Biomedical subjects

R Ferrari

Publications and source records attributed to R Ferrari.

At least 307 records · Page 17Linked to original sources

PubMed1991

Role of timing of administration in the cardioprotective effect of iloprost, a stable prostacyclin mimetic.

We administered iloprost, a stable prostacyclin mimetic, 27 nM, to isolated and perfused rabbit hearts submitted, after 60 min of equilibration, to an ischaemic period (60 min at a coronary flow of 1 ml/min) followed by a period of reperfusion (30 min at a coronary flow of 25 ml/min). Iloprost was delivered at different times during the experimental protocol: 60 min before ischaemia, at the onset and after 30 min of ischaemia and only during reperfusion. The iloprost 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 (respiratory control index), QO2, ADP/O), ATP and creatine phosphate (CP) tissue contents, calcium homeostasis and by measuring several parameters of oxidative stress: reduced and oxidized glutathione release and tissue contents, Mn and Cu-Zn superoxide dismutase activities; glutathione reductase and peroxidase activities. Our data show that the cytoprotective action of iloprost is closely related to the time of administration. Optimal myocardial preservation was achieved when it was given before or at the onset of ischaemia. Iloprost administration 30 min after the onset of ischaemia was still beneficial, although to a lesser extent. Iloprost lost its protective effect when given only on reperfusion. The data suggest that the iloprost cardioprotective effect is related to maintainance of membrane integrity.

Adenosine Triphosphate↗

PubMed1991

Effects of prolonged infusion of human alpha calcitonin gene-related peptide on hemodynamics, renal blood flow and hormone levels in congestive heart failure.

We have previously demonstrated that short-term infusion of calcitonin gene-related peptide (CGRP) has beneficial effects in congestive heart failure. The effects of prolonged infusion of CGRP on hemodynamic functions, plasma hormones and renal blood flow were studied in 9 patients with congestive heart failure (New York Heart Association class III or IV, ejection fraction less than 35%). Hemodynamic variables were measured at 30-minute intervals for 8 hours during CGRP infusion (8 ng/kg/min) and for 2 hours after discontinuation. CGRP caused a decrease in right atrial (28%, p less than 0.05), pulmonary artery (22%, p less than 0.02), pulmonary artery wedge (37%, p less than 0.001) and systemic arterial (18%, p less than 0.05) pressures. Systemic vascular resistance decreased more than pulmonary vascular resistance. Cardiac output (72%, p less than 0.001) and stroke volume (60%, p less than 0.02) increased. Heart rate did not change. There was no evidence of tolerance throughout the infusion. The hemodynamic effects were lost within 30 minutes of stopping CGRP. Renal blood flow (34%, p less than 0.01) and glomerular filtration rate (43%, p less than 0.01) increased. Atrial natriuretic peptide decreased (p less than 0.05), while plasma cortisol (p less than 0.02) increased. Plasma epinephrine, norepinephrine, renin activity, aldosterone and growth hormone were unchanged. It is concluded that in patients with severe congestive heart failure, CGRP has sustained beneficial effects on hemodynamic functions and has no adverse effects on hormones. Unlike many other vasodilators, CGRP also increases renal blood flow and glomerular filtration.

Calcitonin Gene-Related Peptide↗

PubMed1991

L-dopa does not affect electron transfer chain enzymes and respiration of rat muscle mitochondria.

Alterations in mitochondrial respiratory chain enzymes have been found in skeletal muscle of parkinsonian patients. Most of these patients had received treatment with L-dopa in combination with an inhibitor of peripheral decarboxylase for several years. In order to determine whether these effects are only dependent on the disease or are partially due to its therapy, the effects of L-dopa methyl ester and benserazide, a peripheral dopa decarboxylase inhibitor, were studied on various parameters related to energy metabolism in rat skeletal muscle mitochondria. The maximum activities related to complexes of the respiratory chain: rotenone-sensitive NADH-cytochrome c reductase, succinate-cytochrome c reductase, cytochrome c oxidase, state 3, state 4, uncoupled state, and respiratory control ratio were measured after 17-19 days of treatment. The results indicate that L-dopa treatment does not interfere with any of the parameters investigated and suggest that changes in muscle mitochondrial function found in parkinsonian patients are the result of the disease process and not its treatment.

