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Biomedical subjects

R Ferrari

Publications and source records attributed to R Ferrari.

At least 325 records · Page 18Linked to original sources
PubMed1991

Abnormal skeletal and cardiac muscle mitochondria induced by zidovudine (AZT) in human muscle in vitro and in an animal model.

To examine the mechanism of mitochondrial myocytotoxicity caused by long-term administration of zidovudine (AZT) in human immunodeficiency virus-positive patients, we examined the effect of AZT in vitro on human muscle in tissue culture and in vivo in rats treated with daily intraperitoneal injections of AZT at doses equivalent to the total daily dose used in acquired immunodeficiency syndrome patients. After 19 days, the AZT-treated myotubes in tissue culture exhibited abnormal mitochondria characterized by proliferation (mean +/- SD, 27.5 +/- 8 mitochondria/16 microns2 surface area, compared with 12.8 +/- 4 in the control cultures (p less than 0.001], enlarged size, abnormal cristae and electron-dense deposits in their matrix. The changes were partially reversible after AZT withdrawal. Rats treated with AZT developed weight loss, 100-fold elevation of creatine kinase, and increased serum lactate and glucose. In tissues, AZT had its highest concentration in the skeletal muscle and the heart. Skeletal and heart muscles from the treated animals, but not the controls, showed enlarged mitochondria with disorganized or absent cristae and electron-dense deposits in their matrix. Study of the mitochondrial functions assessed by evaluating stimulated oxygen consumption rate, enzymatic activities of electron transport chain and coupling state of oxidative phosphorylation (respiratory control ratio) revealed a decrease in rotenone-sensitive NADH cytochrome C reductase (complex I + III) and an uncoupling effect demonstrated by decreased respiratory control ratio. We conclude that AZT, a DNA chain terminator, is a muscle mitochondrial toxin that affects the oxidation-phosphorylation coupling and the activity of complex I and III of the mitochondrial respiratory chain.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Diuretics as initial and sole treatment in chronic cardiac failure.

Six patients with chronic congestive cardiac failure, who had never received any drug treatment, were studied before and after one month of therapy with frusemide alone at a dose of 40 mg a day. Measurements were made at rest of plasma epinephrine, norepinephrine, renin activity, aldosterone, atrial natriuretic peptide, cortisol, growth hormone and prolactin, together with central hemodynamics, body fluid volumes and renal function. The initial measurements of hemodynamics, body fluid compartments and renal function confirmed the presence of the physiopathology typical of congestive cardiac failure. Plasma concentrations of norepinephrine, atrial natriuretic peptide, aldosterone and growth hormone were significantly increased. The mean value of plasma renin activity, although high, was not significantly different from normal. After one month of treatment, body weight, body fluid volumes and exchangeable sodium were reduced. Hemodynamics and renal plasma flow and glomerular filtration were not significantly affected. Plasma norepinephrine fell to within normal limits; atrial natriuretic peptide increased significantly; plasma renin activity and cortisol increased to levels which were abnormally high; growth hormone increased to levels similar to those associated with acromegaly. Increased circulating concentrations of atrial natriuretic peptide during treatment by frusemide may have an important influence on the kidney, blood vessels and neuro-endocrine response.

Extracellular Space↗
PubMed1991

Pulmonary peptides, norepinephrine and endocrine cells in monocrotaline pulmonary hypertension.

The concentrations of norepinephrine and of the peptides bombesin, calcitonin gene-related peptide and neurotensin were measured in rats with monocrotaline pulmonary hypertension. The numbers of pulmonary endocrine cells showing positive immunoreactivity for calcitonin, calcitonin gene-related peptide, protein gene product 9.5 and bombesin were counted in a second group of rats with monocrotaline pulmonary hypertension. The concentration of norepinephrine in the lungs decreased significantly in the test rats but this could be attributed to dilution by an increased mass of tissue. The pulmonary concentration of all three peptides showed a decrease in the rats treated with monocrotaline but this was highly significant only in the case of bombesin. The pulmonary content of bombesin showed a substantial and significant decrease in the test rats. No neuroendocrine cells immunopositive for bombesin were identified in any of the control or test rats. There was no difference between the control and test rats with respect to the form or distribution of the cells immunoreactive for the other three The lack of pulmonary endocrine cells showing immunoreactivity for bombesin may be related to the absence of intimal proliferation in the pulmonary arteries in this species. This is in striking contrast to what occurs in plexogenic pulmonary arteriopathy in man and suggests that monocrotaline-induced pulmonary hypertension in rats is not a good animal model for this disease.

