Effect of omapatrilat on the aging process of the normal rat

Previous results have shown that inhibition of the renin-angiotensin system (RAS) either with an angiotensin II (Ang II), type 1 receptor blocker (losartan) or with an angiotensin converting enzyme inhibitor (ACEI, enalapril) has a protective effect on cardiovascular, renal, hepatic and cerebral structure and function during aging. The present study has analyzed the effect of chronic administration of a newly developed compound, omapatrilat, on clinical, histological and biochemical changes due to aging. Omapatrilat combines the action of an ACEI and of an inhibitor of a neutral endopeptidase involved in the metabolism of the atrial natriuretic peptide. The final effect is a decrease of a vasoconstrictor and proinflammatory mechanism like the RAS and the potentiation of two vasodilating compounds like bradykinin and the atrial natriuretic peptide. Based on these actions, its protective effect might be greater than formerly used pharmacological agents. Determinations have been performed on young adults (6 months old), adults (12 months old) or senile (18 months old) rats. Omapatrilat (35 mg/kg/day during 6 months and 20 mg/kg/day thereafter) was administered in the drinking water since weaning until sacrifice. Cardiovascular, renal, and cerebral structure as well as cognitive behavior, cardiovascular and renal function has been analyzed. The biochemical analysis has also established whether the beneficial action of Ang II inhibition is related to an increased activity of the nitric oxide synthase as observed in previous studies. Moreover, this study has tried to determine the relationship between the protective effect of these drugs and the levels of antioxidant defenses present in the blood and/or in the tissues. Hence, enzymatic and non-enzymatic antioxidants have been evaluated.