Animals↗

PubMed1991

Stunning: damaging or protective to the myocardium?

There are several potential outcomes of myocardial ischemia. When ischemia is severe and prolonged, irreversible damage occurs and there is no recovery of contractile function. Interventions aimed at reducing mechanical activity and oxygen demand, either before ischemia or during reperfusion, have been shown to delay the onset of ischemic damage and to improve recovery on reperfusion. When myocardial ischemia is less severe but still prolonged, myocytes may remain viable but exhibit depressed contractile function. Under these conditions, reperfusion restores complete contractile performance. This type of ischemia, leading to a reversible, chronic left ventricular dysfunction, has been termed hibernating myocardium. Depression of mechanical activity is, actually, a protective mechanism whereby the hibernating cells reduce their oxygen demands in the setting of reduced oxygen supply. A third possible outcome after a short period of myocardial ischemia is a transient postischemic ventricular dysfunction, a situation termed stunned myocardium. As in the case of hibernating myocardium, the depressed contractile function occurring during stunning could be a protective mechanism, allowing the reperfused cells to gradually recover their metabolism and function.

Animals↗

PubMed1991

The occurrence of oxidative stress during reperfusion in experimental animals and men.

Reperfusion is the prerequisite for the ischemic myocardium to recover its metabolic and mechanical function. However, reperfusion after a prolonged period of ischemia in the experimental animal may exacerbate, or at least accelerate, the occurrence of ischemic injury, whilst in humans at the least it is not beneficial. This entity has been called reperfusion damage, since much of the damage is believed to be caused by events occurring at the moment of reperfusion rather than by changes occurring during ischemia. The existence of reperfusion damage, however, has been questioned, and evidence in favour of the concept is sparse. At the moment the molecular events occurring at the time of reperfusion are not completely understood, and the relative importance of several proposed deleterious mechanisms is not yet established. One of the most fashionable ideas for the cause of reperfusion damage is that the function of cell membrane is modified by oxygen radicals generated at the moment of reperfusion. Evidence in favour of and against this hypothesis is described in detail in the present article.

Animals↗

PubMed1991

Effect of propionyl-L-carnitine on mechanical function of isolated rabbit heart.

We studied the acute and chronic effects of propionyl-L-carnitine (PLC) on mechanical function of isolated rabbit heart. Propionyl-L-carnitine was either directly delivered in the perfusate (10(-9) to 10(-3) M) or intraperitoneally injected (250 mg/kg) for 10 days to the animals. When added acutely, propionyl-L-carnitine had no effect on inotropism, heart rate, or coronary perfusion pressure. When added chronically, propionyl-L-carnitine induced a positive inotropic effect, with no changes in heart rate or in coronary perfusion pressure, and it ameliorated the pressure-volume relationship. This effect of propionyl-L-carnitine was independent of the calcium concentration of the perfusion medium, but it was correlated with an increase in the myocardial content of propionyl-L-carnitine. The effect was not apparent after 5 days of treatment, although the tissue content of propionyl-L-carnitine remained unchanged. These data suggest that propionyl-L-carnitine, when given chronically, exerts a positive inotropic effect.

Acetylcarnitine↗

PubMed1991

Effects of some L-carnitine derivatives on heart membrane ATPases.

