Biomedical subjects

Jean-Paul Henry

Publications and source records attributed to Jean-Paul Henry.

8 recordsLinked to original sources

PubMed2007

NADPH oxidase inhibition prevents cocaine-induced up-regulation of xanthine oxidoreductase and cardiac dysfunction.

Oxidative stress is involved in the pathogenesis of cocaine-induced cardiomyopathy. In the present study, we aimed to determine the enzymatic sources of reactive oxygen species (ROS) production, namely NADPH oxidase and xanthine oxidoreductase (XOR) in male Wistar rats treated for 7 days with cocaine (2x7.5 mg/kg/day, ip) or cocaine with a NADPH oxidase inhibitor (apocynin, 50 mg/kg/day, po) or a XOR inhibitor (allopurinol, 50 mg/kg/day, po). Cocaine-induced cardiac dysfunction is associated with an increase in NADPH oxidase and XOR activities (59% and 29%, respectively) and a decrease in catalase activity. Apocynin or allopurinol treatment prevents the cocaine-induced cardiac alteration by restoration of cardiac output, stroke volume and fractional shortening. This is associated with a reduction of the myocardial production of superoxide anions and an enhancement of catalase activity. Surprisingly, apocynin treatment prevents XOR up-regulation supporting the hypothesis that NADPH oxidase-derived ROS play a role in modulating ROS production by XOR. These data suggest that NADPH and xanthine oxidase act synergically to form myocardial ROS and clearly demonstrate that their inhibition may be critical in preventing the initiation and progression of cocaine-induced LV dysfunction.

Acetophenones↗

PubMed2006

Improvement of peripheral endothelial dysfunction by protein tyrosine phosphatase inhibitors in heart failure.

BACKGROUND: Chronic heart failure (CHF) induces endothelial dysfunction characterized by a decrease in nitric oxide (NO) production in response to flow (flow-mediated dilatation [FMD]). Because activation of endothelial NO synthase (eNOS) by flow requires tyrosine phosphorylation, we tested whether endothelial dysfunction could be corrected by increasing phosphotyrosine levels using protein tyrosine phosphatase (PTP) inhibitors and especially inhibitors of PTP1B. METHODS AND RESULTS: CHF was induced by coronary ligation in mice, and FMD was assessed in isolated and cannulated mesenteric artery segments (2 mm in length and <300 microm in diameter). CHF almost abolished FMD but only moderately affected the response to acetylcholine. In mice with CHF, the PTP1B inhibitors AS279, AS098, and AS713 restored FMD to levels similar to those of normal mice. This restoration was reduced by inhibitors of eNOS and phosphatidylinositol-3 kinase. Polymerase chain reaction and Western blot showed that arteries express PTP1B, and this expression was not affected by CHF. Immunolocalization revealed the presence of PTP1B in the endothelium and the adventitia. Flow induced a transient eNOS phosphorylation that was absent in CHF. PTP1B inhibition stimulated early eNOS phosphorylation and increased phosphorylation of Akt. CONCLUSIONS: Our results demonstrate for the first time that PTP1B inhibitors may be potent treatments for endothelial dysfunction.

Acetylcholine↗

PubMed2006

Inhalation of diluted diesel engine emission impacts heart rate variability and arrhythmia occurrence in a rat model of chronic ischemic heart failure.

Both increase in cardiac arrhythmia incidence and decrease in heart rate variability (HRV) have been described following human and experimental animal exposures to air pollutants. However, the potential causal relationship between these two factors remains unclear. Incidence of ventricular arrhythmia and HRV were evaluated during and after a 3 h period of Diesel engine exhaust exposure in ten healthy and ten chronic ischemic heart failure (CHF, 3 months after coronary ligation) Wistar rats using implantable ECG telemetry. Air pollutants were delivered to specifically designed whole body individual exposure chambers at particulate matter concentrations similar to those measured inside cabins of cars inserted in congested urban traffic. Recordings were obtained from unrestrained and unsedated vigil rats. Immediate decrease in RMSSD was observed in both healthy (6.64 +/- 2.62 vs. 4.89 +/- 1.67 ms, P < 0.05) and CHF rats (8.01 +/- 0.89 vs. 6.6 +/- 1.37 ms, P < 0.05) following exposure. An immediate 200-500% increase in ventricular premature beats was observed in CHF rats only. Whereas HRV progressively returned to baseline values within 2.5 h after exposure start, the proarrhythmic effect persisted as late as 5 h after exposure termination in CHF rats. Persistence of ventricular proarrhythmic effects after HRV normalization suggests that HRV reduction is not the mechanism of cardiac arrhythmias in this model. Our methodological approach, closely reflecting the real clinical situations, appeared to be a unique tool to provide further insight into the pathophysiological mechanisms of traffic related airborne pollution health impact.

