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 >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.

Figures

Fig. 1.

A, effect of l-NMMA, ISDN, and sildenafil on FBF response to exogenous bradykinin in all subjects. Neither ISDN nor sildenafil altered the FBF response to bradykinin during l-NMMA. B and C, effect of l-NMMA on FBF response to exogenous bradykinin in women (B) and men (C). ANOVA results are for the comparison between women and men.

Fig. 2.

A, effect of l-NMMA, ISDN, and sildenafil on FVR response to exogenous bradykinin in all subjects. Neither ISDN nor sildenafil altered the FVR response to bradykinin during l-NMMA. Effect of l-NMMA on FVR response to exogenous bradykinin in women (B) and men (C). ANOVA results are for the comparison between women and men.

Fig. 3.

A, effect of l-NMMA, ISDN, and sildenafil on net t-PA response to exogenous bradykinin in all subjects. Effect of l-NMMA on t-PA response to exogenous bradykinin in women (B) and men (C). The increase in bradykinin-stimulated t-PA release in the presence of l-NMMA was significantly greater in women compared with men (F = 6.7, P = 0.02).

Fig. 4.

Effect of l-NMMA, ISDN, and sildenafil on net glucose uptake response to exogenous bradykinin. Bradykinin caused a significant increase in net glucose uptake (P = 0.02). *, P < 0.05 versus baseline; †, P < 0.05 versus control.