Pretorius M, Brown NJ
Endogenous Nitric Oxide Contributes to Bradykinin-Stimulated Glucose Uptake but Attenuates Vascular t-PA Release. [JOURNAL ARTICLE]
J Pharmacol Exp Ther 2009 Oct 19.
Bradykinin causes vasodilation, stimulates tissue-type plasminogen activator (t-PA) release and, in rodents, increases muscle glucose uptake. While 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 (BMI>25kg/m(2)), normotensive, non-diabetic subjects with normal cholesterol. We measured the effect of intra-arterial N(omega)-monomethyl-L-arginine (L-NMMA, 12mumol/min) on forearm blood flow (FBF), net t-PA release, and glucose uptake at baseline and in response to intra-arterial bradykinin (50-200ng/min) in subjects pre-treated with the cyclooxygenase inhibitor aspirin. Measurements were repeated after isosorbide dinitrate (ISDN) 5mg or sildenafil 50mg. 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 mug/min/100ml at 200ng/min bradykinin, P=0.02) and L-NMMA (-143+/-50 mug/min/100ml at 200ng/min, P=0.045) attenuated this effect. In contrast, L-NMMA enhanced bradykinin-stimulated t-PA release (39.9+/-7.0 ng/min/100ml versus 30.0+/-4.2 ng/min/100ml at 200ng/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.
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