title: Hemodynamic and cardiac effects of chronic eprosartan and moxonidine therapy in stroke-prone spontaneously hypertensive rats.
abstract: The renin-angiotensin and sympathetic nervous systems play critical interlinked roles in the development of left ventricular hypertrophy, fibrosis, and dysfunction. These studies investigated the hemodynamic and cardiac effects of monoblockade and coblockade of renin-angiotensin and sympathetic nervous systems. Stroke-prone spontaneously hypertensive rats (16 weeks old; male; n=12 per group) received the sympatholytic imidazoline compound, moxonidine (2.4 mg/kg per day); the angiotensin-receptor blocker eprosartan (30 mg/kg per day), separately or in combination; or saline vehicle for 8 weeks, SC, via osmotic minipumps. Blood pressure and heart rate were continuously measured by radiotelemetry. After 8 weeks, in vivo cardiac function and structure were measured by transthoracic echocardiography and a Millar conductance catheter, and the rats were then euthanized and blood and heart ventricles collected for various determinations. Compared with vehicle, the subhypotensive dose of moxonidine resulted in lower (P<0.01) heart rate, left ventricular hypertrophy, cardiomyocyte cross-sectional area, interleukin 1 beta, tumor necrosis factor-alpha, and mRNA for natriuretic peptides. Eprosartan reduced pressure (P<0.01), as well as extracellular signal-regulated kinase (ERK) 44 phosphorylation, Bax/Bcl-2, and collagen I/III, and improved left ventricular diastolic function (P<0.03). Combined treatment resulted in greater reductions in blood pressure, heart rate, left ventricular hypertrophy, collagen I/III, and inhibited inducible NO synthase and increased endothelial NO synthase phosphorylation, as well as reduced left ventricular anterior wall thickness, without altering the other parameters. Thus, in advanced hypertension complicated with cardiac fibrosis, sympathetic inhibition and angiotensin II blockade resulted in greater reduction in blood pressure and heart rate, inhibition of inflammation, and improved left ventricular pathology but did not add to the benefits of angiotensin II blockade on cardiac function.
authors.affiliation: University of Montreal Hospital Research Center (CRCHUM), Montreal, Quebec, Canada. suhayla.mukaddam-daher@umontreal.ca
authors.forename: Suhayla
authors.initials: S
authors.lastname: Mukaddam-Daher
authors.forename: Ahmed
authors.initials: A
authors.lastname: Menaouar
authors.forename: Pierre-Alexandre
authors.initials: PA
authors.lastname: Paquette
authors.forename: Marek
authors.initials: M
authors.lastname: Jankowski
authors.forename: Jolanta
authors.initials: J
authors.lastname: Gutkowska
authors.forename: Marc-Antoine
authors.initials: MA
authors.lastname: Gillis
authors.forename: Yan-Fen
authors.initials: YF
authors.lastname: Shi
authors.forename: Angelo
authors.initials: A
authors.lastname: Calderone
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
mesh_terms: D000179:Acrylates / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D009320:Atrial Natriuretic Factor / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects*; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D011918:Rats, Inbred SHR; D020521:Stroke / Q000209:etiology; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D000179:Acrylates; D000959:Antihypertensive Agents; D007093:Imidazoles; D013876:Thiophenes; C068373:eprosartan; D009320:Atrial Natriuretic Factor; C043482:moxonidine; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat