Biomedical subjects

G Gouverneur

Publications and source records attributed to G Gouverneur.

9 recordsLinked to original sources

PubMed2001

Cardioprotection by ischemic preconditioning preserves mitochondrial function and functional coupling between adenine nucleotide translocase and creatine kinase.

M. N. Laclau, S. Boudina, J. B. Thambo, L. Tariosse, G. Gouverneur, S. Bonoron-Adèle, V. A. Saks, K. D. Garlid and P. Dos Santos. Cardioprotection by Ischemic Preconditioning Preserves Mitochondrial Function and Functional Coupling Between Adenine Nucleotide Translocase and Creatine Kinase. Journal of Molecular and Cellular Cardiology (2001) 33, 947-956. This study investigates the effect of ischemic preconditioning on mitochondrial function, including functional coupling between the adenine nucleotide translocase and mitochondrial creatine kinase, which is among the first reactions to be altered in ischemia. Three groups of Langendorff-perfused rat hearts were studied: a control group, a group subjected to 30 min ischemia followed by 15 min reperfusion, and a group subjected to ischemic preconditioning prior to 30 min ischemia and 15 min reperfusion. Ischemic preconditioning significantly delayed the onset and amplitude of contracture during ischemia, decreased enzymatic release, and improved the recovery of heart contractile function after reperfusion. Mitochondrial function was assessed in permeabilized skinned fibers. The protective effect of preconditioning was associated with preservation of mitochondrial function, as evidenced by maintenance of the high K(1/2)for ADP in regulation of mitochondrial respiration and V(max)of respiration, the near absence of respiratory stimulation by exogenous cytochrome c, and preservation of functional coupling between mitochondrial creatine kinase and adenine nucleotide translocase. These data suggest that ischemic preconditioning preserves the structure-function of the intermembrane space, perhaps by opening the mitochondrial ATP-sensitive K(+)channel. The consequence is preservation of energy transfer processes from mitochondria to ATP-utilizing sites in the cytosol. Both of these factors may contribute to cardioprotection and better functional recovery of preconditioned hearts.

Adenosine Diphosphate↗

PubMed1996

Development of the model of rat isolated perfused heart for the evaluation of anthracycline cardiotoxicity and its circumvention.

1. In order to develop a predictive model for the preclinical evaluation of anthracycline cardiotoxicity and the means of preventing it, we have studied the functional parameters of perfused hearts isolated from rats receiving repeated doses of several anthracyclines. 2. The anthracyclines studied were doxorubicin, epirubicin, pirarubicin and daunorubicin, and we also studied a liposomal formulation of daunorubicin (DaunoXome) and the co-administration of dexrazoxane (ICRF-187) and doxorubicin. 3. Anthracyclines were administered i.p. at equimolar doses corresponding to 3 mg kg-1 per injection of doxorubicin, every other day for a total of six doses. Dexrazoxane was used at the dose of 30 mg kg-1 per injection and was administered either 30 min before or 30 min after doxorubicin. We evaluated any general toxicity towards the animals as well as alterations of left ventricular contractility and relaxation ex vivo. 4. Epirubicin and daunorubicin were significantly less cardiotoxic than doxorubicin, and neither pirarubicin nor DaunoXome caused significant alterations in cardiac function. There was a direct relationship between the decrease in cardiac contractility or relaxation and anthracycline accumulation in the heart, evaluated after the same treatment schedule. 5. Dexrazoxane induced a significant protection against doxorubicin-induced cardiac toxicity when administered 30 min before doxorubicin, whereas this protection was ineffective when administered 30 min after doxorubicin. Direct perfusion of DaunoXome in isolated hearts of untreated animals resulted in a 12-fold reduction of the accumulation of daunorubicin in heart tissue as compared to the perfusion of free daunorubicin, and did not cause alterations in cardiac function at a dosage for which free daunorubicin induced major alterations. 6. The isolated perfused rat heart appears to be a valuable model for screening of new anthracyclines and of strategies for circumventing anthracycline cardiotoxicity.

Animals↗

PubMed1995

Evaluation of anthracycline cardiotoxicity with the model of isolated, perfused rat heart: comparison of new analogues versus doxorubicin.

