LIMB BLOOD-FLOW DURING EXERCISE IS DEPENDENT ON NITRIC-OXIDE

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-derive d nitric oxide (EDNO) production, and urinary nitrate excretion. These findings led us to test the hypothesis that EDNO production contribut es significantly to limb blood flow during exercise and to determine w hether loss of EDNO production is responsible for the decline in exerc ise capacity observed in hypercholesterolemia. Methods and Results-Twe lve-week-old wild-type (E+; n=9) and apoE-deficient (E-; n=9) C57BL/6J mice were treadmill-tested to measure indices defining exercise capac ity on a metabolic chamber-enclosed treadmill capable of measuring oxy gen uptake and carbon dioxide excretion. Urine was collected before an d after treadmill exercise for determination of vascular NO production assessed by urinary nitrate excretion. The wild-type mice were then g iven nitro-L-arginine (E+ LNA) in the drinking water (6 mg/dL) for 4 d ays before undergoing a second treadmill testing and urinary nitrate m easurement. An additional set of 12-week-old wild-type mice was divide d into 2 groups: 1 receiving regular water (E+; n=8) and 1 administere d 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 (Vo(2)max), 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 Vo(2)max. When the mic e 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 de monstrated a markedly reduced postexercise urinary nitrate excretion, aerobic capacity, and %COrm at Vo(2)max compared with E+. Conclusions- EDNO contributes significantly to limb blood flow during exercise. Con ditions that reduce EDNO production disturb the hyperemic response to exercise, resulting in a reduced exercise capacity.