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R Ferrari

Publications and source records attributed to R Ferrari.

At least 253 records · Page 14Linked to original sources
PubMed1993

Myocardial damage during ischaemia and reperfusion.

Reperfusion, without doubt, is the most effective way to treat the ischaemic myocardium. Late reperfusion may, however, cause further damage. We attempted to identify the nature and time-course of metabolic changes occurring during ischaemia followed by reperfusion either in isolated and perfused rabbit hearts or in coronary artery disease (CAD) patients undergoing intracoronary thrombolysis or aortocoronary bypass grafting. In isolated hearts, reperfusion after prolonged ischaemia causes exacerbation of cell damage, leading to a breakdown of the permeability barrier of ions as well as of larger molecules, such as creatine phosphokinase. As consequence, reperfusion results in a large increase in intracellular calcium, leading to mitochondrial calcium overload with subsequent damage to the mitochondrial structure and loss of the ability to produce adenosine triphosphate (ATP). The ultimate mediator of the membrane damage is not known. It has been suggested that myocardial production of oxygen free radicals above the neutralizing capacity of the myocytes is an important cause of reperfusion damage. There is evidence that prolonged ischaemia reduces the naturally occurring defence mechanisms of the heart against oxygen free radicals, particularly mitochondrial manganese superoxide dismutase, and the intracellular pool of reduced glutathione. Consequently, reperfusion results in severe oxidative damage, as evidenced by tissue accumulation and release of oxidized glutathione. An oxygen free radical-mediated impairment of mechanical function also occurs during reperfusion of the human heart. During surgical reperfusion of CAD patients, we observed a prolonged and sustained release of oxidized glutathione; the degree of oxidative stress can inversely correlated with recovery of mechanical and haemodynamic function.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Pathogenesis of oedema in chronic severe anaemia: studies of body water and sodium, renal function, haemodynamic variables, and plasma hormones.

BACKGROUND: Patients with chronic severe anaemia often retain salt and water. Fluid retention in these patients is not caused by heart failure and the exact mechanisms remain unclear. This study was designed to examine some of the possible mechanisms. METHODS AND RESULTS: Haemodynamic variables, body fluid compartments, renal function, and plasma hormones were measured in four patients with oedema caused by chronic severe anaemia (mean (SE) haematocrit 13 (1.7)) who had never received any treatment. Cardiac output was increased (6.1 (0.6) l/min/m2) and right atrial (7.8 (1) mm Hg), mean pulmonary arterial (20.5 (2.0) mm Hg), and mean pulmonary arterial wedge (13 (2.7) mm Hg) pressures were slightly increased. The mean systemic arterial pressure (81 (1.3) mm Hg) and systemic vascular resistance (12.3 (1.1) mm Hg x min x m2/l were low. There were significant increases in total body water (+14%), extracellular volume (+32%), plasma volume (+70%), and total body exchangeable sodium (+30%). Renal blood flow was moderately decreased (-46%) and the glomerular filtration rate was slightly reduced (-24%). There were significant increases in plasma noradrenaline (2.1-fold), renin activity (15-fold), aldosterone (3.2-fold), growth hormone (6.3-fold), and atrial natriuretic peptide (12-fold). CONCLUSION: In patients with oedema caused by chronic severe anaemia there is retention of salt and water, reduction of renal blood flow and glomerular filtration rate, and neurohormonal activation similar to that seen in patients with oedema caused by myocardial disease. However, unlike patients with myocardial disease, patients with anaemia have a high cardiac output and a low systemic vascular resistance and blood pressure. It is suggested that the low concentration of haemoglobin in patients with anaemia causes a reduced inhibition of basal endothelium-derived relaxing factor activity and leads to generalised vasodilatation. The consequent low blood pressure may be the stimulus for neurohormonal activation and salt and water retention.

Adolescent↗
PubMed1993

No evidence for altered muscle mitochondrial function in Parkinson's disease.

