Biomedical subjects

C Ceconi

Publications and source records attributed to C Ceconi.

118 records · Page 7Linked to original sources

PubMed1984

Reversible and irreversible ischaemic damage: importance of energy metabolism.

In this study the effects of different degrees and duration of coronary flow reduction on pressure development of the isolated and perfused rabbit hearts has been studied. Three different degrees of ischaemia lasting for 30, 60 and 90 minutes have been investigated, after which the effects of post-ischaemic reperfusion have been followed. The effects of substituting FFA for glucose as myocardial substrate has also been investigated. Reperfusion resulted in a recovery of mechanical function or in a further worsening of mechanical function, depending upon the degree, duration of flow reduction and substrate employed. To establish the causes of reperfusion damage, in a separate series of experiments the effects of reperfusion after 90 minutes of severe ischaemia on lactate, CPK and Mg++ release, tissue and mitochondrial calcium content tissue ATP and CP concentration and mitochondrial function have been determined. The ultrastructural damage of the myocardial cell have also been established. The results obtained suggest that mitochondria play an important role in reperfusion damage.

Adenosine Triphosphate↗

PubMed1983

Effect of superoxide generation on rat heart mitochondrial pyruvate utilization.

Previous research has shown that heart mitochondria are able to produce reactive species of oxygen such as superoxide radicals, hydrogen peroxide and hydroxyl radicals [10, 11]. When these compounds are formed beyond a certain level they are not completely removed by the enzymatic and metabolic processes which neutralize their toxicity, and as a result they are able to produce structural and functional damages that impair mitochondrial function [5, 10]. In order to study the molecular mechanism/s by which the oxygen radicals may function as mediators of cellular injury a flow of these radicals by chemical, enzymatic or photochemical methods has been generated in vitro in the presence of cellular preparations. For example, the exposure of isolated subcellular particles to the enzymatic flow of oxygen radicals produced by the reaction of xanthine oxidase upon xanthine reduced both calcium uptake velocity and Ca2+-ATPase activity in sarcoplasmic reticulum [7], while it reduced Ca2+-stimulated ATPase activity in myofibrillar preparations [4]. In addition, incubation with the xanthine oxidase reaction produced an impairment of the respiratory functions associated with an increased lipid peroxidation in the isolated mitochondria [5, 10]. These negative effects were augmented in alpha-tocopherol-deficient mitochondria [3], but were opposed by the exogenous addition of superoxide dismutase [10]. This report shows that the superoxide radicals generated by the xanthine oxidase reaction reduced rat heart mitochondrial respiration induced by pyruvate. This negative effect was partially prevented by superoxide dismutase and catalase and by thiol protecting agents. Moreover, the generation of free radicals caused a significant reduction in the rate of (1-14C) -pyruvate decarboxylation, while it did not change the transport of pyruvate into mitochondria.

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PubMedDate not supplied

Protective effect of propionyl-L-carnitine against ischaemia and reperfusion-damage.

Reperfusion of isolated rabbit heart after 60 min of ischaemia resulted in poor recovery of mechanical function, release of reduced (GSH) and oxidized glutathione (GSSG), reduction of tissue GSH/GSSG ratio and shift of cellular thiol redox state toward oxidation, suggesting the occurrence of oxidative stress. Pretreatment of the isolated heart with propionyl-L-carnitine (10(-7) M) improved the functional recovery of the myocardium, reduced GSH and GSSG release and attenuated the accumulation of tissue GSSG. This effect was specific for propionyl-L-carnitine as L-carnitine and propionic acid did not modify myocardial damage.

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PubMedDate not supplied

Relation between energy metabolism, glycolysis, noradrenaline release and duration of ischemia.