In order to understand the role of carnitine metabolites in the genesis of cellular dysfunction and damage due to myocardial ischemia, the effects of 1-100 microM L-carnitine, acetylcarnitine, propionylcarnitine, and palmitoylcarnitine were investigated on rat heart sarcolemmal, sarcoplasmic reticular, and mitochondrial ATPase activities. Palmitoylcarnitine, unlike acetylcarnitine, propionylcarnitine and carnitine, produced marked inhibitory actions on sarcolemmal Na,K-ATPase and Ca2(+)-stimulated ATPase, as well as sarcoplasmic reticular Ca2(+)-stimulated ATPase activities; Na,K-ATPase was most sensitive. Although palmitoylcarnitine, unlike carnitine or its short-chain fatty-acid derivatives, also depressed sarcolemmal Ca2+ ATPase or Mg2+ ATPase, sarcoplasmic reticular Mg2+ ATPase, and mitochondrial Mg2+ ATPase, mitochondria were less sensitive in comparison to other organelles. Myofibrillar Ca2(+)-stimulated ATPase was slightly inhibited by very high concentrations of palmitoylcarnitine only. It is suggested that the observed depression of the sarcolemmal Na(+)-pump system by low concentrations of long-chain acyl derivatives of carnitine may contribute towards the pathogenesis of arrhythmias due to myocardial ischemia. Furthermore, the inhibition of Ca2(+)-pump mechanisms in the sarcolemmal and sarcoplasmic reticular membranes by relatively high concentrations of palmitoylcarnitine may result in the occurrence of intracellular Ca2+ overload and subsequent cell damage, as well as cardiac dysfunction due to myocardial ischemia.

Acetylcarnitine↗

PubMed1991

The effect of propionyl-L-carnitine on the ischemic and reperfused intact myocardium and on their derived mitochondria.

To assess whether propionyl-L-carnitine protects rabbit heart against the deterioration caused by ischemia and reperfusion, isolated hearts were infused with a medium containing it in different concentrations. During control, normoxic perfusion, and 60 minutes of low-flow ischemia (37 degrees C) followed by 30 minutes of reperfusion, diastolic, and developed pressures were monitored; coronary effluent was collected and assayed for lactate and creatine phosphokinase (CPK); mitochondria were harvested and assayed for oxidative phosphorylation and calcium content; and tissues for concentration of adenosine triphosphate (ATP) and creatine phosphate. Propionyl-L-carnitine reduced the ischemic deterioration of mitochondrial function and the depletion of tissue stores of ATP. On reperfusion, hearts treated with it recovered better than the untreated hearts with respect to left ventricular performance, replenishment of ATP and CP stores, and mitochondrial function. The reperfusion-induced mitochondrial calcium overload and release of CPK were also reduced. The effect of propionyl-L-carnitine was dose dependent. At 10(-8) M it failed to modify ischemic and reperfusion damage but protected well at 10(-7) M. No further protection was obtained at 10(-6) M. Propionyl-L-carnitine thus protects the myocardium against some of the deleterious effects of ischemia and reperfusion. In particular it protects mitochondrial function, perhaps partly by preventing mitochondrial calcium overload. Because this protection occurs in the absence of a negative inotropic effect during normoxia or of a coronary dilatatory effect during ischemia, it cannot be attributed to an energy-sparing effect or to the improvement of oxygen delivery.

Adenosine Triphosphate↗

PubMed1991

The influence of right heart catheterisation on pulmonary arterial pressure in chronic heart failure: relationship to neuroendocrinal changes.

Continuous ambulatory measurement of pulmonary arterial pressure was used to investigate changes following right heart catheterisation in patients with chronic heart failure. Ten males, mean age 56 years, with chronic heart failure, underwent 24 hour pressure recording using a micromanometer tipped catheter with in vivo calibration and frequency modulated recording. Eight patients were taking diuretics and 3 vasodilators. Blood was drawn for catecholamines, plasma renin activity and atrial natriuretic peptide 1 hour before catheterisation (-1 h), at the time of catheterisation (0 h) and 1, 2, 3, 4 and 6 hours later and aldosterone, cortisol and growth hormone at -1, 0 and 6 hours. Analysis of variance was used to determine changes in pulmonary arterial pressure, heart rate and hormones from the time of catheterisation in lying, sitting and standing postures. There was no significant change in pulmonary arterial pressure or heart rate over the 12 hours following or 24 hours after catheterisation in any posture. In the majority of patients plasma noradrenaline, plasma renin activity, atrial natriuretic peptide, aldosterone and cortisol were elevated. There was no significant change in hormone levels during the 6 hours following catheterisation. These findings suggest that the effect of invasive haemodynamic monitoring and chronic medical therapy on central haemodynamics is minor, and that a delay between insertion of catheters and measurement of pressure is unnecessary.