Animals↗
PubMed1991

[New findings on cardiac metabolism in ischemic cardiopathy].

This article review the biological and clinical importance of 2 potential outcomes of myocardial ischemia: the stunned and the hibernated myocardium. As for the stunned myocardium it is considered the possibility that either or oxygen free radicals, energy deficient or calcium overload are involved. As for the hibernated myocardium an hypothesis linked to the effects of intracellular acidosis and residual coronary flow on the metabolism of the myocyte is proposed.

Animals↗
PubMed1991

Temporal relations of the endocrine response to exercise.

We have followed the hormonal response to exercise in twelve normal males cycling at a constant moderate load for ten minutes. Plasma concentrations of a variety of hormones were measured at set times before and during exercise and for twenty minutes afterward. The plasma concentration of norepinephrine and epinephrine and plasma activity of renin rose to a maximum at the end of exercise and then declined. The plasma concentrations of neurotensin and atrial natriuretic peptide followed a similar course. Plasma vasopressin rose to a peak at the end of exercise and then fell transiently below the initial value ten minutes after exercise. The plasma concentrations of aldosterone, prolactin and adrenocorticotropin increased during exercise but continued to do so, reaching a peak at ten minutes after exercise. Plasma growth hormone increased during exercise and continued to increase throughout the period of twenty minutes' recovery. Cortisol did not change during exercise but rose progressively during the recovery period. Plasma concentrations of glucagon did not change while that of insulin decreased during exercise. The plasma concentration of bombesin slowly increased during exercise and declined during recovery, reaching a basal value 10 minutes later.

Adult↗
PubMed1991

[Toxicity of fatty acids during myocardial reperfusion: a new possible mechanism of action].

To assess the value of myocardial substrate in the occurrence of ischemic-reperfusion damage, isolated, electrically paced rabbit hearts were perfused for 60 min under aerobic condition (25 ml/min with oxygenated Krebs-Henseleit solution containing glucose 11 mM). Thereafter the hearts were made ischemic for 30 min by reducing coronary flow to 3 ml/min. During ischemia, 3 different substrates were used glucose 11 mM (Group I), palmitate 1.2 mM (Group II) and palmitate 1.2 mM + glucose 11 mM (Group III). The hearts were then reperfused (25 ml/min) for 30 min under aerobic condition using glucose 11 mM as the only substrate. In the presence of glucose with or without palmitate (Group I and III) ischemic damage was mild. Recovery of the developed pressure was 95% and there was no contracture during ischemia and or reperfusion. During ischemia and reperfusion there was a small release of CPK, GSSG and GSH. In the presence of palmitate (Group II) ischemic and reperfusion damage was profound. Recovery of developed pressure was reduced (25%) and diastolic pressure significantly increased (68 +/- 5.1 vs 3 +/- 1.5, 5 +/- 1.8 mmHg). These mechanical data were concomitant with an important release of CPK (580 +/- 50 vs 180 +/- 35, 210 +/- 48 mU/min/gww) and oxidised glutathione (0.38 +/- 0.3 vs 0.05 +/- 0.001, 0.09 +/- 0.003 nmoles/min/gww). In addition the redox state of the cells of the Group II was significantly shifted through the oxidative state at the end of ischemia and of reperfusion. These results indicate that palmitate as substrate increases the deleterious effects of ischemia; glucose is able to overcome the negative effects of palmitate.

Aerobiosis↗
PubMed1991

The role of free radicals in the ischemic myocardium.