We studied the effect of 12-36 min of global ischemia followed by 36 min of reperfusion in Langendorff perfused rabbit hearts (n = 26). Metabolism was determined in terms of peak and total release of purines (adenosine, inosine, hypoxanthine), lactate and noradrenaline during reperfusion; and myocardial content of nucleotides (ATP, ADP, AMP), glycogen and noradrenaline at the end of reperfusion. An inverse relationship (r = -0.79) existed between duration of ischemia and developed pressure post-ischemia. Early during reperfusion, after 12 min of ischemia, the purine concentration (peak release) increased 100x (p < 0.01), that of lactate and noradrenaline 10x (p < 0.05). Total purine release rose with progression of the ischemic period (30x after 36 min of ischemia; p < 0.01), concomitant with a reduction in nucleotide content. Lactate release was independent from the duration of ischemia, although glycogen had declined by 30% (p < 0.01) after 36 min of ischemia. The acid insoluble glycogen fraction, which presumably contains proglycogen, increased substantially during short-term ischemia. Peak noradrenaline increased 100x, and 200x, (p < 0.05) after 24 and 36 min of ischemia, respectively. Total noradrenaline release due to various periods of ischemia mirrored its peak release. Function recovery was inversely related to total purine and noradrenaline efflux (both r = -0.81); it correlated with tissue nucleotide content (r = 0.84). In conclusion, larger amounts of noradrenaline are released only after a substantial drop in myocardial ATP. During severe ischemia ATP consumption more than limited ATP production by anaerobic glycolysis, is a key factor affecting recovery on subsequent reperfusion. In contrast to lactate efflux, purine and noradrenaline release are useful markers of ischemic and reperfusion damage.

Adenosine↗

PubMedDate not supplied

Effect of D-600 on ischemic and reperfused rabbit myocardium: relation with timing and modality of administration.

In this study we have investigated the possibility that D-600, a phenylalkylamine calcium antagonist, protects the isolated rabbit heart against ischemia and reperfusion-induced damage. D-600 was either subcutaneously injected (2mg/kg, twice daily for 5 to 6 days) in the rabbit before isolation of the heart, or delivered to the isolated hearts in the perfusate (10(-7) M), either at the onset of ischemia and during reperfusion, or only during post-ischemic reperfusion. Ischemia (90 min) was induced by reducing coronary flow from 25 to 1 ml/min, followed by 30 min of reperfusion. Myocardial damage was determined in terms of mechanical function, release of creatine phosphokinase (CPK) and noradrenaline, mitochondrial function, calcium homeostasis, and endogenous stores of ATP and creatine phosphate (CP). Administration of D-600 to the rabbits or to the isolated hearts at the time of ischemia exerted protection. There are four groups of evidence in support of this conclusion: 1) the rise in diastolic pressure during ischemia was diminished with greater recovery of developed pressure during reperfusion; 2) CPK and noradrenaline release during reperfusion were reduced; 3) the oxygen consumption and ATP generating capacities of mitochondria were better maintained; and 4) associated with this preservation of mitochondrial function was the maintenance of near normal calcium homeostasis and of endogenous ATP and CP stores. The two different modalities of administration did not produce substantially different results. When administered to the isolated hearts after the ischemic period, D-600 failed to improve mechanical recovery and release of endogenous substances. However, it reduced mitochondrial calcium overload and improved ATP production. The mechanism of the protective effect of D-600 seems to be multiple: energy-sparing effect, reduction of the toxicity mediated by endogenous catecholamines, and direct inhibition of mitochondrial calcium transport.

Adenosine Triphosphate↗

PubMedDate not supplied

No evidence of oxygen free radicals-mediated damage during the calcium paradox.

Reperfusion of an isolated mammalian heart with a calcium-containing solution after a brief calcium-free perfusion results in irreversible cell damage: the calcium paradox. We investigated whether the calcium paradox is associated with oxidative damage. We measured the tissue changes of glutathione status and the release of oxidized glutathione from isolated perfused rabbit hearts as indicators of cellular oxidative events. After 10 min of calcium-free perfusion, tissue content of reduced (GSH) and oxidized (GSSG) glutathione, and of protein and non-protein sulfhydryl groups were not significantly different from control values. Restoration of the calcium concentration resulted in an immediate and massive release of GSH and a depletion of tissue content of GSH, GSSG, and non-protein sulfhydryl groups. However, only a minimal release of GSSG into the coronary effluent was observed. In addition, the characteristic features of the calcium paradox were present: development of an irreversible contracture and massive release of creatine kinase. The calcium paradox did not lead to a decrease of the tissue content of protein sulfhydryl groups. These observations indicate that the calcium paradox is not associated with oxidative damage.

