From the Section of Vascular Medicine (A.J.M., E.S., J.P.C.) and the
Divisions of Cardiovascular Medicine and Pediatric Cardiology (D.B.), Stanford
University, Stanford, Calif.
Correspondence to John P. Cooke, MD, PhD, Director, Section of Vascular Medicine, Division of Cardiovascular Medicine, Stanford University, 300 Pasteur Dr, Stanford, CA 94305-5246.
Background—We have recently reported
that hypercholesterolemia reduces aerobic
exercise capacity in mice and that this is associated with a reduced
endothelium-dependent vasodilator function,
endothelium-derived nitric oxide (EDNO)
production, and urinary nitrate excretion. These findings led
us to test the hypothesis that EDNO production contributes
significantly to limb blood flow during exercise and to determine
whether loss of EDNO production is responsible for the decline
in exercise capacity observed in
hypercholesterolemia.
Methods and Results—Twelve-week-old wild-type (E+;
n=9) and apoE-deficient (E-; n=9) C57BL/6J mice were
treadmill-tested to measure indices defining exercise capacity on a
metabolic chamber–enclosed treadmill capable of measuring
oxygen uptake and carbon dioxide excretion. Urine was collected before
and after treadmill exercise for determination of vascular NO
production assessed by urinary nitrate excretion. The wild-type
mice were then given nitro-L-arginine (E+LNA)
in the drinking water (6 mg/dL) for 4 days before undergoing a second
treadmill testing and urinary nitrate measurement. An additional set of
12-week-old wild-type mice was divided into 2 groups: 1 receiving
regular water (E+; n=8) and 1 administered LNA for 4 days
(E+LNA; n=8). These mice, along with an additional set of
E- mice (n=8), underwent treadmill testing to determine
maximal oxygen uptake (
Conclusions—EDNO contributes significantly to limb blood flow
during exercise. Conditions that reduce EDNO production disturb
the hyperemic response to exercise, resulting in a reduced
exercise capacity.
© 1998 American Heart Association, Inc.
Basic Science Reports
Limb Blood Flow During Exercise Is Dependent on Nitric Oxide
O2max). The mice
were then cannulated such that the tip of the tubing was positioned in
the ascending aorta. Fluorescent microspheres (20 000)
were infused into the carotid cannula while the mice were sedentary and
again while approaching O2max. When the
mice were euthanized, the running muscles were collected and
fluorescence intensity was measured to determine the
peak-exercise redistribution of blood flow to the running muscles
(expressed as percentage of total cardiac output, %COrm) during both
states. Both E+LNA and E- mice demonstrated a
markedly reduced postexercise urinary nitrate excretion, aerobic
capacity, and %COrm at O2max compared
with E+.
Key Words: oxygen • vasculature • apolipoproteins • nitric oxide • microspheres
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