title: Cytochrome P450 2C9 plays an important role in the regulation of exercise-induced skeletal muscle blood flow and oxygen uptake in humans.
abstract: Previous studies show that exercise-induced hyperaemia is unaffected by systemic inhibition of nitric oxide synthase (NOS) and it has been proposed that this may be due to compensation by other vasodilators. We studied the involvement of cytochrome P450 2C9 (CYP 2C9) in the regulation of skeletal muscle blood flow in humans and the interaction between CYP 2C9 and NOS. Seven males performed knee extensor exercise. Blood flow was measured by thermodilution and blood samples were drawn frequently from the femoral artery and vein at rest, during exercise and in recovery. The protocol was repeated three times on the same day. The first and the third protocols were controls, and in the second protocol either the CYP 2C9 inhibitor sulfaphenazole alone, or sulfaphenazole in combination with the NOS inhibitor N(omega)-monomethyl-L-arginine (L-NMMA) were infused. Compared with control there was no difference in blood flow at any time with sulfaphenazole infusion (P > 0.05) whereas with infusion of sulfaphenazole and L-NMMA, blood flow during exercise was 16 +/- 4 % lower than in control (9 min: 3.67 +/- 0.31 vs. 4.29 +/- 0.20 l min(-1); P < 0.05). Oxygen uptake during exercise was 12 +/- 3 % lower (9 min: 525 +/- 46 vs. 594 +/- 24 ml min(-1); P < 0.05) with co-infusion of sulfaphenazole and L-NMMA, whereas oxygen uptake during sulfaphenazole infusion alone was not different from that of control (P > 0.05). The results demonstrate that CYP 2C9 plays an important role in the regulation of hyperaemia and oxygen uptake during exercise. Since inhibition of neither NOS nor CYP 2C9 alone affect skeletal muscle blood flow, an interaction between CYP 2C9 and NOS appears to exist so that a CYP-dependent vasodilator mechanism takes over when NO production is compromised.
authors.affiliation: Copenhagen Muscle Research Centre, August Krogh Institute, University of Copenhagen and Rigshospitalet, Copenhagen, Denmark.
authors.forename: Thore
authors.initials: T
authors.lastname: Hillig
authors.forename: Peter
authors.initials: P
authors.lastname: Krustrup
authors.forename: Ingrid
authors.initials: I
authors.lastname: Fleming
authors.forename: Takuya
authors.initials: T
authors.lastname: Osada
authors.forename: Bengt
authors.initials: B
authors.lastname: Saltin
authors.forename: Ylva
authors.initials: Y
authors.lastname: Hellsten
mesh_terms: D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000502:physiology*; D001794:Blood Pressure; D065729:Cytochrome P-450 CYP2C9; D015444:Exercise / Q000502:physiology*; D006339:Heart Rate; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019344:Lactic Acid / Q000097:blood; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000378:metabolism; D010101:Oxygen Consumption / Q000502:physiology*; D012039:Regional Blood Flow / Q000502:physiology; D013848:Thigh; D014018:Tissue Distribution; D014655:Vascular Resistance
chemical_list: D019344:Lactic Acid; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases