PT  - JOURNAL ARTICLE
AU  - Mias Pretorius
AU  - Nancy J. Brown
TI  - Endogenous Nitric Oxide Contributes to Bradykinin-Stimulated Glucose Uptake but Attenuates Vascular Tissue-Type Plasminogen Activator Release
AID  - 10.1124/jpet.109.160168
DP  - 2010 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 291--297
VI  - 332
IP  - 1
4099  - http://jpet.aspetjournals.org/content/332/1/291.short
4100  - http://jpet.aspetjournals.org/content/332/1/291.full
SO  - J Pharmacol Exp Ther2010 Jan 01; 332
AB  - 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/m2), normotensive, nondiabetic subjects with normal cholesterol. We measured the effect of intra-arterial Nω-monomethyl-l-arginine (l-NMMA, 12 μmol/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 μg/min/100 ml at 200 ng/min bradykinin, P = 0.02), and l-NMMA (−143 ± 50 μg/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.© 2010 by The American Society for Pharmacology and Experimental Therapeutics