Recent reports indicate that reductions in mitochondrial respiratory chain function occur in substantia nigra, platelets, and muscle from patients with Parkinson's disease. To confirm and further characterise the presence of a generally distributed mitochondrial defect, mitochondrial metabolism was evaluated in muscle obtained from subjects with Parkinson's disease and from normal controls. Oxygen consumption rates in muscle mitochondria represented by complex I, complexes II-III, or complex IV did not differ between the two groups. Likewise, activities of rotenone sensitive NADH cytochrome c reductase, succinate cytochrome c reductase, or cytochrome oxidase in muscle mitochondria were not significantly different between Parkinsonian and control subjects. These findings fail to provide support for a generalised defect in mitochondrial function in Parkinson's disease but do not exclude an abnormality in respiratory function confined to the substantia nigra.

Adult↗
PubMed1993

Body fluid compartments, renal blood flow, and hormones at 6,000 m in normal subjects.

We previously described a syndrome of congestive heart failure occurring in healthy young men at extreme altitude (Anand et al. Lancet 335: 561-565, 1990). The pathogenesis of this condition is unclear. We therefore measured body fluid compartments, renal blood flow, and a variety of plasma hormones in 10 asymptomatic young men staying above 6,000 m for > 10 wk and compared the results with controls at sea level. Body compartments were measured with isotope dilution techniques and renal blood flow with o-[125I]iodohippurate sodium. There was a marked expansion of all the fluid spaces: total body sodium was 14% above normal (P < 0.05), total body water was 18% above normal (P < 0.05), plasma volume was 33% above normal (P < 0.05), and blood volume was 84.5% above normal (P < 0.001). The effective renal plasma flow was lower than normal by 55% (P < 0.001), but the reduction in the effective renal blood flow was 37% below normal (P < 0.001) because the hematocrit was high (41.6% above normal). Plasma norepinephrine was nearly 3 times normal (P < 0.01), cortisol 3 times normal (P < 0.001), and growth hormone 18 times normal (P < 0.01). Aldosterone was twice normal (P < 0.03). Plasma epinephrine, atrial natriuretic peptide, and plasma renin activity were unchanged. The degree of fluid retention in these normal subjects was similar to that in patients with severe untreated congestive heart failure (Anand et al. Circulation 80: 299-305, 1989), whereas sodium retention and reduction in effective renal blood flow were less.(ABSTRACT TRUNCATED AT 250 WORDS)

Acclimatization↗
PubMed1993

Early and late effects of leukopenic reperfusion on the recovery of cardiac contractile function. Studies in the transplanted and isolated blood-perfused rat heart.

