0032: Exercise failed to improve NO pathway in SHR rats and markedly increases eNOS dependent ROS production

AimThe spontaneously hypertensive rat (SHR) is widely described as an animal model which shares with human essential hypertension several similitudes and notably endothelial dysfunction. This study investigated whether exercise, a recognized strategy to prevent endothelial dysfunction, could have beneficial effects on arterial vasomotricity and blood pressure in SHR rats. A specific attention was paid to endothelium-dependent relaxing factors.MethodArterial blood pressure was assessed by tail-cuff method in WKY, SHR and SHR exercised (1 hour 70% of VO2max; 5 days/week for 6 weeks) rats. Arterial function was evaluated on isolated aortic rings in response to ACh or SNP in presence or not of different inhibitors (L-NAME, indomethacin, TRAM34 and Apamine) to discriminate the role of different vasodilator triggers (NO, PGI2, EDHF). Finally, aortic total and NOS-dependent ROS production were measured using Electron paramagnetic resonance.ResultsAn unexpected result was that exercise training did not moderate hypertension in SHR rats. Although, endothelium-dependent vasorelaxation was altered in SHR, no beneficial effect of exercise was observed. This altered response to ACh in SHR rats was mainly explained by COX, since inhibition of this enzyme markedly correct endothelium dysfunction. However, COX pathways were not impacted by exercise. Although exercise is largely recognized as increasing eNOS activity, we reported that exercise has no effect on eNOS-dependent vasorelaxation. Especially, exercise in SHR rats resulted in increased NOS-dependent ROS production suggesting increased eNOS uncoupling and resulting then in increased total ROS production in arterial tissue.In conclusionwe can postulate that, the lack of positive effect of exercise training on essential hypertension could be explained by unexpected eNOS uncoupling with exercise. This hypothesis has to be confirmed by the use of a recoupling agent and by biochemical assays of eNOS dimerized state