Reperfusion is beyond doubt the most effective way to treat the ischaemic myocardium. Late reperfusion may cause further damage, the extent of which can be modified, although the underlying mechanism is still not understood and is likely to be of multifactorial origin. Myocardial production of oxygen free radicals exceeding the neutralizing capacity of the myocytes may be important cause of reperfusion damage. This possibility, however, has by no means been proven. There is evidence that prolonged ischaemia reduces the natural defence mechanism of the heart against oxygen free radicals. Although each method has its limitations, comparison several different methods provided evidence, albeit preliminary, that the formation of these toxic species is enhanced after ischaemia and particularly after reperfusion. It seems that the presence of blood is not a prerequisite for oxygen free radical formation and that the mitochondria are likely to be an important site of production. Experimental work does indicate that the oxygen free radicals-mediated component of the reperfusion damage can be circumvented, which gives rise to optimism for the pharmacologist. However, several controversies exist regarding the meaning of studies in which agents known to interfere with oxygen free radicals have provided protection and conclusions derived from such studies should be considered with caution. Almost no data are available on the role of oxygen free radicals in reperfusion injury in man. This, in our opinion, is the goal to achieve in the very near future, before antioxidant therapy will be blindly and irrationally combined with thrombolytic therapy in the treatment of acute myocardial infarction in man.

Animals↗
PubMed1990

A pharmacological model for studying the role of Na+ gradients in the modulation of synaptosomal free [Ca2+]i levels and energy metabolism.

Lactate production (Jlac), oxygen consumption rate (QO2), plasma membrane potentials (Em) and cytosolic free calcium levels [Ca2+]i were studied on synaptosomes isolated from rat brains, incubated in presence of high doses of nicardipine (90 microM), diltiazem (0.5 mM) and verapamil (0.25 mM), and submitted to depolarizing stimulation or inhibition of mitochondrial respiration. Nicardipine was able to completely prevent the veratridine-induced stimulation of Jlac, QO2 and Em depolarization, whereas diltiazem and verapamil were less effective, although the concentrations used were 5 and 3 times higher, respectively, than nicardipine. Diltiazem, verapamil and nicardipine (9 microM) also prevented the veratridine-induced increase in [Ca2+]i, this effect being much less pronounced if the drugs were added after veratridine. Monensin (20 microM) was also able to increase [Ca2+]i but this effect was not affected by verapamil. Synaptosomes were also submitted to an inhibition of respiration of intrasynaptic mitochondria by incubation with rotenone (5 microM); in this condition of mimicked hypoxia Em was more positive of about 11 mV; none of the drugs utilized modified this situation. The rotenone-induced 3-fold increase in Jlac was barely modified by diltiazem and verapamil but it was completely abolished by nicardipine. The possible mechanism of the counteracting action of the drugs towards veratridine stimulation and rotenone inhibition and the involvement of Na+/Ca2+ exchanger in affecting [Ca2+]i are discussed.

Animals↗
PubMed1990

Effects of anipamil on myocardial sarcolemmal and mitochondrial calcium transport, comparison with verapamil and nifedipine.

The calcium antagonists anipamil, verapamil and nifedipine inhibited, dose dependently, passive and ATP-driven 45Ca2(+)-uptake in purified rabbit ventricular sarcolemmal vesicles exposed to a wide range of free calcium concentration (from 0 to 200 microM). The IC50 values for passive binding were virtually identical for all calcium antagonists and the inhibition was relatively independent of the amount of free calcium employed. On the contrary, the order of potency for inhibition of the ATP-driven calcium uptake was: anipamil greater than verapamil greater than nifedipine. The inhibition of nifedipine, at free calcium concentrations lower than 80 microM, was preceded by a slight stimulation. The inhibitory effects of anipamil and verapamil, but not those of nifedipine, on the ATP-driven calcium uptake were more evident with increasing external calcium concentration. Verapamil and nifedipine failed to modify the initial rate of mitochondrial calcium transport either in the presence or in the absence of ADP; on the contrary, anipamil induced a dose-dependent inhibition of mitochondrial calcium transport. The inhibition occurred over the whole range of calcium concentrations tested, independent of the presence of ADP. The effects of anipamil, but not those of verapamil and nifedipine, on sarcolemmal and mitochondrial calcium transport were long lasting and survived membrane isolation.

Adenosine Triphosphate↗
PubMed1990

Effects of temperature and osmolality on the release of atrial natriuretic peptide.

In isolated rat atria a 10 degrees C increase in temperature approximately doubled the output of atrial natriuretic peptide during relaxation and stretch. The effect was not due to the increased rate of contraction. Increasing the osmolality of the superfusate within the physiological range (290 to 320 m osmols) with sodium, potassium or glucose had no appreciable effect on the release of atrial natriuretic peptide.

Animals↗
PubMed1990

Correlation between retinal afferent distribution, neuronal size, and functional activity in the guinea pig medial terminal accessory optic nucleus.

