title: Differential effects of late-life initiation of low-dose enalapril and losartan on diastolic function in senescent Fischer 344 x Brown Norway male rats.
abstract: No proven pharmacological therapies to delay or reverse age-related diastolic dysfunction exist. We hypothesized that late-life low-dose (non-blood-pressure-lowering) angiotensin-converting enzyme inhibition vs. angiotensin II receptor blockade would be equally efficacious at mitigating diastolic dysfunction in the senescent Fischer 344 × Brown Norway rat. Enalapril (10 mg/kg/day; n = 9) initiated at 24 months of age and continued for 6 months, increased myocardial relaxation (e'), reduced Doppler-derived indices of filling pressure (E/e'), favorably lowered the ratio of phospholamban-SERCA2 and reduced oxidative stress markers, Rac1 and nitrotyrosine, in aged hearts. Treatment with losartan (15 mg/kg/day; n = 9) similarly mitigated signs of cardiac oxidative stress, but impairments in diastolic function persisted when compared with untreated rats (n = 7). Our findings favor the idea that the lusitropic benefit of low-dose angiotensin-converting enzyme inhibitor initiated late in life may be related to an antioxidant-mediated modulation of SERCA2, resulting in improved relaxation rather than via overt effects on cardiac structure or blood pressure.
authors: Department of Anesthesiology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1009, USA. lgroban@wfubmc.edu
authors: Leanne
authors: L
authors: Groban
authors: Sarah
authors: S
authors: Lindsey
authors: Hao
authors: H
authors: Wang
authors: Marina S
authors: MS
authors: Lin
authors: Kimberly A
authors: KA
authors: Kassik
authors: Frederico S M
authors: FS
authors: Machado
authors: Christy S
authors: CS
authors: Carter
mesh_terms: D000375:Aging / Q000187:drug effects*; D000704:Analysis of Variance; D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects; D003971:Diastole / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D015150:Echocardiography, Doppler; D004656:Enalapril / Q000494:pharmacology*; D006334:Heart Function Tests / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects*; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D012016:Reference Values; D012680:Sensitivity and Specificity; D016277:Ventricular Function, Left / Q000187:drug effects* / Q000502:physiology
chemical_list: D004656:Enalapril; D019808:Losartan