BACKGROUND: Since there is considerable evidence that leukocytes contribute to tissue injury during ischemia and reperfusion, the present study was designed to: (1) determine whether reperfusion in vivo with leukopenic blood affords protection in a model of reversible hypothermic ischemia, (2) determine the duration of any protection, (3) characterize the relation between protection and duration of leukopenic perfusion, and (4) assess the effect of leukopenic reperfusion on myocardial glutathione content. METHODS AND RESULTS: Rat hearts (n = 12 per group) were excised, immediately arrested with an infusion (2 minutes at 4 degrees C) of St Thomas' cardioplegic solution, and subjected to 4 hours of global ischemia (4 degrees C). The hearts were then transplanted (1 hour additional ischemic time) into the abdomen of saline-treated or leukopenic recipients. Leukopenia was induced by intraperitoneal administration of mustine hydrochloride (2 mg/kg) 3 days before study. Hearts were then reperfused in situ for 1, 4, or 24 hours, after which they were excised and either processed for histological examination (n = 4 per group) or perfused aerobically with bicarbonate buffer for 20 minutes, and contractile function was assessed (n = 8 per group); at the end of this period, some hearts (n = 5 per group) were taken for metabolite analysis. After 1 hour of reperfusion, contractile function in the saline-treated control group was significantly reduced compared with aerobic controls that had not been subjected to ischemia (left ventricular developed pressure [LVDP], 108 +/- 5 vs 126 +/- 3 mm Hg at an end-diastolic pressure of 12 mm Hg; P < .05). However, in the hearts with leukopenic reperfusion, LVDP (119 +/- 2 mm Hg) was similar to that of aerobic controls. This benefit, however, was lost after 4 and 24 hours of reperfusion. Cardiac compliance was not influenced by leukopenia. Coronary flow recovered significantly better in the leukopenic hearts during the first 4 hours of reperfusion (11.8 +/- 0.5 vs 9.3 +/- 0.4 mL/min at 1 hour and 10.0 +/- 0.5 vs 8.0 +/- 0.4 mL/min at 4 hours, P < .05), but again this benefit was lost after 24 hours of reperfusion. The myocardial contents of reduced and oxidized glutathione after 1, 4, and 24 hours of reperfusion were similar in saline-treated and leukocyte-depleted animals. In additional studies, the period of ischemia was extended to 8 hours, and similar results were obtained, with improved recovery of contractile function and coronary flow but not cardiac compliance in the leukopenic group after 1 hour of reperfusion. In further studies with the isolated blood-perfused rat heart, ischemia was induced for 8 hours; this was followed first by reperfusion for 0, 2, 10, 30, or 60 minutes with leukopenic blood and then by perfusion with blood from saline-treated animals for 60, 58, 50, 30, or 0 minutes, respectively. Reperfusion with leukopenic blood for 2 minutes did not improve the recovery of LVDP (106 +/- 7 vs 96 +/- 10 mm Hg in controls; NS) but when continued for 10, 30, or 60 minutes resulted in significant improvements (137 +/- 5, 138 +/- 3, and 150 +/- 10 mm Hg, respectively). Although coronary flow tended to be greater in all leukopenic groups, by the end of 60 minutes of reperfusion, only those hearts reperfused with leukopenic blood for the entire reperfusion period showed a significant improvement (3.4 +/- 0.3 vs 2.5 +/- 0.2 mL/min in controls; P < .05). Histological studies revealed no intravascular aggregation of leukocytes or features of myocyte necrosis. CONCLUSIONS: Reperfusion with leukopenic blood accelerated the rate of recovery of cardiac function after reversible myocardial injury but did not lead to a sustained increase in the eventual extent of recovery. Reperfusion with leukopenic blood for the first 10 minutes of reflow is sufficient to obtain this benefit.

Animals↗
PubMed1993

[Congestive heart failure: from cardiac muscle to skeletal muscle].

It is well established that in patients with chronic heart failure, exercise capacity and clinical symptoms such as fatigue or dyspnea correlate poorly with the extent of left ventricular dysfunction. The increase in cardiac output caused by vasodilators, cannot be translated immediately into increased exercise capacity and peak oxygen consumption in patients with chronic heart failure. These observations have prompted the hypothesis that in chronic heart failure intrinsic abnormalities of skeletal muscle emerge that prevent acute improvement in peak VO2 and blood lactate accumulation. Studies using nuclear magnetic resonance demonstrate abnormal skeletal muscle metabolism during exercise, even in the absence of reduced flow or under ischaemic conditions. Histological examination of skeletal muscle reveals a variable extent of atrophy, increased interstitial cellularity and increase in type IIb fibres. Ultrastructural analysis shows abnormalities indicative of depressed oxidative capacity. Biochemical analysis of skeletal muscle biopsies demonstrates reduced activity of enzymes involved in aerobic metabolism and free fatty acid accumulation. These data indicate morphological, biochemical and metabolic alterations of skeletal muscle that should contribute significantly to the reduced muscle strength and rapid fatigue in patients with chronic heart failure. It has also been speculated that a generalized myopathy may occur in a subset of patients with dilated cardiomyopathy. These findings have clinical implications. Prolonged immobilization of patients with chronic heart failure was often suggested, is not practised anymore. Physical training in chronic heart failure has been shown to improve skeletal muscle function, exercise capacity and clinical symptoms in small controlled trials. Pharmacological treatment might be targeted for skeletal muscle disorders in patients with heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic Disease↗
PubMed1993

Pancreatitis arthritis with periarticular fat necrosis.

We describe the case of a 76-year-old man hospitalized for 14 months because of a complicated hip fracture who developed pancreatitis and polyarthritis. He had no evidence of subcutaneous fat necrosis away from his joints and his pancreatitis was virtually asymptomatic otherwise. Polyarthritis is a rare complication of this disorder, and rarer still is polyarthritis without evidence of subcutaneous fat necrosis elsewhere.