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PubMedDate not supplied

Tumor necrosis factor in congestive heart failure: a mechanism of disease for the new millennium?

Tumor necrosis factor alpha (TNF-alpha), a protein belonging to the family of cytokines, is one of the leading mediators of the immune response to inflammation. Its widespread biological effects are modulated by two circulating binding proteins corresponding to the extracellular domain of the membrane receptors, namely soluble TNF receptors. TNF-alpha was first supposed to be linked with congestive heart failure (CHF) on a cachexia-inducing basis. In patients with advanced CHF, elevated levels of circulating TNF-alpha and soluble TNF receptors have been found. The pathophysiological implications of activation of the TNF system in CHF seem to rely mainly on its effects on the heart and the endothelium. TNF-alpha exerts a negative inotropic effect both directly and indirectly, this latter being mediated by enhancement of nitric oxide production. Moreover, TNF-alpha has been suggested to trigger the apoptotic process in cardiac myocytes. There is consensus on the detrimental role played by TNF-alpha in CHF further supported by the evidence of a temporal association between TNF activation and transition from asymptomatic to symptomatic CHF.

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PubMedDate not supplied

Superoxide dismutase: possible therapeutic use in cardiovascular disease.

Superoxide dismutase (SOD) for parenteral administration is in clinical use in several European countries, where it is prescribed principally for treatment of musculoskeletal inflammation, especially osteoarthritis. However, new possibilities for its usefulness are arising from recent progresses of the pathophysiology of several diseases. From the beginning of this decade there has been a virtual explosion of the available informations about the mechanisms and control of free radical-mediated tissue injury. This progress has led us to the threshold of what will probably be broad clinical applications in the next future. Taking into account the mortality and morbidity caused by cardiovascular injury, the most promising application of SOD in human therapy seems to relay in the protection against ischaemia and post-ischaemic reperfusion damage of various organs and tissues but, particularly, of the myocardium. A large body of evidence suggests that myocardial damage following both global or regional ischaemia can be ameliorated by the blockade of free radical mediated injury. SOD has been proposed as a protective agent in various experimental models. The premises of this action, and the available results will be reviewed.

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PubMedDate not supplied

Long-term changes in left ventricular mass, chamber size and function after valve replacement in patients with severe aortic stenosis and depressed ejection fraction.

We studied 21 patients undergoing valve replacement for severe aortic stenosis and marked left ventricular dysfunction (mean ejection fraction 27 +/- 7.9%) without significant coronary disease or other valve diseases. At 5-60 months (average 26 +/- 18) after surgery, the patients underwent a clinical history, physical examination and a complete M-mode, two-dimensional and Doppler transthoracic echocardiographic study. Thirteen patients were examined with cardiopulmonary exercise testing. Two patients with a low preoperative transvalvular pressure gradient (<50 mm Hg) died postoperatively. Nineteen patients were tested at follow-up. All patients showed an improvement in functional class, an increase in ejection fraction (EF), a normalization in left ventricular diameters, volumes and stress indices and a reduction in left ventricular mass which correlated with EF increase. Cardiopulmonary exercise testing showed a good exercise capacity. In conclusion, in patients affected by severe aortic stenosis and marked preoperative left ventricular dysfunction valve replacement induces a favorable remodeling of the left ventricle, as shown by a late postoperative examination. The regression of hypertrophy is a positive event which correlates with the improvement in EF.

Aged↗

PubMedDate not supplied

[New findings on calcium antagonism].

The family of calcium antagonist substances is continuously increasing. Often it is difficult, if not impossible, to have clear, objective criteria to differentiate between the available molecules. We have considered some molecular aspects of calcium channels and of the effects of calcium antagonists which may be relevant for the clinical utilization of these drugs. In particular, differences between L and T type of calcium channels in the myocytes and between VOC and ROC calcium channels in the smooth muscle are described. Then we have considered the main differences in the mechanism of action and clinical use of the three prototypes of calcium antagonists: phenilalkilamines, dihydropyridines and benzothiazepines. Finally, we have synthetically depicted the characteristic of the second generation agents such as nisoldipine, amlodipine, felodipine, isradipine, lacidipine and gallopamil.

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