Endogenous Nitric Oxide Contributes to Bradykinin-Stimulated Glucose Uptake but Attenuates Vascular Tissue-Type Plasminogen Activator Release

Abstract

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 Ͼ25 kg/m 2 ), normotensive, nondiabetic subjects with normal cholesterol. We measured the effect of intra-arterial N -monomethyl-L-arginine (L-NMMA, 12 mol/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 Ͻ 0.001), increased baseline forearm vascular resistance (P Ͻ 0.001), and increased the t-PA arterial-venous gradient (P ϭ 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 ϭ 0.06). L-NMMA blunted bradykinin-stimulated vasodilation (P Ͻ 0.001 for FBF and FVR). Bradykinin increased net glucose extraction (from Ϫ80 Ϯ 23 to Ϫ320 Ϯ 97 g/min/100 ml at 200 ng/min bradykinin, P ϭ 0.02), and L-NMMA (Ϫ143 Ϯ 50 g/ min/100 ml at 200 ng/min, P ϭ 0.045) attenuated this effect. In contrast, L-NMMA enhanced bradykinin-stimulated t-PA release (39.9 Ϯ 7.0 ng/min/100 ml versus 30.0 Ϯ 4.2 ng/min/100 ml at 200 ng/min, P ϭ 0.04 for L-NMMA). In gender-stratified analyses, L-NMMA significantly increased bradykinin-stimulated t-PA release in women (F ϭ 6.7, P ϭ 0.02) but not in men. Endogenous NO contributes to bradykinin-stimulated vasodilation and glucose uptake but attenuates the fibrinolytic response to exogenous bradykinin.Endothelial dysfunction, which is characterized by an impaired vasodilatory response to nitric-oxide synthase (NOS)-dependent agonists or by a decreased capacity of the endothelium to release tissue-type plasminogen activator (t-PA), predicts the development of cardiovascular events in patients at risk for coronary artery disease Robinson et al., 2007;Van Guilder et al., 2008). Endothelial t-PA release occurs through both constitutive and regulated pathways. In constitutive release, newly synthesized t-PA is transported directly from the Golgi apparatus to the cell membrane and secreted, even in the absence of an extracellular stimulus, whereas in regulated secretion, stored t-PA is released from endothelial granules in response to activation of membrane receptors (van den Eijnden-Schrauwen et al., 1995;Emeis et al., 1996;Parmer and Miles, 1998).The mechanisms governing the regulated secretion of t-PA are not completely understood. In vitro, in human microvascular endothelial cells, thrombin stimulates t-PA release via...

Endothelium-Derived Hyperpolarizing Factor Mediates Bradykinin-Stimulated Tissue Plasminogen Activator Release in Humans

“…However, with similar increases in blood flow with SNP, we and previous investigators found no increase in t-PA. 6, 11, 27, 45, 46 Moreover, infusion of L-NMMA selectively attenuated FBF without affecting t-PA response to bradykinin.…”

Metabolites as novel biomarkers for childhood obesity‐related traits in Mexican–American children

“…Pretorius et al . found that administration of bradykinin improved glucose uptake in overweight/obese adults. As reported by Iozzo et al .…”

“…In addition to the above‐mentioned functions, bradykinin also helps in the insulin‐dependent transportation and metabolism of glucose . Pretorius et al .…”

Nitric Oxide/Reactive Oxygen Species Generation and Nitroso/Redox Imbalance in Heart Failure: From Molecular Mechanisms to Therapeutic Implications

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