Adult↗

PubMed1991

Cardiovascular and hormonal effects of calcitonin gene-related peptide in congestive heart failure.

The effects of infusing human alpha-calcitonin gene-related peptide were studied in eight patients with congestive heart failure, five normal rabbits and five rabbits with adriamycin-induced cardiomyopathy. In patients with heart failure, calcitonin gene-related peptide caused a dose-dependent increase in cardiac output and decrease in pulmonary and systemic vascular resistance and pulmonary artery pressure. The systemic blood pressure and right atrial and pulmonary wedge pressures decreased only at the highest infusion rate (16 ng/kg per min). Heart rate remained unchanged. Plasma epinephrine increased (p less than 0.05), whereas aldosterone, atrial natriuretic peptide and prolactin concentrations decreased (p less than 0.05). Plasma norepinephrine, renin activity, cortisol and growth hormone concentrations remained unchanged. In both groups of rabbits, the drug decreased blood pressure and increased cardiac output and heart rate. There was a significant increase in renal blood flow (p less than 0.05). The peptide did not affect the contraction amplitude of human and rabbit ventricular myocytes. These findings suggest that calcitonin gene-related peptide is a vasodilator in the rabbit and humans with little direct effect on ventricular myocardium. This peptide may be useful in some forms of heart failure.

Adult↗

PubMed1991

Time course of human atrial natriuretic factor release during cardiopulmonary bypass in mitral valve and coronary artery diseased patients.

We determined the time-course of the release of atrial natriuretic factor (ANF) during cardiopulmonary bypass (CPB) in six patients undergoing coronary artery bypass (CAD) and eight patients undergoing valve replacement for mitral stenosis (MS). Before CPB, the arterial ANF was significantly higher in MS patients than in CAD patients (243 +/- 38 and 29 +/- 5.8 pg/ml respectively, P less than 0.01). With the onset of CPB, the acute pressure unloading of the atria induced a significant, rapid decrease of ANF only in MS patients (-64% of pre-CPB value at 5 min) and no major changes in CAD patients. Clamping of the aorta induced a further progressive reduction of ANF release to almost zero in both groups. Readmission of coronary flow to the empty atria with declamping resulted in an increase in the plasma level of ANF in both groups to reach the concentration present in MS patients before CPB. After CPB, the ANF levels decreased in CAD patients while remaining elevated in MS patients. These data suggest that ANF release from human atria depends on atrial filling pressure and other unknown factors.

Adult↗

PubMed1991

Role of oxygen free radicals in ischemic and reperfused myocardium.

In recent years there has been considerable interest concerning the role of oxygen radicals in myocardial ischemia and reperfusion injury. The sequential univalent reduction of oxygen gives rise to very reactive intermediate products. Normally, the tissue concentration of these intermediate products of oxygen is limited and the aerobic myocardium survives because of the existence of a delicate balance between the generation of the various oxidants and the maintenance of the antioxidant defense mechanism. Several possible sources have been identified for the production of active oxygen species after ischemia and reperfusion and these sources may be mutually interactive. The ability of scavengers of oxygen free radicals, including vitamin E, to improve mechanical, mitochondrial, and sarcoplasmic reticulum function in animal models of ischemic-reperfusion injury also suggests that oxygen free radicals are partly responsible for myocardial damage in these models, although caution in the interpretation of these data is necessary.

Animals↗

PubMed1991

Calcium channel blockers and ischaemic heart disease: theoretical expectations and clinical experience.