Aged↗
PubMed1993

Femoral fracture mimicking acute arthritis in Down's syndrome.

We describe a 38-year-old white woman with Down's syndrome with a history of chronic arthritis and hyperuricemia who presented with acute left knee pain, patellar tenderness and patello-femoral instability. Findings appeared due to a fracture of the lateral femoral condyle, which responded to conservative therapy with a spica cast. Patellofemoral instability in Down's syndrome can be associated with significant morbidity including femoral condyle fracture. Patients with Down's syndrome who present with acute knee arthritis responding poorly to antiinflammatory agents and other conventional therapy should be assessed for fractures related to patellar dislocation, as treatments for the 2 disorders differ.

Acute Disease↗
PubMed1993

Myocardial xanthine oxidoreductase activity in hypertensive and hypercholesterolemic rats.

In several species, xanthine oxidoreductase activity seems to be a major source of free radicals in myocardial tissue. Its activity changes during development and aging, at least in the rat heart. Hardly any data are available about its activity in two important diseases, hypertension and hypercholesterolemia, in which the production of free radicals induced by xanthine oxidoreductase activity could play a role. Therefore we measured the activity of xanthine oxidase and dehydrogenase in myocardial tissue of spontaneously hypertensive. Wistar (control hypertensive), Yoshida (hypercholesterolemic) and Brown Norway (control hypercholesterolemic) rats of various ages. Cytosolic fractions were incubated at 30 degrees C, pH 8.3, with 60 microM xanthine, and the formation of urate was measured with high performance liquid chromatography. In the Wistar group, xanthine oxidoreductase activity was relatively constant during aging (about 1.8 U/g protein). In the hypertensive group, the activity increased gradually from 1.7 to 2.3 U/g at 18 months (p < 0.05 compared with Wistar at 18 months). Xanthine oxidase was about twice as high in both groups at 18 months (p < 0.001 compared with 2 and 6 months). The ratio of xanthine dehydrogenase to xanthine oxidase had decreased 42% at this age (p < 0.001). In the Yoshida and Brown Norway groups, xanthine oxidoreductase activity was similar, with a peak at 6 months. These data suggest that the hypercholesterolemic state does not influence xanthine oxidoreductase activity. In contrast, in hypertrophied myocardium, xanthine oxidoreductase activity was higher than in the control, suggesting a different potential for free-radical generation.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1992

Effect of prolonged treatment with propionyl-L-carnitine on erucic acid-induced myocardial dysfunction in rats.

The aim of this study was to evaluate the ability of propionyl-L-carnitine to prevent cardiac damage induced by erucic acid. Rats were fed for 10 days with normal or 10% erucic acid-enriched diets with or without propionyl-L-carnitine intraperitoneally injected, (1 mM/kg daily, for 10 days). The erucic acid diet produced increases in triglycerides (from 5.6 to 12.4 mg/gww, P less than 0.01), and free fatty acids (from 2.0 to 5.1 mg/gww, P less than 0.01), but no changes in phospholipids. When the hearts were perfused aerobically with an isovolumic preparation there was no difference in mechanical activity. On the contrary, when pressure-volume curves were determined, the pressure developed by hearts from the erucic acid-treated rats were reduced. Independent of diet, propionyl-L-carnitine treatment always produced positive inotropy. This was concomitant with improved mitochondrial respiration (RCI 5.1 vs 9.3, P less than 0.01), higher tissue ATP content (10.3 vs 18.4 mumol/gdw P less than 0.01) and reduction of triglycerides (12.4 vs 8.0 mg/gww, P less than 0.01). These data suggest that propionyl-L-carnitine, when given chronically, is able to prevent erucic acid-induced cardiotoxicity, probably by reducing triglyceride accumulation and improving energy metabolism.

Adenosine Triphosphate↗
PubMed1992

Effects of calcium antagonists on glycolysis of rat brain synaptosomes.

