title: Effects of olmesartan on Apelin/APJ and Akt/endothelial nitric oxide synthase pathway in Dahl rats with end-stage heart failure.
abstract: Apelin and its cognate G protein-coupled receptor APJ constitute a signaling pathway with a positive inotropic effect on cardiac function, and the apelin/APJ pathway seems to have opposing physiological role to the renin-angiotensin system. We investigated whether angiotensin II receptor blocker olmesartan could improve cardiac function associated with apelin/APJ and Akt/endothelial nitric oxide synthase (eNOS) pathway in Dahl salt-sensitive hypertensive (DS) rats with end-stage heart failure using NOS inhibitor L-N(G)-nitroarginine methyl ester (L-NAME). High salt-loaded DS rats were treated with (1) vehicle, (2) olmesartan, and (3) olmesartan plus L-NAME for 7 weeks. Decreased end-systolic elastance and percent fractional shortening in failing rats were significantly ameliorated by olmesartan. Increased atherosclerosis and vascular remodeling and fibrosis factors such as procollagen type I and III and fibronectin expression in DS rats were inhibited by olmesartan. Downregulation of apelin and APJ expression and phosphorylation of Akt and eNOS in failing rats were significantly increased by olmesartan. In addition,administration of L-NAME completely abrogated the olmesartan-mediated improvement of cardiac function and remodeling, and apelin/APJ expression and Akt/eNOS phosphorylation. These findings suggest that olmesartan may improve cardiac dysfunction and remodeling associated with apelin/APJ and Akt/eNOS pathway in DS rats with end-stage heart failure.
authors.affiliation: Department of Hypertension and Cardiorenal Medicine, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Fukushima
authors.forename: Naohiko
authors.initials: N
authors.lastname: Kobayashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takeshima
authors.forename: Wataru
authors.initials: W
authors.lastname: Koguchi
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Ishimitsu
mesh_terms: D054392:Adipokines; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000073861:Apelin; D000075244:Apelin Receptors; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D054392:Adipokines; D047228:Angiotensin II Type 1 Receptor Blockers; D000073861:Apelin; D000075244:Apelin Receptors; C402826:Apln protein, mouse; C491285:Aplnr protein, mouse; D002352:Carrier Proteins; D007093:Imidazoles; D036341:Intercellular Signaling Peptides and Proteins; D043562:Receptors, G-Protein-Coupled; D013777:Tetrazoles; C437965:olmesartan; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D019331:NG-Nitroarginine Methyl Ester