Lori S. Kang

Date of Graduation

2009

Document Type

Dissertation/Thesis

Abstract

Study I examined the effects of aging and reactive oxygen species on flow-mediated vasodilation in coronary arterioles. Isolated coronary arterioles of young (4 mo) and aged (24 mo) male Fisher 344 rats were subjected to stepwise increases in flow (0–50 nL/sec) in the presence and absence of superoxide dismutase (SOD) mimetic Tempol (100 µM), hydrogen peroxide (H2 O2) scavenger catalase (100 U/mL), Tempol + catalase, or Tempol + deferoxamine (100 µM), an iron chelator and inhibitor of hydroxyl radical formation. Flow-induced nitric oxide (NO) and H2O 2 production decline with age, as measured by diaminofluorescein (DAF) and dichlorodihydrofluorescein (DCF) fluorescence, respectively. Catalase reduced flow-induced dilation in all groups. Deferoxamine reversed Tempol-mediated impairment of flow in young rats, and improved flow in old rats compared to control. Immunoblot analysis revealed an incongruent increase in endogenous SOD, catalase, and nitrotyrosine protein levels with aging. Study II investigated the effects of aging and estrogen status on NO-availability during flow-induced dilation. Flow-induced dilation of coronary arterioles from young and old intact (CON), ovariectomized (OVX), or ovariectomized with estrogen replacement (OVE) rats was evaluated in the presence and absence of Tempol or catalase. Flow-induced NO and H2O2 production were assessed by DAF and DCF fluorescence, respectively. OVX reduced flow-mediated NO release in young females, while OVE enhanced NO release in old females. SOD protein was diminished by ovariectomy and increased with estrogen replacement. Tempol reduced flow in CON and OVE groups but had no significant effect in OVX. The contribution of H2O2 to flow-mediated dilation did not differ with age or estrogen status. Collectively, these data indicate that in males NO- and H2O 2-mediated flow-induced signaling decline with age in coronary arterioles, and that elevated hydroxyl radical formation contributes to the age-related impairment of flow-induced vasodilation. Variations in flow response correlate with estrogen status in CON, OVX, and OVE females, and most likely do not involve changes in H2O2-mediated signaling.

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