Nitric oxide (NO) production is known to be impaired in
heart failure. A new compound (
NCX 899), a NO-releasing derivative of
enalapril was characterized, and its actions were evaluated in Bio 14.6 cardiomyopathic (CM) hamsters with
heart failure. The hamsters were randomized to oral treatment for 4 weeks with vehicle (n=11),
NCX 899 (NCX, 25 mg/kg, n=10), or
enalapril (25 mg/kg, n=10). In the vehicle group, fractional shortening by echocardiography decreased (-23.6+/-2.0%) and LV end-diastolic dimension) increased (+10.9+/-1.0%), whereas fractional shortening increased (+17.5+/-4.4%) in NCX and was unchanged in the
enalapril group (both P<0.01 vs. vehicle). End-diastolic dimension decreased only in NCX. LV contractility (LVdP/dt max and Emax) was significantly greater in NCX than in
enalapril or vehicle, while relaxation (Tau) was shortened in both NCX and
enalapril vs. vehicle. ACE activity was inhibited equally by NCX and
enalapril in the CM hamster, and plasma
nitrate levels were increased only in NCX (P<0.05 vs.
enalapril and vehicle). In aortic strips endothelium-independent relaxation occurred only with NCX. The superior effects of NO-releasing
enalapril (NCX) vs.
enalapril alone to enhance vascular effects, increase LV contractility and prevent unfavorable remodeling and are consistent with vascular delivery of exogenous NO.
NCX 899 may hold promise for the future treatment of
heart failure.