The effects of calcium antagonists nimodipine, nicardipine and flunarizine on lactate production and specific activities of some enzymes regulating glycolytic flux have been evaluated in synaptosomes isolated from rat whole brain and submitted to in vitro chemical hypoxia induced by rotenone, an inhibitor of mitochondrial respiration. The following enzymes have been tested; hexokinase (ATP: D-hexose-6-phosphotransferase, EC2.7.1.1), phosphofructokinase (ATP: D-fructose-6-phosphate 1-phosphotransferase, EC 2.7.1.11) and pyruvate kinase (ATP: pyruvate 2-O-phosphotransferase, EC 2.7.1.40). The results show that rotenone increases by about eight times the production of lactate; nicardipine and nimodipine, starting from a concentration of 10(-4) M, were able to counteract the rotenone-induced stimulation of glycolysis, but flunarizine was without effect. The dihydropyridines but not flunarizine decreased the maximum activity of phosphofructokinase. This effect was already detectable at a concentration of 10(-5) M. Neither hexokinase nor pyruvate kinase were affected by any of the drugs studied.

Animals↗
PubMed1992

Effect of aging and dopaminomimetic therapy on mitochondrial respiratory function in Parkinson's disease.

Oxygen consumption and enzyme activity were evaluated in platelet mitochondria from 17 patients with Parkinson's disease. In comparison with age-matched controls, no consistent abnormality could be discerned in complex I, complex II-III, or complex IV oxygen consumption, or in the enzyme activity of these respiratory chain complexes. Neither chronic therapy with levodopa/carbidopa alone nor in combination with deprenyl significantly affected any measure of mitochondrial respiratory function. There was no discernible relationship between patient age or disease severity and any parameter of mitochondrial respiration. Moreover, blood lactate levels following glucose loading were not different in patients and controls. These results fail to support the occurrence of a generalized defect in any mitochondrial respiratory function in Parkinson's disease.

Age Factors↗
PubMed1992

Role of timing of administration in the cardioprotective effect of fructose-1,6-bisphosphate.

We administered fructose-1,6-bisphosphate (FDP), 1 mM, to isolated and perfused rabbit hearts submitted, after 90 minutes of equilibration, to an ischemic period (60 minutes at a coronary flow of 0.17 ml/min/g), followed by a period of reperfusion (30 minutes at a coronary flow of 3.6 ml/min/g). FDP was delivered at different times following the experimental protocol: 60 minutes before ischemia and for the entire experiment; 60 minutes before and during ischemia, but not at reperfusion; at the onset of ischemia and during reperfusion; and only during reperfusion. The FDP cardioprotective effect was evaluated in terms of recovery of left ventricular pressure developed during reperfusion, creatine phosphokinase (CPK) and noradrenaline release, mitochondrial function (expressed as yield, RCI, QO2, ADP/O), ATP and creatine phosphate (CP) tissue contents, calcium homeostasis, and by measuring oxidative stress in terms of reduced and oxidized glutathione release and tissue contents. Our data show that the cytoprotective action of FDP is closely related to the time of administration. Optimal myocardial preservation was achieved when it was present prior to ischemia and during reperfusion. When given at the time of ischemia or only on reperfusion, FDP does not exert cardioprotection. The data suggest that the FDP cardioprotective effect is related to improvement of energy metabolism.

Adenosine Triphosphate↗
PubMed1992

Hibernating myocardium in patients with coronary artery disease: identification and clinical importance.

The term hibernating myocardium describes a particular outcome of myocardial ischemia in which myocytes show a chronically depressed contractile ability but remain viable. Revascularization of hibernating tissue causes a recovery of mechanical function that correlates with long-term survival. Therefore it is important clinically to distinguish hibernating from infarcted myocardium, since asynergies due to hibernation will improve on reperfusion, whilst those due to infarct will not. One suggested technique to identify hibernating myocardium is to stimulate the myocytes acutely, but briefly, by administration of inotropic agents while monitoring contractile function by echocardiography. We report our experience on the use of low dosages of dobutamine. Myocardial viability was validated by measuring the recovery in contraction of the akinetic areas after coronary artery bypass surgery by means of intraoperative epicardial echocardiography. The test has a sensitivity of 93% and a specificity of 78%. It is useful for identification of viable myocardium and also for quantification of intraoperative risk in individual patients. Limitations of this test are related to the presence of downregulation of beta receptors and to the impossibility of differentiating hibernating from stunned myocardium. Another useful technique of identifying hibernating myocardium is the use of radionuclear markers for viability. In our experience the two most important tests are (1) rest-redistribution imaging of thallium 201 (which has a high sensitivity of 93% but a low specificity of 44%) and (2) 99mTc-Sestamibi imaging, which provides information on both perfusion and function with a single injection. This latter technique allows differentiation between stunning and hibernating on the basis of coronary flow which is preserved in stunning and reduced in hibernation.