Administration, Inhalation↗

PubMed2005

Role of alpha1-adrenoreceptors in cocaine-induced NADPH oxidase expression and cardiac dysfunction.

OBJECTIVE: We assessed whether alpha1-adrenoreceptor (alpha1-AR) stimulation contributes to activation of myocardial NADPH oxidase in a rat model of cocaine-induced cardiac dysfunction. METHODS AND RESULTS: After 7 days of cocaine injection (2 x 7.5 mg/kg/day, i.p., Coc), NADPH activity assessed by chemiluminescence increases as well as phosphorylation of p47phox, one of the cytosolic components of NADPH oxidase. The alpha1-AR antagonist prazosin (Prz), administered 1 h before each cocaine injection (2 x 1 mg/kg/day, i.p., Coc+Prz), prevents these effects. Moreover, Prz pretreatment reduces left ventricular/body weight (LV/BW) ratio and partially prevents the cocaine-induced alterations in fractional shortening and cardiac index assessed by echocardiography. In order to confirm the involvement of alpha1-AR stimulation in NADPH oxidase up-regulation in vivo, we used phenylephrine (Phe) administration with the same protocol of injections as that used with cocaine (2 x 5 microg/kg/day, i.p.). After Phe administration, as expected, NADPH oxidase activity increases as well as phosphorylation of p47phox. These effects occur in the absence of sustained hemodynamic changes. CONCLUSION: This study demonstrates the involvement of the alpha1-AR in NADPH oxidase activation and in cocaine-induced LV dysfunction. We suggest that alpha1-AR stimulation, at least in part via NADPH oxidase induction, plays a critical role in the events leading to the cardiomyopathy observed after cocaine abuse.

Adrenergic alpha-Agonists↗

PubMed2004

Selenium diet-supplementation improves cocaine-induced myocardial oxidative stress and prevents cardiac dysfunction in rats.

Chronic cocaine abuse causes cardiac dysfunction and induces oxidative stress. The goal of this study was to evaluate whether an enhanced antioxidant pool, induced by the administration of selenium, may prevent the myocardial dysfunction induced by cocaine. Cocaine was administered for 7 days (15 mg/kg/day, i.p.) to rats pretreated for 4 weeks with selenium (1.16 mg/L/day, p.o.). Cardiac function was evaluated by cardiac index and left ventricular (LV) fractional shortening (FS) measured by echocardiography. The redox ratio and enzymatic activities of glutathione peroxidase (GPX) and superoxide dismutase (SOD) were measured in the LV myocardium. Cocaine administration induced a cardiac dysfunction, as evidenced by a decrease in cardiac index and LV FS as well as by an increase in LV diameters. Moreover, antioxidant markers and redox ratio were altered in rats after cocaine exposure. Selenite supplementation induced a significant limitation of cardiac index and FS alterations observed after cocaine administration. This improvement in cardiac function was associated with a redox ratio recovery while SOD and GPX activities remained unchanged. Thus, selenite reversed both the oxidative stress and the contractile dysfunction induced by cocaine administration. These results suggest a major role of oxidative stress in the cocaine-induced cardiotoxicity.

Animals↗

PubMed2002

Long-term survival and hemodynamics after endothelin-a receptor antagonism and angiotensin-converting enzyme inhibition in rats with chronic heart failure: monotherapy versus combination therapy.

