title: Impaired flow-induced dilation of coronary arterioles of dogs fed a low-salt diet: roles of ANG II, PKC, and NAD(P)H oxidase.
abstract: Low-salt (LS) diet has been considered to be beneficial in the prevention and treatment of hypertension; however, it also increases plasma angiotensin (ANG) II and may cause adverse cardiovascular effects, such as endothelial dysfunction. We assessed endothelial function of coronary arterioles and vascular superoxide production, as a function of LS diet. Dogs were fed with LS (0.05% NaCl) or a normal-salt (NS, 0.65% NaCl) diet for 2 wk. There were threefold increases in plasma ANG II, associated with a 60% reduction in flow-induced dilation (FID) in coronary arterioles of LS compared with NS dogs. In vessels of NS dogs, FID was primarily mediated by nitric oxide (NO), as indicated by an eliminated FID by N(ω)-nitro-l-arginine methyl ester (l-NAME). In vessels of LS dogs, however, FID was eliminated. Administration of apocynin, a NAD(P)H oxidase inhibitor, partially restored FID and additional l-NAME eliminated FID. Generation of superoxide, measured with dihydroethidium, was significantly greater in vessels of LS than in NS dogs, which was further increased in response to ANG II or phorbol 12,13-dibutyrate, an agonist of protein kinase C (PKC). The enhanced superoxide was normalized by apocynin, losartan (a blocker of angiotensin type 1 receptor), and chelerythrine chloride (an antagonist of PKC). Western blotting indicated an upregulation of gp91(phox) and p47(phox), associated with increased expression of phosphorylated PKC in vessels of LS dogs. In separate experiments, dogs were fed simultaneously with LS and losartan (LS + Losa) for 2 wk. There was a significant increase in plasma ANG II in LS + Losa dogs, which, however, was associated with normal FID and gp91(phox) expression in coronary arterioles. In conclusion, LS led to endothelial dysfunction, as indicated by an impaired flow-induced dilation caused by decreasing NO bioavailibility, a response that involves angiotensin-induced activation of PKC that, in turn, activates vascular NAD(P)H oxidase to produce superoxide.
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, New York 10595, USA.
authors.forename: An
authors.initials: A
authors.lastname: Huang
authors.forename: Changdong
authors.initials: C
authors.lastname: Yan
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Suematsu
authors.forename: Azita
authors.initials: A
authors.lastname: Cuevas
authors.forename: Yang-Ming
authors.initials: YM
authors.lastname: Yang
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kertowidjojo
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Hintze
authors.forename: Gabor
authors.initials: G
authors.lastname: Kaley
authors.forename: Dong
authors.initials: D
authors.lastname: Sun
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D004285:Dogs; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D023421:Models, Animal; D019255:NADPH Oxidases / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D017673:Sodium Chloride, Dietary / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D017673:Sodium Chloride, Dietary; D013481:Superoxides; D000804:Angiotensin II; D009569:Nitric Oxide; D019255:NADPH Oxidases; D011493:Protein Kinase C; D019808:Losartan