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AuthorPearson, James T.
AuthorThambyah, Hamish P.
AuthorWaddingham, Mark T.
AuthorInagaki, Tadakatsu
AuthorSukumaran, Vijayakumar
AuthorNgo, Jennifer P.
AuthorOw, Connie p.C.
AuthorSonobe, Takashi
AuthorChen, Yi Ching
AuthorEdgley, Amanda J.
AuthorFujii, Yutaka
AuthorDu, Cheng-Kun
AuthorZhan, Dong-Yun
AuthorUmetani, Keiji
AuthorKelly, Darren J.
AuthorTsuchimochi, Hirotsugu
AuthorShirai, Mikiyasu
Available date2023-08-29T10:21:47Z
Publication Date2021
Publication NameClinical Science
ResourceScopus
ISSN1435221
URIhttp://dx.doi.org/10.1042/CS20201441
URIhttp://hdl.handle.net/10576/46994
AbstractA high salt intake exacerbates insulin resistance, evoking hypertension due to systemic perivascular inflammation, oxidative-nitrosative stress and endothelial dysfunction. Angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blockers (ARBs) have been shown to abolish inflammation and redox stress but only partially restore endothelial function in mesenteric vessels. We investigated whether sympatho-adrenal overactivation evokes coronary vascular dysfunction when a high salt intake is combined with insulin resistance in male Goto–Kakizaki (GK) and Wistar rats treated with two different classes of β-blocker or vehicle, utilising synchrotron-based microangiography in vivo. Further, we examined if chronic carvedilol (CAR) treatment preserves nitric oxide (NO)-mediated coronary dilation more than metoprolol (MET). A high salt diet (6% NaCl w/w) exacerbated coronary microvessel endothelial dysfunction and NO-resistance in vehicle-treated GK rats while Wistar rats showed modest impairment. Microvascular dysfunction was associated with elevated expression of myocardial endothelin, inducible NO synthase (NOS) protein and 3-nitrotyrosine (3-NT). Both CAR and MET reduced basal coronary perfusion but restored microvessel endothelium-dependent and -independent dilation indicating a role for sympatho-adrenal overactivation in vehicle-treated rats. While MET treatment reduced myocardial nitrates, only MET treatment completely restored microvessel dilation to dobutamine (DOB) stimulation in the absence of NO and prostanoids (combined inhibition), indicating that MET restored the coronary flow reserve attributable to endothelium-derived hyperpolarisation (EDH). In conclusion, sympatho-adrenal overactivation caused by high salt intake and insulin resistance evoked coronary microvessel endothelial dysfunction and diminished NO sensitivity, which were restored by MET and CAR treatment in spite of ongoing inflammation and oxidative-nitrosative stress presumably caused by uninhibited renin–angiotensin–aldosterone system (RAAS) overactivation.
SponsorThis work was supported by the National Health and Medical Research Council Senior Research Fellowship and Programme grant [grant number 1092642 (to D.J.K.)]; travel funded by the International Synchrotron Access Program [grant number ISAP, AS/IA131] managed by the Australian Synchrotron, part of ANSTO, and funded by the Australian Government; the Intramural Research Funds [grant numbers 22-2-3, 22-3-2] of the National Cerebral and Cardiovascular Center; and the JSPS KAKENHI [grant number 19H03405].
Languageen
PublisherPortland Press Ltd
Subjectinsulin resistance
sympathetic nervous system
vascular dysfunction
Titleβ-blockade prevents coronary macro- and microvascular dysfunction induced by a high salt diet and insulin resistance in the Goto–Kakizaki rat
TypeArticle
Pagination327-346
Issue Number2
Volume Number135
dc.accessType Abstract Only


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