We have compared the cardiotoxicity of 3 anthracyclines in a model of isolated perfused rat heart using the Langendorff technique. The contractile state and ventricular compliance were studied. Doxorubicin, epirubicin and pirarubicin were perfused at concentrations of 10(-6) and 10(-5) M during 70 min. The cardiac accumulation of the drugs was studied by HPLC. No significant alteration of cardiac functional parameters was observed at 10(-6) M. At 10(-5) M, epirubicin produced a significantly greater alteration of cardiac contractility than doxorubicin, whereas pirarubicin exerted first an inotropic effect followed by a recovery to initial values at the 60th min. Anthracycline accumulation in the heart was dose-dependent; epirubicin accumulated to a 30% greater extent than doxorubicin and pirarubicin heart concentrations were 4-5 times higher than those of doxorubicin at the end of the perfusion. These results suggest that doxorubicin and epirubicin have the same intrinsic cardiac toxicity, and that their distinct clinical cardiotoxicity must be explained by pharmacokinetic differences, whereas pirarubicin is much less cardiotoxic than the other anthracyclines because of different pharmacodynamic properties.

Animals↗

PubMed1994

Effect of angiotensin II on calcium release phenomena in normal and hypertrophied single cardiac myocytes.

The effects of angiotensin II (Ang II) (10(-9) M to 10(-7) M) on calcium releases were established in ventricular myocytes from normal and renal hypertensive adult rats. From each peak systolic indo-1 ratio (405 nm/480 nm), amplitude variation, duration (rise time and fall time), and frequency of spontaneous calcium releases were investigated on freshly isolated cardiomyocytes at rest or under electrical stimulation. The following changes were observed: (1) in spontaneous contracting myocytes, an increase in frequency of calcium transients at 10(-7) M in normal cells (+157%, P < 0.05) and at whatever angiotensin II concentration in hypertrophied cells (10(-9) M: +79% P < 0.05; 10(-8) M +82%, P < 0.01; 10(-7) M: +285%, P < 0.01) with a greater sensitivity of hypertrophied cells to Ang II (P < 0.05 at 10(-9) M, P < 0.01 at 10(-8) M). (2) In stimulated myocytes, a prolongation of the duration of calcium transients at 10(-7) M in normal cells (+68%, P < 0.01) and at 10(-9) M, 10(-8) M, 10(-7) M in hypertrophied cells: (+36%, P < 0.05; +39%, P < 0.01; +77%, P < 0.01) with a greater sensitivity of hypertrophied myocytes (P < 0.05 at 10(-9) M and 10(-8) M). An increase in duration may be explained by the occurrence of calcium releases during the fall time of calcium transients. Thus, both in normal and hypertrophied myocytes, Ang II induced the occurrence of calcium releases with increased sensitivity of hypertrophied cells to Ang II. Such calcium releases are known to be a possible cause of arrhythmias termed "triggered activity".

Angiotensin II↗

PubMed1994

[Effects of angiotensin II on spontaneous cytosolic calcium releases in ventricular myocytes of adult normal and hypertensive rats].

This study investigated the effects of angiotensin II (Ang II) (10(-9)M to 10(-7)M) on calcium releases in ventricular myocytes from normal and renal hypertensive adult rats (Goldblatt 2K-1C). Newly, isolated myocytes were loaded with fluorescent indo-1/AM and studied at rest or under electrical stimulation. The variation of the ratio of indo-1 emission (405 nm/480 nm) was taken as a measure of cytosolic calcium variations. Five parameters were investigated from each peak systolic indo-1 ratio before and after Ang II addition: amplitude variation, duration with analysis of a rise time and a fall time, and frequency of spontaneous calcium releases. Following changes were observed: in unstimulated myocytes exhibiting spontaneous contractile activity, increase in frequency of calcium transients, at 10(-7)M, in normal cells (+ 157 +/- 27%; p < 0.01) and whatever Ang II concentration in hypertrophied cells (+ 79 +/- 31%; p < 0.01; + 82 +/- 25%, p < 0.01; + 285 +/- 50%, p < 0.01 à 10(-9)M, 10(-8)M, 10(-7)M); in stimulated myocytes, prolongation of the duration of calcium transients explained by the occurrence of calcium releases during fall time. In addition, 50% of myocytes exhibited spontaneous releases of calcium in the interstimulus interval. Increase in calcium transients duration was statistically significant, whatever Ang II concentration in hypertrophied cells (+ 36 +/- 20%, p < 0.05; + 39 +/- 18%, p < 0.01; + 77 +/- 34%, p < 0.01 à 10(-9)M, 10(-8)M, 10(-7)M) and only at 10(-7)M in normal cells (+ 68 +/- 22% p < 0.01). Similar results were observed in fall time.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗

PubMed1993

[Metabolic aspects of hemodynamic behavior in left ventricular hypertrophy by 13C NMR].

