Acute NEP/ACE inhibition by omapatrilat is superior to ace inhibition alone in mediating favorable cardiorenal and humoral actions in mild heart failure

Abstract

Mild heart failure (HF) is characterized by increases in the cardiac peptides ANP and BNP without activation of the renin-angiotensin-aldosterone system (RAAS). Both ANP and BNP, which possess natriuretic, vasodilating and renin inhibiting properties, are degraded by neutral endopeptidase 24.11 (NEP). Omapatrilat (OMA) is the first of a novel class of cardiovascular agents that inhibit both NEP and angiotensin-converting enzyme (ACE). As the RAAS is not activated in mild HF, we hypothesized that dual NEP-ACE inhibition will result in greater cardiorenal and humoral actions as compared to ACE inhibition alone. We compared the cardiorenaI and humoral actions of OMA (1 txmol/kg iv bolus) (n-6), to ACE inhibition(ACEI) with Fosinoprilat (1 /~mol/kg iv bolus) (n 5), in anaesthetized dogs with mild HF produced by rapid ventricular pacing at 180 beats/min for 10 days. OMA resulted in a greater natriuretic response as compared with ACEI (78+15 vs 3229/xEq/min, p<0.05). This OMA mediated natriuresis was associated with increased plasma cGMP (18+3 to 25292 pmol/mI*), ANP (144---15 to 259+ 14 pg/ml*) and BNP (100-+ 18 to 152233 pg/ml*) levels, urinary cGMP (13842250 to 2408-+514 pmol/min*) and urinary ANP (33210 to 125--40 pg/min*) excretion and glomerular filtration rate (30-+4 to 4725 ml/min*) (* p<0.05 vs baseline). Pulmonary capillary wedge pressure (1522 to 11-+1 mmHg, p<0.05) decreased only in the OMA group while the reduction in right atrial pressure was more sustained with OMA as compared ACEI. Plasma renin and aldosterone levels were increased only in the ACEI group (p<0.05 vs baseline). This study reports for the first time that acute OMA administration in mild HF results in a greater natriurefic response as compared to ACEI and is associated with reductions in cardiac filling pressures. These favorable actions occur secondary to the potentiation of the natriuretic peptides as evident by the increase in plasma and urinary excretion of both the natriuretic peptides and their second messenger cGMP. Furthermore, unlike ACEI, there is no activation of renin and aldosterone with OMA. This study provides new insight into a unique new compound that has beneficial actions in mild heart failure beyond those observed with ACE inhibition alone. The Third Annual Scientific Meeting • HFSA 13