BACKGROUND: In patients with congestive heart failure (CHF) receiving ACE inhibitors, acute administration of selective endothelin (ET) antagonists additionally improves systemic and cardiac hemodynamics. We investigated, in a rat model of CHF, whether such acute synergistic effects are sustained and accompanied, in the long term, by an additional limitation of left ventricular remodeling or an increase in survival. METHODS AND RESULTS: Rats were subjected to coronary artery ligation and treated for 3 or 9 months with vehicle or with the ACE inhibitor trandolapril (Tr) (0.3 mg/kg(-1) per day(-1)), the ET(A) antagonist LU 135252 (LU, 30 mg/kg(-1) per day(-1)), or their combination starting 7 days after ligation. After 3 months, the combination decreased LV systolic- and end-diastolic pressures (-32% and -80%, respectively) more markedly than Tr (-21% and -61%, respectively) or LU alone (-14% and -48%, respectively). Echocardiographic studies revealed that all treatments limited LV dilatation and increased LV fractional shortening and cardiac index. All treatments equally reduced left ventricular collagen density, whereas only Tr or the combination reduced LV weight. Finally, although LU did not modify long-term survival, Tr and the combination of Tr with LU induced a similar improvement of survival. CONCLUSIONS: In this rat model, long-term combined administration of an ET(A) antagonist and an ACE inhibitor induces additional effects in terms of systemic and cardiac hemodynamics; however, this is not associated with an additional increase in long-term survival.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2002

Tissue Doppler imaging differentiates physiological from pathological pressure-overload left ventricular hypertrophy in rats.

BACKGROUND: The myocardial velocity gradient (MVG) is a recent index of regional myocardial function derived from endocardial and epicardial velocities obtained by tissue Doppler imaging (TDI). This index might be useful for discriminating between physiological and pathological left ventricular hypertrophy (LVH) and for documenting the early transition from compensated LVH to heart failure. We sought to compare MVG measured across the left ventricular posterior wall between normal rats and rats with physiological (exercise) and pathological (pressure-overload) LVH. METHODS AND RESULTS: Wistar rats were assigned to one of the following groups: sedentary, exercise (swimming), and 2-month or 9-month abdominal aortic banding. Compared with sedentary rats, exercise and 2-month banding led to similar and significant LVH. After 2-month banding, conventional parameters of systolic function (left ventricular fractional shortening and dP/dt(max)) were not affected. However, systolic and diastolic MVG were similar in exercise and sedentary rats but were significantly lower in rats with aortic banding. Aortic debanding after 2 months led to a full recovery of MVG, whereas MVG remained decreased when debanding was performed after 9 months. CONCLUSIONS: Myocardial contraction and relaxation assessed by TDI were impaired in pressure-overload LVH but not in exercise LVH. Therefore, TDI is more sensitive than conventional echocardiography for assessing myocardial dysfunction in pressure-overload LVH and for predicting early recovery in myocardial function after loading conditions normalization.

Animals↗

PubMed2002

Heat stress increases endothelium-dependent relaxations and prevents reperfusion-induced endothelial dysfunction.

1. Heat stress has been widely used to stimulate the expression of stress proteins and is associated with various cardiovascular changes, including anti-ischaemic effects. However, the effect of heat stress on endothelial function is less clear. 2. Heat stress was induced in anaesthetized rats by increasing body temperature to 42 degrees C for 15 min. Twenty-four hours later, segments of rat aorta and mesenteric and coronary arteries were mounted in organ chambers. 3. Heat stress markedly increased relaxation to acetylcholine (ACh) in all three blood vessels studied, without affecting the response to the nitric oxide (NO) donor sydnonimine-1. 4. Heat stress also increased aortic relaxation to histamine and the calcium ionophore A23187. 5. In the aorta, an inhibitor of NO synthesis abolished the response to ACh in both control and heat stressed-rings, whereas a cyclo-oxygenase inhibitor had no effect. 6. Heat stress also prevented completely the impaired response to ACh in coronary arteries isolated from rats subjected to myocardial ischaemia and reperfusion. 7. Thus, heat stress increases the stimulated release of NO the rat aorta and mesenteric and coronary arteries and prevents reperfusion-induced injury at the level of the coronary endothelium.

Animals↗