NITRIC OXIDE PATHWAY IN HYPERTROPHIED HEART: NEW THERAPEUTIC USES OF NITRIC OXIDE DONORS

C. Delgado. Facultad de Medicina, Universidad Complutense, Madrid, Departamento de Farmacologia, 28040, Spain

Cardiac hypertrophy is a major predictor of progressive heart disease and an adverse prognosis. Cardiac hypertrophy is recognized as an adaptive process to a variety of physiological and pathological conditions. It is often associated with diseases like hypertension, myocardial infarction and ischaemia associated with coronary artery disease. Cardiac hypertrophy is usually considered to be initially adaptive by normalizing wall stress. However, chronic pressure overload leads eventually to contractile depression, ventricular dilatation, interstitial cardiac fibrosis, and the development of heart failure. Despite the fact that hypertrophy was described more than a century ago, the mechanisms underlying progression of hypertrophy to heart failure have yet to be clearly understood. The NO signalling cascade remains an important target to prevent or reverse pathological heart rebuilding, and several novel compounds designed to modulate this pathway have demonstrated beneficial effects on cardiac hypertrophy and remodelling. The main focus of this presentation will be to describe the role of NO pathway modulation in the left ventricle during its hypertrophic remodelling. We will also describe some new NO-based therapeutic approaches that aim to prevent/reduce the pathological growth of the left ventricle. The most promising therapeutic approach is represented by a new neutral sugar organic nitrate, LA-419, the thiol group of which seems to protect NO from degradation, thereby increasing its bioavailability. In a model of aortic stenosis induced pressure overload, chronic administration of LA419 inhibited dilated cardiac hypertrophy and myocardial fibrosis without modifying high arterial blood pressure. These effects of LA419 treatment were mediated, at least in part, by the re-establishment of the eNOS signaling pathway. The generation of new, tolerance-free organic nitrates, such as LA-419, seem to represent a promising therapeutic approach against pathological cardiac hypertrophy.