Benjamin Lauzier

Increased beta2-adrenoceptors in doxorubicin-induced cardiomyopathy in rat.

Background The toxicity of doxorubicin, leading to an irreversible heart failure, limits its use as chemotherapeutic agent. The beneficial effects of early administration of β-blocker were reported in patients with heart failure due to doxorubicin, suggesting an important role of β-adrenoceptors (β-ARs). This study aimed to identify a putative target (β-AR and/or its effectors) at the early phase of a chronic doxorubicin-induced cardiomyopathy (Dox-CM) in a rat model. Methodology Dox-CM was induced by six doxorubicin injections (cumulative dose: 15 mg.kg−1) and validated by echocardiography and left ventricle (LV) catheterization. The β-AR protein expressions in LV were evaluated by western-blot at days 35 (d35) and 70 (d70) after the first doxorubicin injection. Ex vivo cardiac contractility (dP/dtmax, dP/dtmin) was evaluated on isolated heart in response to specific β-AR stimulations at d35. Results At d35, Dox-CM hearts were characterized by mild LV systolic and diastolic dysfunctions, which were exacerbated at d70. In Dox-CM hearts, β3-AR expression was only decreased at d70 (-37±8%). At d35, β1-AR expression was decreased by 68±6%, but ex vivo β1-AR function was preserved due to, at least in part, an increased adenylyl cyclase response assessed by forskolin. β2-AR expression was increased both at d35 (+58±22%) and d70 (+174±35%), with an increase of ex vivo β2-AR response at d35. Inhibition of Gi protein with pertussis toxin did not affect β2-AR response in Dox-CM hearts, suggesting a decoupling of β2-AR to Gi protein. Conclusion This study highlights the β1/β2-AR imbalance in early Dox-CM and reveals the important role that β2-AR/Gi coupling could play in this pathology. Our results suggest that β2-AR could be an interesting target at early stage of Dox-CM.

Cardiac Protective Effects of Moringa oleifera Seeds in Spontaneous Hypertensive Rats

BACKGROUND Hypertension is characterized by a maintained high blood pressure leading to cardiac complications such as left ventricular hypertrophy and fibrosis and an increased risk of heart failure and myocardial infarction. This study investigated the cardiac effects of oral administration of Moringa oleifera (MOI) seed powder in spontaneous hypertensive rats (SHR). METHODS SHR received food containing MOI seed powder (750mg/d, 8 weeks) or normal food. In vivo measurement of hemodynamic parameters by telemetry and cardiac structure and function analysis by echocardiography were performed. Histological studies were performed to determine fibrosis and protein expression. RESULTS MOI treatment did not modify blood pressure in SHR but reduced nocturnal heart rate and improved cardiac diastolic function (reduction of isovolumetric relaxation time and deceleration time of the E wave, increase of ejection volume and cardiac output compared to nontreated SHR). Left ventricular anterior wall thickness, interseptal thickness on diastole, and relative wall thickness were reduced after MOI treatment. Furthermore, we found a significant reduction of fibrosis in the left ventricle of MOI-treated SHR. This antihypertrophic and antifibrotic effect of MOI was associated with increased expression of peroxisome proliferator-activated receptor (PPAR)-α and δ, reduced cardiac triglyceride level, and enhanced plasmatic prostacyclins. CONCLUSIONS Our data show a beneficial effect of MOI on the cardiac structure and function in SHR associated with an upregulation of PPAR-α and δ signaling. This study thus provides scientific rational support for the empirical use of MOI in the traditional Malagasy medicine against cardiac diseases associated with blood pressure overload.

231: At early phase of endotoxemic shock the increased β-adrenergic contractility is dependent of the endothelial β1-adrenoceptor

Cardiovascular alterations in the septic shock include an hypotension associated with a cardiomyopathy. The sympathetic regulation of the cardio-vascular system is impaired during the shock and associated with an altered endothelial function. However, involved cellular mechanisms are not clear. The aims of this project were to determine the role of the three β-adrenoceptor subtypes, β1, β2 and β3-AR in the cardiac dysfunction in endotoxemic rats. Methods Rats (12w) received either endotoxin (LPS, 5mg. kg-1) or saline i.v. (C). 3h later, cardiac parameters were studied in vivo by echocardiography. Selective β-AR responses were studied on papillary muscle contractility with or without a functional endothelium. Endothelium damage was realized with 3s Triton X-100 at 0.5%. Results In vivo, LPS rats presented altered systolic (shortening fraction -21±4% vs C p Conclusion Our results demonstrate, for the first time, an increased β1-AR contractility, on papillary muscle form LPS rats, dependent of the functional endothelium. This suggests that β1-AR could be involved in the persistent tachycardia observed in the shock leading to propose β1-AR blockers in this disease.

262 Are Zucker Obese Rats a Useful Model for Cardiovascular Complications in Metabolic Syndrome? Physical, Biochemical and Oxidative Stress Considerations

We wondered if Zucker obese (ZO) rats would be a good experimental model to evaluate cardiovascular complications of Metabolic Syndrome (MS). ZO rats were compared with both their littermate controls, Zucker lean (ZL) rats and to Wistar rats (reference strain). We designed this work 1) to measure certain physical and biochemical characteristics of MS 2) to evaluate coronary and cardiac function in isolated conditions and after ischemia 3) to study plasma and heart tissue oxidative stress markers. In vivo , ZO rats had higher levels of plasma glucose, cholesterol and triglycerides than their ZL littermates, but there was no difference between the groups for systolic arterial blood pressure and heart rate. I n vitro , coronary endothelial function was notably impaired in ZO and ZL rats. After global ischemia, the worse ventricular recovery in ZO and ZL rats was associated with arrhythmias during reperfusion. We detected similar levels of plasma ascorbyl free radical, Oxygen Radical Absorbance Capacity and vitamin C concentrations in the three groups. DHE staining showed higher superoxide production in the coronary vessels of ZO rats than in ZL and Wistar rats. Our results show that ZO might only correspond to early-stage cardiovascular complications associated with MS.

264 Effects of Angiotensin-1 Converting Enzyme inhibition on oxidative stress and bradykinin receptor expression during doxorubic in-induced cardiomyopathy in rats

To evaluate the mechanisms and the impact of the ACE-inhibitor perindopril (P) in a model of doxorubicin (D)- induced cardiotoxicity, male Wistar rats received D (1mg/kg/d, i.p. for 10 days), P (2 mg/kg/d by gavage from day 1 to day 18), D (for 10 days) + P (for 18 days) or saline. D decreased systolic blood pressure, body and heart weights. Left ventricular diastolic diameter was increased by D (p In conclusion, D induced cardiac functional alterations, inflammation and plasma OS whereas tissue OS, and cardiac kinin receptors expression were not modified. P did not improve cardiac performance, but modulated kinin receptor expression and enhanced antioxidant defense.