Background:

A chronic NO deficiency occurs under several physiological and pathophysiological conditions. The reduction in NOS activity during heart failure must also be considered, such as the reduced NO levels in chronic renal insufficiency. On the other hand, a chronic decrease in NO is considered responsible for a variety of cardiovascular diseases. There is evidence that chronic NO deficiency contributes to increased matrix deposition and fibrosis. The current study investigates to what extent a chronic deficiency in nitric oxide affects the structural and functional remodeling of the left (LV) and right (RV) ventricle.

Methods:

NO deficit was achieved in adult rats by feeding them the NO-synthase-inhibitor L-NAME alone (L) and in combination with captopril (L/C) or tempol (L/T) (n=8 each group). Heart weight to body weight ratio, the expression of fibrotic and hypertrophic genes (RT-PCR, Western Blot) as well as the cardiac function (Millar Tip-catheter) and the postmortal ventricular geometry were determined after four weeks.

Results:

No changes occurred in any parameters in the LV independent of the treatment scheme. In contrast, RV of the L group displayed a significant increase in TGFβ (+94%) and collagen (+80%) expression and displayed anatomical and functional features of a restrictive cardiomyopathy. These changes could be prevented by additional feeding of captopril (L/C) or tempol (L/T). In isolated cardiomyocytes of untreated rats L-NAME treatment led to an increased ROS production (+49%) which could be blocked by preincubation with captopril. The observation that only RV was affected by this mechanism could be explained by a different expression pattern of superoxid dismutases (SOD). However, in contrast to a significant upregulation of SOD2 in the left ventricle of L-NAME fed animals, even a decrease of SOD2 expression took place in the RV.

Conclusion:

Increased levels of ROS are responsible for the negative remodeling of right ventricles in chronic NO deficient rats. The cardioprotective effects of captopril and tempol are mediated through a normalization of ROS levels independent of blood pressure reducing effects.