There are several reasons for using calcium antagonists to protect ischaemic and reperfused myocytes and to treat coronary artery disease (CAD) patients. At the molecular level, calcium antagonists induce: coronary dilatation and improvement of the supply of oxygen and substrate to the area at risk; energy sparing secondary to dilatation of the peripheral vasculature and, at least in the case of phenylalkylamines and benzothiazepines, a reduction in contractility and heart rate; attenuation of reperfusion-induced arrhythmias; inhibition of platelet aggregation (only at high concentration); reduction of loss of adenosine precursor; reduction of the release of lysosomal enzymes; a direct protective effect on the sarcolemma (for the phenylalkylamines); a protective effect of the mitochondria and specific reduction of mitochondrial calcium transport (for benzothiazepines and some phenylalkylamines; attenuation of the ischaemia-reperfusion-induced displacement of endogenous noradrenaline (for the phenylalkylamines). Evidence of a protective role has been obtained in a variety of experiments provided the calcium antagonists were introduced prior to ischaemia. It is believed that this protective effect is an indirect consequence of the ability to modulate the function of the calcium channels and the energy-sparing effect is of major importance. Conversely, protection has not been obtained when calcium antagonists are added after ischaemia or during reperfusion. Thus is not surprising that when administered after the signs of human myocardial infarction, calcium antagonists do not reduce infarct size or avoid subsequent complications or decrease mortality. Diltiazem and verapamil, however, are two recent exceptions to this general tendency.

Calcium Channel Blockers↗

PubMed1991

Evaluation of phospholipid peroxidation as malondialdehyde during myocardial ischemia and reperfusion injury.

Peroxidation of membrane phospholipid polyunsaturated fatty acids is considered a major mechanism of the damage occurring on reperfusion of the myocardium after a prolonged period of ischemia. The evidence in support of this mechanism of damage is 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 min of severe ischemia plus 30 min 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 that leads to overestimation of the extent of lipid peroxidation. On the contrary, by direct HPLC quantitation, there was a decrease of tissue malondialdehyde during ischemia and during the early phases of reperfusion. Our results demonstrate that TBA test is not a reliable index of lipid peroxidation in organ systems.

Animals↗

PubMed1991

Pathogenesis of edema in constrictive pericarditis. Studies of body water and sodium, renal function, hemodynamics, and plasma hormones before and after pericardiectomy.

BACKGROUND: The pathogenesis of sodium and water accumulation in chronic constrictive pericarditis is not well understood and may differ from that in patients with chronic congestive heart failure due to myocardial disease. This study was undertaken to investigate some of the mechanisms. METHODS AND RESULTS: Using standard techniques, the hemodynamics, water and electrolyte spaces, renal function, and plasma concentrations of hormones were measured in 16 patients with untreated constrictive pericarditis and were measured again in eight patients after pericardiectomy. The average hemodynamic measurements were as follows: cardiac output, 1.98 l/min/m2; right atrial pressure, 22.9 mm Hg; pulmonary wedge pressure, 24.2 mm Hg; and mean pulmonary artery pressure 30.2 mm Hg. The systemic and pulmonary vascular resistances (36.3 +/- 2.5 and 3.2 +/- 0.3 mm Hg.min.m2/l, respectively) were increased. Significant increases occurred in total body water (36%), extracellular volume (81%), plasma volume (53%), and exchangeable sodium (63%). The renal plasma flow was only moderately decreased (49%), and the glomerular filtration rate was normal. Significant increases also occurred in plasma concentrations of norepinephrine (3.6 times normal), renin activity (7.2 time normal), aldosterone (3.4 times normal), cortisol (1.4 times normal), growth hormone (21.8 times normal), and atrial natriuretic peptide (5 times normal). The ratio of left atrial to aortic diameter measured by echocardiography was only minimally increased (1.29 +/- 0.04), indicating that in constrictive pericarditis the atria are prevented from expanding. The studies repeated after pericardiectomy in the eight patients showed that all measurements returned toward normal. CONCLUSIONS: The restricted distensibility of the atria, in constrictive pericarditis, limits the secretion of atrial natriuretic factor and, thus, reduces its natriuretic and diuretic effects. This results in retention of water and sodium greater than that occurring in patients with edema from myocardial disease. The arterial pressure is maintained more by the expansion of the blood volume than by an increase in the peripheral vascular resistance.