During myocardial hypertrophy, histological modifications induce a partial ischemic state and hemodynamic perturbations are responsible for an increased myocardial oxygen demand. The purpose of this study is to better characterize the alterations of intermediary metabolism linked to hemodynamic perturbations by carbon 13 NMR using enriched substrates. Left ventricular hypertrophy was consecutive to a renal hypertension (Goldblatt 2K-1C, 9 weeks). Myocardial compliance and contractility (left ventricular end diastolic pressure (LVEDP), +dP/dt max, +dP/dt max normalized to developed pressure (+dP/dt max/DEVP)) were estimated on Langendorff isolated perfused hearts at a constant perfusion pressure (normo and hypertensive rats (RHR)). Using (2-13C) acetate enriched (10 nm) substrate, 13C NMR spectra were obtained from tissue perchloric extracts. Mathematical model proposed by Malloy was used to analyze these 13C NMR spectra terms of metabolic fluxes: Fc2 = The fraction of (2-13C) acetyl-CoA entering the tricarboxylic acid cycle; y = The ratio between the activity of anaplerotic reactions to that of citrate synthetase. The results showed after hypoxia: an increase of LVEDP more pronounced in RHR (RHR: 48 +/- 15 mmHg VS SHAM: 22 +/- 6 mmHg, p < 0.01); a significant impairment of coronary blood flow more important in RHR; a significant increase of the ratio y in hypertrophied hearts (RHR: 0.062 +/- 0.09 VS SHAM: 0.15 +/- 0.02, p < 0.05). In conclusion, this study allowed a new approach to correlate diastolic dysfunction with metabolic data consecutive to an increased sensitiveness hypertrophy to hypoxic damages.

Animals↗

PubMed1988

Serum type III procollagen peptide levels in coronary artery disease (a marker of atherosclerosis).

The known shift in collagen synthesis from procollagen type I to type III in patients with atherosclerosis, suggested measurement of serum procollagen III peptide (PIIIP) levels in patients with coronary artery disease (CAD). Two groups of patients were studied: group I--thirty-six patients with CAD (male, mean age 56.9 +/- 7.5 years, hospitalized for coronary angiography. Risk factors included 16 patients with high blood pressure, four diabetics, 31 smokers and 15 with hypercholesterolaemia. Five patients had no significant lesions, seven had one vessel with over 50% stenosis, 10 had two vessels and 14 had three vessels. Group II--35 patients (male, mean age 39.4 +/- 13.3 years), with normal physical examination and ECG according to WHO criteria, formed the control group: the risk factors included nine patients with high blood pressure, 14 smokers and one with hypercholesterolaemia. Procollagen III peptide levels were determined by radioimmunoassay. In group I, PIIIP levels were 26.8 +/- 16 ng ml-1 vs. 10.4 +/- 3.2 for group II. Sixty-one per cent of group I had pathological levels of PIIIP with an absence of correlation with the severity of atherosclerosis or risk factors. Only 2.8% of patients in group II had pathological levels. Procollagen III peptide determination would appear to be a sensitive, specific and predictive test for atherosclerosis in patients with CAD.

Adult↗

PubMed1988

[Effects of ventricular hypertrophy following experimental renovascular hypertension on the elasticity of the papillary muscle].

A precise method was developed for detecting muscular stiffness changes in the left ventricular hypertrophy by chronic pressure overload in rats (2 kidney-1 clip renal hypertensive rats). The technique of Quick-Release allowed the measurement of the "stress-strain" relation (delta-epsilon), the elastic stiffness (d delta/d epsilon) and the stiffness constant (K) in isolated papillary muscle from normal and hypertrophied hearts at rest and at the maximal time course of activation during isometric contraction. (Table: see text). The results of this study reported that the cardiac hypertrophy induced by experimental pressure overload was not associated with significant alteration of myocardial stiffness. So, it would seem that a muscular stiffness modification was unresponsible for the ventricular compliance change of clinical and experimental results.

Animals↗

PubMed1988

[Protease inhibitors and ectasia in coronary atherosclerosis].

The possibility of elastase contributing to degradation of the arterial wall in atherosclerosis and to the formation of ectasia has prompted us to assay the main protease inhibitors, alpha 1-antitrypsin and alpha 2-macroglobulin, in patients with angiographic coronary disease with and without coronary ectasia. Serum concentrations of these two proteins were measured by immunonephelometry in 203 patients admitted for coronary arteriography. The results obtained were analyzed according to the presence of atheromatous lesions and their severity and to the presence or absence of ectasia. There was no correlation between the values observed and the presence or severity of coronary atherosclerosis, but the concentration of alpha 1-antitrypsin was significantly higher in patients with coronary ectasia (247.2 +/- 40.5 mg/ml) than in patients without ectasia (213.5 +/- 36.6 mg/100 ml; p less than 0.001). This study shows that coronary ectasia is associated with disturbances in the protease-antiprotease system, which may be consecutive to initial changes in elastase activity. Our results support the theory that elastase and protease inhibitors play a specific role in some atheromatous processes.

Adult↗