Reduced endogenous nitric oxide (NO) production has been described in many cardiovascular disorders, including cardiac hypertrophy and heart failure (HF). The therapy with conventional nitrates is limited by their hemodynamic effects and drug tolerance. The NO-donor LA-419, an organic nitrate with a thiol group in its molecule, has previously demonstrated important anti-thrombotic and anti-ischemic properties without adverse effects. The aim of this study was to evaluate the effect of LA-419 chronic treatment on cardiac hypertrophy development in a progressive model of left ventricular hypertrophy (LVH) model. Sprague-Dawley rats were subjected to aortic stenosis for up to 14 weeks and treated with LA-419 (30 mg/kg per day) once LVH was established (7 weeks after the surgery).

Cardiac hypertrophy assessed by an increase in heart weight, heart weight/body weight ratio, left ventricular (LV) diameter, and LV cavity size was significantly reduced in stenosed rats after LA-419 treatment. Histological analysis also confirmed that LA-419 was able to attenuate ventricular dilatation and myocardial fibrosis without modifying the high blood pressure observed in rats with pressure overload. In addition, LA-419 treatment restored endothelial NO synthase (eNOS) and caveolin-3 expression levels, enhanced the interaction between eNOS and its positive regulator the heat shock protein 90 (Hsp90), and re-established the normal cardiac content of cGMP in stenosed rats. Thus, chronic treatment with LA-419 prevented the progression to maladaptative cardiac hypertrophy in response to prolonged pressure overload without modifying blood pressure and through a mechanism that involved the re-establishment of eNOS signalling pathway.