Adult↗

PubMed1991

Protective effects of calcium antagonists against ischaemia and reperfusion damage.

The most positive results in this area have been those of the second Danish Study Group on Verapamil in Myocardial Infarction (1990) which assessed the benefit of treatment with verapamil from the second week after myocardial infarction. Verapamil produced a significant reduction in both mortality and reinfarction rates. Consequently, it may be concluded that treatment with calcium antagonists, such as verapamil and diltiazem, should not be used in the acute phase of myocardial infarction, but rather as prophylaxis to prevent reinfarction by protecting against myocardial ischaemia. The lack of reported cardioprotective efficacy with calcium antagonists, which contrasts with experimental predictions, can be explained by the inappropriate timing of administration and the use of dihydropyridine, which can be detrimental in myocardial infarction. These is little or no evidence to show that calcium antagonists are cardioprotective in patients with myocardial infarction or unstable angina. Thus, the randomised trials studying acute myocardial infarction reveal no overall effect of treatment on mortality in the short or long term. The prototype calcium antagonists differ in their effects on the reinfarction rate in these patients. With verapamil there is a small tendency for a reduction in reinfarction, with nifedipine a clear worsening, and with diltiazem a reduction almost reaching statistical significance. The general lack of protective efficacy is presumably a result of the drugs being administered too late after the onset of ischaemia.

Calcium↗

PubMed1991

Functional impairment of the rat superior colliculus after kainic acid intraocular injection: a 2-deoxyglucose study.

Long Evans rats monocularly injected with the kainic acid (KA), were exposed to "tonic" (diffuse steady light, stationary pattern, total darkness) and "phasic" (flashing, moving pattern) stimulations. By means of the autoradiographic 2-deoxyglucose (2DG) technique we assessed the functional activity of the Superior Colliculus (SC) contralateral to the injected eye as compared to the normal eye SC. In the control SC all "tonic" stimulations determined low 2DG uptake not modified by the intraocular KA injection. On the contrary, "phasic" stimulations elicited a strong 2DG consumption in the normal SC, with a peculiar pattern of distribution depending on the kind of stimulus. Considering the total 2DG uptake as the added intrinsic and afferent metabolism, KA was able to affect only the latter, decreasing two-fold that expected for the afferent input loss. These findings can suggest a possible KA effect on off-line ganglion cells and, on the other side, they confirm the role of the SC in discriminating "phasic" and sudden phenomena from "tonic" and continuous ones.

Animals↗

PubMed1991

[Is lipid peroxidation responsible for the damage caused by postischemic reperfusion?].

Peroxidation of membrane phospholipid polyunsaturated fatty acids is considered a major mechanism of the damage occurring during post-ischemic reperfusion. The evidences in support for this mechanism of damage are based on tissue malondialdehyde (MDA) 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 min of severe ischemia plus 30 min of reperfusion. At appropriate time points MDA 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 2 compared assays. During reperfusion, there was the formation of non-lipid related, MDA like, TBA-reactive substance which leads to overestimation of the extent of lipid peroxidation. On the contrary, by direct HPLC quantitation, there was a decrease of tissue MDA during ischemia and during the early phases of reperfusion. Our results demonstrate that TBA-test is not a reliable index of lipid peroxidation in organ systems and that MDA accumulation does not precede the evidence of the functional alterations occurring on reperfusion of the previously ischemic myocardium. These results are of relevance in the understanding of the exact mechanism of reperfusion damage as, in the same experimental model, oxy radicals have been shown to be generated and antioxidants are protective.

Animals↗