Endothelial permeability in vitro and in vivo: protective actions of ANP and omapatrilat in experimental atherosclerosis.
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.
Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, United States. Electronic address: ichiki.tomoko@mayo.edu.
Tomoko
T
Ichiki
Ririko
R
Izumi
Alessandro
A
Cataliotti
Amy M
AM
Larsen
Sharon M
SM
Sandberg
John C
JC
Burnett
D000809:Angiotensins / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000473:pathology; D050197:Atherosclerosis / Q000188:drug therapy* / Q000473:pathology; D009320:Atrial Natriuretic Factor / Q000008:administration & dosage* / Q000378:metabolism; D059305:Diet, High-Fat; D042783:Endothelial Cells / Q000187:drug effects; D006801:Humans; D015260:Neprilysin / Q000378:metabolism; D009924:Organ Culture Techniques; D010539:Permeability / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage*; D011817:Rabbits; D013841:Thiazepines / Q000008:administration & dosage*; D014664:Vasodilation / Q000187:drug effects*
D000809:Angiotensins; D011725:Pyridines; D013841:Thiazepines; C106266:omapatrilat; D009320:Atrial Natriuretic Factor; D015260:Neprilysin
ACE; ACE inhibition; ACEI; ANG; ANP; Angiotensin converting enzyme inhibitor; Atherosclerosis; Atrial natriuretic peptides; B-type natriuretic peptide.; BNP; EC; ECP; Endothelium; GC-A; HAECs; HDL-C; LDL-C; MAP; NEP; NEP inhibition; NEPI; NO; Neprilysin inhibitor; OMA; VSMCs; angiotensin; angiotensin converting enzyme; atrial natriuretic peptide; cGMP; cyclic guanosine monophosphate; endothelial cell; endothelial cell permeability; guanylyl cyclase-A receptor; high density lipoprotein cholesterol; human aortic endothelial cells; low density lipoprotein cholesterol; mean arterial pressure; neprilysin; nitric oxide; omapatrilat; vascular smooth muscle cells