The intrinsic morpho-functional organization of the medial terminal nucleus of the accessory optic system was investigated in the guinea pig. The distribution of the retinal afferents, as assessed by the axoplasmic transport of 14C-valine, showed a remarkable asymmetry within the nucleus. Thus, while the retinal terminal field covered the entire medial terminal nucleus, by far the largest density of labeled retinofugal axon terminals was found within its dorsal division. In this same portion of the nucleus, we found the greatest density of large cells and the maximum intensity of functional activation, this latter as estimated by the increase in metabolic activity of neurons using the 14C-2-deoxyglucose autoradiographic method in the vertical and horizontal whole-field movement in the visual field.

Amino Acids↗
PubMed1990

Enalapril as initial and sole treatment in severe chronic heart failure with sodium retention.

Five patients, who had never received any drug treatment but who had severe chronic congestive heart failure with salt and water retention, were studied before and after a single dose of enalapril (10 mg orally). Three patients continued on enalapril as monotherapy (10 mg b.d. orally) for one month. Central haemodynamics, body fluid volumes, renal function and plasma hormones were measured at rest. The initial mean right atrial pressure was 13 +/- 4 mm Hg, pulmonary wedge pressure 29 +/- 4 mm Hg and cardiac index 1.8 +/- 0.21/min/m2. Enalapril, given acutely, caused only small changes. Two patients were withdrawn after the single dose of enalapril and treated with diuretics for clinical reasons. The remaining three patients each lost more than 4 kg in weight after one month of treatment with enalapril alone. Total body exchangeable sodium and total body water were reduced but central haemodynamics were unchanged. Although enalapril was of some benefit when given alone to patients with severe congestive heart failure, all five patients were finally treated with diuretics for clinical reasons. Enalapril is not recommended as the initial and only therapy for patients with severe congestive heart failure.

Adult↗
PubMed1990

Effect of congestive heart failure on rate of atrial natriuretic factor release in response to stretch and isoprenaline.

STUDY OBJECTIVE: The aim was to investigate the pattern of release of atrial natriuretic factor induced by mechanical and adrenergic stimulation from atria of rats with or without congestive heart failure. DESIGN: Monocrotaline, a pyrrolizidine alkaloid, was given to rats to cause severe pulmonary hypertension, leading to a marked degree of right ventricular hypertrophy and failure. Measurements of noradrenaline and atrial natriuretic factor were performed in each cardiac chamber and in plasma. Right and left atria of control rats and rats with congestive heart failure were isolated and subjected to mechanical or adrenergic stimulation to study the in vitro release of atrial natriuretic factor. MATERIALS: Studies were performed on plasma, ventricles, and isolated right and left atria of 276 male Wistar rats, 80-100 g weight, with or without congestive heart failure. MEASUREMENTS AND MAIN RESULTS: In monocrotaline rats right and left ventricular concentrations of noradrenaline were significantly reduced. In the same rats concentrations of atrial natriuretic factor fell to 15.2% in the right atria and to 65.5% in the left atria. Whole heart content of atrial natriuretic factor was diminished, while plasma concentrations were increased sevenfold. Isolated hypertrophied right atria of failing hearts did not release atrial natriuretic factor in response to stretch or to isoprenaline (10(-9)M) and they were insensitive to the inotropic action of isoprenaline. On the other hand, non-hypertrophied left atria from the same animals released increased amounts of atrial natriuretic factor under basal conditions and after both stimuli, despite reduced tissue stores of the peptide. CONCLUSIONS: Heart failure may deplete cardiac stores of noradrenaline and atrial natriuretic factor, especially in hypertrophied chambers, and can result in a decrease in the release of atrial natriuretic factor from atrial tissue in response to mechanical and adrenergic stimulation.

Animals↗
PubMed1990

Na(+)-H+ exchange in cardiac sarcolemmal vesicles isolated from diabetic rats.

