Endogenous nitric oxide contributes to bradykinin-stimulated glucose uptake but attenuates vascular tissue-type plasminogen activator release.
Bradykinin causes vasodilation, stimulates tissue-type plasminogen activator (t-PA) release and, in rodents, increases muscle glucose uptake. Although bradykinin causes vasodilation partly by activating nitric-oxide synthase (NOS), the role of nitric oxide in regulating bradykinin-stimulated t-PA release is uncertain. This study examined the effect of high-dose NOS inhibition on bradykinin-stimulated t-PA release and glucose uptake in humans. We studied 24 healthy (12 women and 12 men), overweight and obese (body mass index >25 kg/m(2)), normotensive, nondiabetic subjects with normal cholesterol. We measured the effect of intra-arterial N(omega)-monomethyl-L-arginine (L-NMMA, 12 micromol/min) on forearm blood flow (FBF), net t-PA release, and glucose uptake at baseline and in response to intra-arterial bradykinin (50-200 ng/min) in subjects pretreated with the cyclooxygenase inhibitor aspirin. Measurements were repeated after isosorbide dinitrate (ISDN; 5 mg) or sildenafil (50 mg). L-NMMA decreased baseline FBF (P < 0.001), increased baseline forearm vascular resistance (P < 0.001), and increased the t-PA arterial-venous gradient (P = 0.04) without affecting baseline net t-PA release or glucose uptake. During L-NMMA, ISDN tended to decrease baseline net t-PA release (P = 0.06). L-NMMA blunted bradykinin-stimulated vasodilation (P < 0.001 for FBF and FVR). Bradykinin increased net glucose extraction (from -80 +/- 23 to -320 +/- 97 microg/min/100 ml at 200 ng/min bradykinin, P = 0.02), and L-NMMA (-143 +/- 50 microg/min/100 ml at 200 ng/min, P = 0.045) attenuated this effect. In contrast, L-NMMA enhanced bradykinin-stimulated t-PA release (39.9 +/- 7.0 ng/min/100 ml versus 30.0 +/- 4.2 ng/min/100 ml at 200 ng/min, P = 0.04 for L-NMMA). In gender-stratified analyses, L-NMMA significantly increased bradykinin-stimulated t-PA release in women (F = 6.7, P = 0.02) but not in men. Endogenous NO contributes to bradykinin-stimulated vasodilation and glucose uptake but attenuates the fibrinolytic response to exogenous bradykinin.
Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. mias.pretorius@vanderbilt.edu
Mias
M
Pretorius
Nancy J
NJ
Brown
D000328:Adult; D001241:Aspirin / Q000494:pharmacology; D001920:Bradykinin / Q000494:pharmacology* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005542:Forearm / Q000098:blood supply; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009765:Obesity / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D012039:Regional Blood Flow / Q000502:physiology; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D010959:Tissue Plasminogen Activator; D005947:Glucose; D001241:Aspirin; D001920:Bradykinin