucleotide degradation and functional impairment during cardioplegia: amelioration by inosine. 684 95

The calcium channel blocker, diltiazem, has been studied in the same model used for evaluation of cold blood-potassium cardioplegia. Six dogs (Group 1) had one hour of myocardial ischemia with topical ice (myocardial temperature, 7 degrees +/- 2 degrees C) after coronary perfusion with 200 ml of cold blood (5 degrees +/- 1 degree C) containing diltiazem, 400 micrograms per kilogram of body weight. Seven dogs (Group 2) had two hours of ischemia after perfusion with 200 ml of cold blood containing 200 micrograms/kg and reperfusion every 30 minutes with 100 ml of cold blood and diltiazem, 100 micrograms/kg. Baseline studies were repeated after rewarming and 40 minutes of reperfusion. No inotropic agents or calcium were used. Heart rate, peak systolic pressure, velocity of the contractile element, peak + rate of rise of left ventricular pressure (dP/dt), peak - dP/dt, dP/dt over common peak isovolumic pressure, left ventricular compliance and stiffness, and heart water were unchanged in Group 1. In Group 2, heart rate slowed (p less than 0.025) and compliance decreased (p less than 0.02). In both groups, coronary vascular resistance declined (p less than 0.001) and recovery of adenosine triphosphate (p less than 0.001), adenosine diphosphate (p less than 0.025), and the adenosine pool (p less than 0.001) was impaired. Ultrastructure was well preserved, but myofibrillar lesions were noted in Group 2. Diltiazem cardioplegia was associated with good functional recovery, but there was impairment of high-energy phosphate metabolism.
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PMID:Cold blood-diltiazem cardioplegia. 706 65

Isolated working rat heart preparations were used to ascertain whether the addition of adenosine and prevention of its catabolism could aid in the functional recovery of hearts following global ischemia. Hearts were infused with either 80 micro M EHNA (an adenosine deaminase inhibitor) or 20 micro M adenosine and EHNA in either normal (2.4 mM) or low (0.05 mM) calcium-containing buffer prior to clamping of the aorta for 30 minutes. In one series of hearts, postischemic concentrations (mumoles/gram wet weight) of adenosine triphosphate (ATP), diphosphate (ADP), and monophosphate (AMP), adenosine, inosine, and hypoxanthine were measured; in another series, the recovery of aortic flow rate was used as a measure of functional recovery of ventricular muscle. With normal electrolyte balance, EHNA was unable to protect hearts against ATP loss and ventricular failure. Hearts with EHNA + adenosine recovered 14% of preischemic aortic output and ATP levels were slightly elevated at 0.93 mumole/gm. Those treated with either EHNA or EHNA + adenosine in low-calcium buffer recoverd 100% of their original aortic output. However, EHNA + adenosine maintained considerably higher ATP levels (1.57 mumoles/gm) than did EHNA alone (1.14 mumoles/gm) and was associated with faster initial recovery of aortic output. Thus the prevention of adenosine catabolism was insufficient for adequate ventricular recovery unless the tissue ATP was maintained above about 1.0 mumole/gm. EHNA + adenosine in a 0.05 mM Ca++ infusion solution conserved ATP, markedly improved the functional recovery of hearts, and thus may have a role to play in myocardial preservation during elective cardiac arrest.
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PMID:Improved functional recovery of ischemic myocardium by suppression of adenosine catabolism. 708 38

Reperfusion following a period of ischemia can salvage the myocardium only if the ischemic episode has not exceeded a certain time limit; beyond this point damage becomes irreversible. A key feature of the transition from reversible to irreversible injury is mitochondrial dysfunction which may involve the opening of a non-specific pore in the mitochondrial inner membrane. Pore opening can be induced in vitro by exposure of isolated mitochondria to high [Ca2+] and Pi. Such pore formation is sensitized by adenine nucleotide depletion and oxidative stress and can be blocked by the immunosuppressant cyclosporin A. Here we show that in isolated perfused rat hearts subjected to 30 min ischemia and 15 min reperfusion, 0.2 microM cyclosporin A restored the ATP/ADP ratio and AMP content (decreased and increased respectively during ischemia) to pre-ischemic values. In separate experiments functional recovery was assessed by monitoring the restoration of left ventricular developed pressure (LVP) during reperfusion after 30, 40 or 45 min ischemia. LVP was substantially improved in the presence of 0.2 microM cyclosporin A but did not return to pre-ischemic levels. The cyclosporin analogues G and H were less effective than cyclosporin A in protecting the heart during reperfusion. This is consistent with their reduced ability to protect isolated mitochondria from damage caused by Ca2+ overload. Surprisingly, reperfusion of hearts with 1 microM cyclosporin A reversed the protective effect seen at 0.2 microM.
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PMID:Protection by Cyclosporin A of ischemia/reperfusion-induced damage in isolated rat hearts. 751 54