Intracellular pH and [Na+] in the heart are regulated by the sarcolemmal membrane Na(+)-H+ exchange pathway. No data are currently available regarding the adaptation of this system to pathological conditions in the heart. Because ionic interactions with the heart are altered in cardiomyopathy during chronic experimental diabetes, it was hypothesized that Na(+)-H+ exchange may become abnormal. In addition, the effects of treating diabetic rats with daily injection of L-propionylcarnitine were investigated to determine whether alterations in lipid metabolism may be involved in any potential changes in ion transport. Rats were injected with streptozotocin (65 mg/kg) and killed 8-10 wk later, and sarcolemmal membrane vesicles were isolated from pooled ventricles. Significant depressions in Na(+)-K(+)-adenosinetriphosphatase (ATPase) activity and Na(+)-Ca2+ exchange were observed in the diabetic preparations in comparison to control. L-Propionylcarnitine treatment of the diabetic rats partially normalized these activities. A striking depression in cardiac sarcolemmal Na(+)-H+ exchange was observed in the diabetic animals in comparison to control, and this was not a result of a nonspecific increase in membrane permeability. L-Propionylcarnitine treatment of the diabetic rats did not improve sarcolemmal Na(+)-H+ exchange.

Amiloride↗
PubMed1990

Occurrence of oxidative stress during reperfusion of the human heart.

We have investigated the relation between occurrence of myocardial oxidative stress and functional recovery during postischemic reperfusion in 20 selected patients subjected to aortocoronary bypass grafting. Patients were selected for having normal percent ejection fraction and left ventricular end-diastolic pressure before the operation. Occurrence of oxidative stress was assessed by measuring the formation and release of oxidized glutathione (GSSG) in the coronary sinus immediately before aortic cross-clamp, 1, 5, 10, and 20 minutes after removal of aortic cross-clamp, and 10 and 20 minutes after the end of cardiopulmonary bypass. Reduced glutathione (GSH), lactate, and creatine phosphokinase release were also monitored with the same timing. Standard hemodynamic measurements were recorded by means of a triple-lumen thermodilution pulmonary artery catheter before sternotomy, 15 minutes after the end of cardiopulmonary bypass, and during the 24 hours after termination of cardiopulmonary bypass. Reperfusion in patients after a short period of ischemia (less than 30 minutes; group 1) resulted in a small and transient release in the coronary sinus of GSSG and GSH and in a progressive improvement of hemodynamic parameters reaching a stable state 4 hours after the operation. In patients with a period of ischemia longer than 30 minutes (group 2), reperfusion induced a marked and sustained release of lactate, GSH, and GSSG; the arteriocoronary sinus difference for GSSG was still negative after the end of cardiopulmonary bypass. The arteriocoronary sinus difference for creatine phosphokinase also remained negative for as long as 20 minutes after cardiopulmonary bypass, and the rate of functional recovery was significantly delayed, reaching the values of group 1 only 12 hours after the operation. In these patients there was a positive correlation (r = 0.88, p less than 0.01) between the duration of ischemia and the myocardial arteriovenous difference for GSSG. In addition, there was a negative correlation between the arteriocoronary sinus difference for GSSG and cardiac index measured 2, 4, and 6 hours after the operation. These data suggest for the first time that, depending on the severity of the ischemic period, oxidative stress occurs during reperfusion of patients with coronary artery disease who are subjected to heart surgery and that it may be linked with a delay in postoperative recovery of cardiac function.

Coronary Artery Bypass↗
PubMed1990

Immunological pattern in heterozygote beta thalassemic subjects.

In heterozygote beta-thalassemic subjects in a higher incidence of infectious diseases and of liver diseases with progression toward chronic hepatitis has been assessed. This predisposition has been suggested as being related to some immunological defects and to an altered immunological reactivity in thalassemia trait carriers. In order to evaluate whether there is a real deficiency of some humoral and cellular parameters in healthy heterozygote beta-thalassemic subjects, 128 symptom-free volunteers have been studied: 40 were heterozygote beta thalassemia carriers and 88 were normal subjects. In both groups there was no difference in: number and percentage of total lymphocytes, gamma globulins, immunoglobulins A and M, number and percentage of CD21, CD3, CD4, CD8, number of OKla*1, CD4/CD8 rations and lymphocytes' ability to respond to phytohemagglutinin. The values of immunoglobulins G and percentages of OKla*1 were found to be higher only in heterozygote beta thalassemic subjects; however, the number of CD2 in these subjects was lower. The result of the present study seems to indicate there is not significant difference between heterozygote beta thalassemic carriers and normal subjects in the more usual humoral and cellular immunological parameters.

Adult↗