title: Roles of nitric oxide synthase and cyclooxygenase in leg vasodilation and oxygen consumption during prolonged low-intensity exercise in untrained humans.
abstract: The vasodilator signals regulating muscle blood flow during exercise are unclear. We tested the hypothesis that in young adults leg muscle vasodilation during steady-state exercise would be reduced independently by sequential pharmacological inhibition of nitric oxide synthase (NOS) and cyclooxygenase (COX) with NG-nitro-L-arginine methyl ester (L-NAME) and ketorolac, respectively. We tested a second hypothesis that NOS and COX inhibition would increase leg oxygen consumption (VO2) based on the reported inhibition of mitochondrial respiration by nitric oxide. In 13 young adults, we measured heart rate (ECG), blood pressure (femoral venous and arterial catheters), blood gases, and venous oxygen saturation (indwelling femoral venous oximeter) during prolonged (25 min) steady-state dynamic knee extension exercise (60 kick/min, 19 W). Leg blood flow (LBF) was determined by Doppler ultrasound of the femoral artery. Whole body VO2 was measured, and leg VO2 was calculated from blood gases and LBF. Resting intra-arterial infusions of acetylcholine (ACh) and nitroprusside (NTP) tested inhibitor efficacy. Leg vascular conductance (LVC) to ACh was reduced up to 53±4% by L-NAME+ketorolac infusion, and the LVC responses to NTP were unaltered. Exercise increased LVC from 4±1 to 33.1±2 ml.min(-1).mmHg(-1) and tended to decrease after L-NAME infusion (31±2 ml.min(-1).mmHg(-1), P=0.09). With subsequent administration of ketorolac LVC decreased to 29.6±2 ml.min(-1).mmHg(-1) (P=0.02; n=9). While exercise continued, LVC returned to control values (33±2 ml.min(-1).mmHg(-1)) within 3 min, suggesting involvement of additional vasodilator mechanisms. In four additional subjects, LVC tended to decrease with L-NAME infusion alone (P=0.08) but did not demonstrate the transient recovery. Whole body and leg VO2 increased with exercise but were not altered by L-NAME or L-NAME+ketorolac. These data indicate a modest role for NOS- and COX-mediated vasodilation in the leg of exercising humans during prolonged steady-state exercise, which can be restored acutely. Furthermore, NOS and COX do not appear to influence muscle VO2 in untrained healthy young adults.
authors.affiliation: Department of Anesthesiology, Mayo Clinic, Rochester, MN, USA. wschrage@education.wisc.edu
authors.forename: William G
authors.initials: WG
authors.lastname: Schrage
authors.forename: Brad W
authors.initials: BW
authors.lastname: Wilkins
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Johnson
authors.forename: John H
authors.initials: JH
authors.lastname: Eisenach
authors.forename: Jacqueline K
authors.initials: JK
authors.lastname: Limberg
authors.forename: Niki M
authors.initials: NM
authors.lastname: Dietz
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Curry
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Joyner
mesh_terms: D000109:Acetylcholine / Q000008:administration & dosage; D000328:Adult; D001794:Blood Pressure; D002395:Catecholamines / Q000097:blood; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D015444:Exercise; D005260:Female; D006339:Heart Rate; D006801:Humans; D007261:Infusions, Intra-Arterial; D020910:Ketorolac / Q000008:administration & dosage; D035002:Lower Extremity; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000187:drug effects / Q000201:enzymology*; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009599:Nitroprusside / Q000008:administration & dosage; D010092:Oximetry; D010100:Oxygen / Q000097:blood; D010101:Oxygen Consumption / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D012039:Regional Blood Flow; D013997:Time Factors; D018608:Ultrasonography, Doppler; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage; D055815:Young Adult
chemical_list: D002395:Catecholamines; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; D009599:Nitroprusside; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases; D000109:Acetylcholine; D010100:Oxygen; D019331:NG-Nitroarginine Methyl Ester; D020910:Ketorolac