Increased arterial endothelial cell permeability (ECP) is considered an initial 
step in atherosclerosis. Atrial natriuretic peptide (ANP) which is rapidly 
degraded by neprilysin (NEP) may reduce injury-induced endothelial cell 
leakiness. Omapatrilat represents a first in class of pharmacological agents 
which inhibits both NEP and angiotensin converting enzyme (ACE). We hypothesized 
that ANP prevents thrombin-induced increases of ECP in human aortic ECs (HAECs) 
and that omapatrilat would reduce aortic leakiness and atherogenesis and enhance 
ANP mediated vasorelaxation of isolated aortas. Thrombin induced ECP determined 
by I(125) albumin flux was assessed in HAECs with and without ANP pretreatment. 
Next we examined the effects of chronic oral administration of omapatrilat (12 
mg/kg/day, n=13) or placebo (n=13) for 8 weeks on aortic leakiness, 
atherogenesis and ANP-mediated vasorelaxation in isolated aortas in a rabbit 
model of atherosclerosis produced by high cholesterol diet. In HAECs, 
thrombin-induced increases in ECP were prevented by ANP. Omapatrilat reduced the 
area of increased aortic leakiness determined by Evans-blue dye and area of 
atheroma formation assessed by Oil-Red staining compared to placebo. In isolated 
arterial rings, omapatrilat enhanced vasorelaxation to ANP compared to placebo 
with and without the endothelium. ANP prevents thrombin-induced increases in ECP 
in HAECs. Chronic oral administration of omapatrilat reduces aortic leakiness 
and atheroma formation with enhanced endothelial independent vasorelaxation to 
ANP. These studies support the therapeutic potential of dual inhibition of NEP 
and ACE in the prevention of increased arterial ECP and atherogenesis which may 
be linked to the ANP/cGMP system.