Cell Survival↗
PubMed1992

Effects of the novel calcium channel blocker, anipamil, on the isolated rabbit heart. Comparison with verapamil and gallopamil.

The calcium channel blocking activity of the novel phenylalkylamine derivative, anipamil, was tested on the isolated rabbit heart, in comparison with verapamil and gallopamil. Anipamil and the other calcium channel blockers lower left ventricular pressure in the same concentration range (10(-8)-10(-4) mol/l). The negative inotropic effect of anipamil is only partially reversed (nearly 65%) by rising calcium concentration in the perfusion fluid, whilst a complete recovery is observed for verapamil and gallopamil. The negative inotropic effect of anipamil is of rapid onset but long lasting, being still present 12 h after washout. On the contrary, that of gallopamil or verapamil completely disappears within 3 h of washout. Verapamil and gallopamil (10(-8)-10(-4) mol/l) depress spontaneous heart rate up to asystolia and abolish the vasopressin- and Bay K 8644-induced coronary spasm. Anipamil, on the contrary, does not modify coronary spasm elicited by both stimulants and spontaneous heart rate up to 10(-4) mol/l. These observations suggest that anipamil, in the isolated rabbit heart, possesses a peculiar pharmacological profile, since its calcium channel blocking activity is confined to the myocardial muscle.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1992

Lipid peroxidation during myocardial reperfusion.

Reperfusion of heart muscle after prolonged ischaemia is associated with metabolic and functional abnormalities and eventual cell death. Free radical induced lipid peroxidation of cell membranes is thought to be a major mechanism in the evolution of reperfusion damage. The evidences in support for this kind of damage are based on tissue malondialdehyde quantitation by the thiobarbituric acid test (TBA-test). In an attempt to verify this topic we have subjected isolated and Langendorff perfused rabbit hearts to a period of 60 minutes of severe ischaemia plus 30 minutes of reperfusion. At appropriate time points malondialdehyde was determined in the tissue by means of TBA-test and directly by reversed phase, high pressure, liquid chromatography (HPLC). We have found no correlation between the two compared assays. During reperfusion, there was the formation of non-lipid related, malondialdehyde-like, TBA-reactive substance which leads to overestimations of the extent of lipid peroxidation. On the contrary, by direct HPLC quantitation, there was a decrease of tissue malondialdehyde during ischaemia and during the early phases of reperfusion. Our results demonstrate that TBA-test is not a reliable index of malondialdehyde accumulation in organ system.

Animals↗
PubMed1992

Occurrence of oxidative stress during myocardial reperfusion.

Reperfusion, without doubt, is the most effective way to treat the ischaemic myocardium. Late reperfusion may however cause further damage. Myocardial production of oxygen free radicals above the neutralizing capacity of the myocytes is an important cause of this reperfusion damage. There is evidence that prolonged ischaemia reduces the naturally occurring defence mechanisms of the heart against oxygen free radicals, particularly mitochondrial manganese superoxide dismutase, and intracellular pool of reduced glutathione. Consequently, reperfusion results in a severe oxidative damage, as evidenced by tissue accumulation and release of oxidized glutathione. An oxygen free radical-mediated impairment of mechanical function also occurs during reperfusion of human heart. In fact we observed during surgical reperfusion of coronary artery disease (CAD) patients, a prolonged and sustained release of oxidized glutathione; the degree of oxidative stress was inversely correlated with recovery of mechanical and haemodynamic function. These findings represent the rationale for therapeutic interventions which increase the cellular antioxidant capacities and improve the efficacy of myocardial reperfusion.

Animals↗