Increased blood flow induces oxidative stress through an endothelium- and nitric oxide-independent mechanism.
Bradykinin, a potent vasodilator, stimulates the formation of reactive oxygen species and F(2)-isoprostanes in vitro. The effect of bradykinin on oxidative stress in humans is not known. This study tested the hypothesis that bradykinin induces oxidative stress through a nitric oxide (NO)-dependent mechanism in the human vasculature. We measured forearm blood flow (FBF) and net F(2)-isoprostane release in response to intraarterial bradykinin (50-200 ng/min), nitroprusside (1.6-6.4 microg/min), or diltiazem (3.6-14.4 microg/min) in the absence and presence of the NO synthase inhibitor N(omega)-monomethyl-L-arginine (L-NMMA) in normotensive and hypertensive subjects pretreated with aspirin. L-NMMA significantly decreased basal FBF and basal net F(2)-isoprostane release (from 28.7+/-5.2 to 13.4+/-3.5 pg/min/100ml, P=0.01) in all subjects. Bradykinin caused a significant increase in FBF and net F(2)-isoprostane release in both normotensive and hypertensive subjects. During NO synthase inhibition, bradykinin significantly increased net F(2)-isoprostane release in both groups (P=0.001) and there was no effect of L-NMMA on bradykinin-stimulated F(2)-isoprostane release (P=0.46). Nitroprusside also significantly increased net F(2)-isoprostane release in hypertensive subjects (P=0.01) and this response was not affected by L-NMMA (P=0.50). Diltiazem increased FBF as well as net F(2)-isoprostane release (from 44.5+/-12.5 to 61.2+/-14.7 pg/min/100ml at the highest dose, P=0.05). Increasing blood flow induces oxidative stress through a NO- and endothelium-independent mechanism.
Fong
Pete
P
Division of Cardiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, USA.
Stafforini
Diana M
DM
Brown
Nancy J
NJ
Pretorius
Mias
M
D000328:Adult; D001920:Bradykinin / Q000008:administration & dosage*; D002121:Calcium Channel Blockers / Q000008:administration & dosage; D004110:Diltiazem / Q000008:administration & dosage; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D028441:F2-Isoprostanes / Q000378:metabolism; D005260:Female; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000008:administration & dosage; D009599:Nitroprusside / Q000008:administration & dosage; D018384:Oxidative Stress; D012039:Regional Blood Flow / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage*; D019323:omega-N-Methylarginine / Q000008:administration & dosage
D002121:Calcium Channel Blockers; D028441:F2-Isoprostanes; D020030:Nitric Oxide Donors; D014665:Vasodilator Agents; D009599:Nitroprusside; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D004110:Diltiazem; D001920:Bradykinin