Isolated rat hearts can be protected by preconditioning, although this has not been found when they are perfused with pyruvate. We addressed the question of whether pyruvate could increase the threshold for preconditioning in isolated rat hearts and whether this could be overcome with increased durations of ischemia. A protocol of four periods of 5 min of ischemic preconditioning (4 x 5 min) protected hearts (improved recovery of function, reduced lactate dehydrogenase release) not perfused with pyruvate from a subsequent 30-min period of global ischemia, but did not protect pyruvate-perfused hearts. Pilot studies indicated that hearts perfused in the presence of pyruvate must be ischemic for approximately 40% longer to produce equivalent ischemic damage in nonpyruvate-treated hearts. Thus the preconditioning period of 5 min was increased by approximately 40% to 7 min to produce equivalent degrees of preconditioning. Hearts preconditioned with the 4 x 7 min protocol with pyruvate were significantly protected against a subsequent severe global ischemia (enhanced recovery of function, reduced lactate dehydrogenase release). High-energy phosphates were measured at the end of the preconditioning protocol (before final global ischemia) to determine whether there was a correlation between cardioprotection and high-energy phosphate levels. There was no correlation between ATP, ADP, or AMP levels and the efficacy of preconditioning. However, an increase in creatine phosphate was associated with cardioprotection, although the importance of this in mediating preconditioning is doubtful. Thus the ability to precondition rat hearts is somewhat dependent on their energy source, but this appears to be due to changes in the severity of the ischemic preconditioning event.
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PMID:Pyruvate increases threshold for preconditioning in globally ischemic rat hearts. 794 85

This study examined the effect of different sodium concentrations in a nondepolarizing solution on myocardial viability and functional recovery of the canine donor heart. Isolated canine hearts were preserved for 6 h at 5 degrees C, followed by normothermic reperfusion for 2 h. Dogs were divided into two groups of nine dogs each: group 1 received a nondepolarizing solution with 70 mM Na+ and group 2 with 30 mM Na+. The myocardial Ca2+ concentration at the end of preservation was significantly higher in group 1 than in group 2 and increased after reperfusion in both groups without any intergroup difference. Myocardial concentrations of ATP, ADP, and total adenine nucleotide at the end of reperfusion were significantly higher in group 1 than in group 2. Myocardial cyclic adenosine monophosphate concentration was significantly higher in group 1 than in group 2 at the end of both preservation and reperfusion. The myocardial cyclic guanosine monophosphate concentration in group 1 increased and was higher than in group 2 at the end of preservation, but had returned to normal levels by the end of reperfusion. However, it remained unchanged through preservation and reperfusion in group 2. The left ventricular systolic and diastolic function, assessed by pressure-volume relationship, was better in group 1 than in group 2. Mitochondrial ultrastructural changes were similar. These results suggest that a nondepolarizing solution containing 70 mM Na+ provides better myocardial protection than a solution containing 30 mM Na+.
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PMID:The effect of sodium concentration on myocardial viability in donor heart preservation using a nondepolarizing solution. 817 98

During induced ischemia for cardiac surgery, 5'-nucleotidase (5NT) catalyzes nucleotide breakdown by dephosphorylating AMP and IMP to diffusible precursors--adenosine and inosine. These precursors become unavailable upon reperfusion washout limiting nucleotide resynthesis, resulting in poor postischemic function. Neonatal hearts, which are more resistant to ischemia than adults, have low 5NT activity, trapping available precursors. Adult rabbit hearts given cardioplegia with a 5NT inhibitor, pentoxifylline, demonstrated improved postischemic contractility, compliance, and myocardial oxygen consumption after 120 min of 34 degrees C ischemia. To determine if this improved function was a result of enhanced nucleotide precursor availability during or following ischemia, total nondiffusible nucleotides, ATP, ADP, AMP, and IMP, and total diffusible nucleotides, adenosine, inosine, hypoxanthine, and xanthine, were measured by HPLC at end ischemia, 1 and 15 min after reperfusion. While all preischemic values were equivalent, pentoxifylline-treated hearts had significantly greater total non-diffusible nucleotides at end ischemia, 1 and 15 min after reperfusion. Additionally, pentoxifylline-treated hearts had significantly greater total diffusible nucleosides at end ischemia and 1 min after reperfusion, but were equal to control at 15 min after reperfusion. Furthermore, coronary sinus effluent had a significantly higher release of total diffusible nucleosides in control vs pentoxifylline-treated hearts. The data indicate that precursor trapping with pentoxifylline prevented nucleotide catabolism to diffusible precursors and enhanced postischemic nucleotide availability. We postulate the increased precursor availability augmented myocardial nucleotide resynthesis and correlated with the improved functional recovery noted. This strategy may have application in adult cardiac surgery.
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PMID:Precursor trapping: a "neonatal" mechanism of myocardial protection. 841 63

Six per cent of rat pheochromocytoma (PC12) cells extended neurites (processes greater than one cell diameter in length) in the presence of 300 microM extracellular GTP or 300 microM guanosine for 48 hr, compared to only 2.5% of cells in control cultures. In the presence of 40 ng/ml of 2.5S NGF, about 20-35% of PC12 cells had neurites after 48 hr, and the addition of 300 microM guanosine or GTP together with NGF synergistically increased the proportion of cells with neurites to 40-65%. GTP and guanosine also increased the average number of branches per neurite, from 0.6 in NGF-treated cultures to 1.2 (guanosine) or 1.5 (GTP). Neurites formed after exposure to NGF alone had axonal characteristics as determined by immunocytochemistry with antibody, SMI-31, against axonal-specific polyphosphorylated neurofilament epitopes. Neurites generated with the addition of both guanosine or GTP had the same characteristics. GTP probably did not exert its effects via the P2X or P2Y purinoceptors because the adenine nucleotides ATP, ATP gamma S, ADP beta S, and ADP, which are all agonists of these receptors, inhibited rather than enhanced, NGF-induced neurite outgrowth. UTP also enhanced the proportion of cells with neurites, although not to the same degree as did GTP. This may indicate activity through a P2U-like nucleotide receptor. However, the response profile obtained, GTP > UTP >> ATP, does not fit the profile of any known P2Y, P2X or P2U receptor. The poorly hydrolyzable GTP analogues, GTP gamma S and GDP beta s were also unable to enhance the proportion of cells with neurites. This implied that GTP may produce its effects through a GTP-specific ectoenzyme or kinase. This idea was supported by results showing that another poorly hydrolyzable analogue, GMP-PCP, competitively inhibited the effects of GTP on neurite outgrowth. GTP did not exert its effects after hydrolysis to guanosine since the metabolic intermediates GDP and GMP were also ineffective in enhancing the proportion of cells with neurites. Moreover, the effects of GTP and guanosine were mutually additive, implying that these two purines utilized different signal transduction mechanisms. The effects of guanosine were not affected by the nucleoside uptake inhibitors nitrobenzylthioinosine (NBTI) and dipyridamole, indicating that a transport mechanism was not involved. Guanosine also did not activate the purinergic P1 receptors, because the A2 receptor antagonists, 1,3-dipropyl-7-methylxanthine (DPMX) or CGS15943, and the A1 receptor antagonist, 1,3-dipropyl-8-(2-amino-4-chloro)xanthine (PACPX) did not inhibit its reaction. Therefore guanosine enhanced neurite outgrowth by a signal transduction mechanism that does not include the activation of the P1 purinoceptors. The enhancement of the neuritogenic effects of NGF by GTP and guanosine may have physiological implications in sprouting and functional recovery after neuronal injury in the CNS, due to the high levels of nucleosides and nucleotides released from dead or injured cells.
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PMID:GTP and guanosine synergistically enhance NGF-induced neurite outgrowth from PC12 cells. 877 5

This study was aimed at evaluating the nature of the early mitochondrial alterations in isolated perfused rat hearts subjected to ischemia (37 degrees C, 0.1 ml/min, 15 or 30 min) and reperfusion (10 min). The functional variables of isolated perfused hearts were continuously evaluated, and the mitochondrial respiration variables were determined at the end of protocol on cardiac permeabilized fibers. In a parallel series of experiments, the myocardial contents of inorganic phosphate (Pi), phosphocreatine (PC) and ATP were monitored by means of P-31 NMR spectroscopy for the 15-min ischemia group. Severe mitochondrial alterations were detected in the 30-min ischemia group: decrease of maximal respiration rate and apparent Km for ADP, loss of the stimulatory effect of creatine (Cr) and disruption of the outer membrane. The functional recovery was no more than 10% of the pre-ischemic value. In contrast, in the 15-min ischemia group, only the stimulatory effect of Cr on respiration was significantly decreased. On reperfusion, a restoration of pre-ischemic levels of Pi and PC and a stabilization of the ATP content were observed, demonstrating the establishment of an energy balance steady state. The functional recovery was 76% of pre-ischemic value. We conclude that the alterations related to energy production control (by ADP and Cr) and to energy transfer are the earliest damages to mitochondrial function during ischemia. In spite of a preserved capacity for ATP production, these alterations, which persist on reperfusion, could be responsible for an altered responsiveness of the mitochondrial function to energy demand.
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PMID:Early alteration of the control of mitochondrial function in myocardial ischemia. 944 45


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