Publication Date

2014

Document Type

Thesis

Committee Members

Roberta Pohlman (Committee Member), Mariana Morris (Advisor), Richard Simman (Committee Member)

Degree Name

Master of Science (MS)

Abstract

Angiotensin Type 1 (AT1) receptors are involved in cardiovascular pathology. Losartan, the AT1 receptor blocker, in combination with exercise has been shown to be effective in improving cardiac performance. The goal of the study was to investigate the role of AT1a receptors on cardiac function, and exercise tolerance in response to aerobic exercise using AT1a receptor knockout (AT1aKO) mice. An exercise wheel system was used for the exercise paradigm. Male (C57BL/6) wild type (WT) and AT1aKO mice were randomly assigned to four groups: WT control (n=6), WT exercise (WTEX, n=8), AT1a KO (KO) control (n=5), and AT1a KO exercise (KOEX, n=8). Mice were forced to run at a velocity of 8 m/min for 1 hour, 3d/wk, for 7 wks. Echocardiography was conducted at baseline and 7 wks. Lactate was measured during several exercise sessions. Electrolytes and cardiac histology were assessed post-sacrifice. Results showed a significant increase in ejection fraction (EF %) in KOEX (72.5±1.5%) vs. WTEX and KO control (63.4±1.2% and 63.2±2.2%, respectively). Mitral valve assessment revealed a marked decrease in E-wave velocity in WTEX compared to WT control at baseline (74±1.9 vs.90±3.5 cm/s, p<0.05), while E/A wave ratio remained unchanged. Cardiomyocyte diameter was larger in WTEX compared to KOEX (29.5±0.7 vs. 25.8±0.5 μm, p<0.05). Heart to body weight ratio was significantly higher in WTEX vs. KOEX (5.5±0.2 vs. 4.3±0.1 mg/g, p<0.001). Masson's Trichrome staining revealed higher collagen levels in WTEX myocardium compared to WT control and KOEX (16% vs. 5%). Blood lactate accumulation values were greater at 5 and 60 min of wheel running in WTEX (4.2±0.4 and 3.9±0.5 mmol/l) vs. KOEX (3.0±0.2 and 2.9±0.2 mmol/l). A basic metabolic panel revealed higher [HCO3-] in KOEX vs. WTEX (21.7±0.6 vs. 13.7±1.8 mmol/l). Cl- was lower in KOEX compared to WTEX (102.5±2.5 vs. 113.5±2.7mmol/l, p<0.05). In conclusion, AT1aKO mice exhibited improved cardiac performance without myocardium hypertrophy, greater exercise endurance, and enhanced metabolic activity in response to chronic exercise. These results suggest that the AT1a receptor is an important mediator of exercise induced cardiac dysfunction and acid-base imbalance during exercise training.

Page Count

97

Department or Program

Department of Pharmacology and Toxicology

Year Degree Awarded

2014

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