Abstract 14762: Neuronal Nitric Oxide Synthase Contributes to Bradykinin, but not Acetylcholine Stimulated Endothelium-Dependent Vasodilation in the Human Forearm Circulation
INTRODUCTION: Nitric oxide (NO) is synthesized by 3 unique isoforms of nitric oxide synthase (NOS): endothelial NOS (eNOS), inducible NOS, and neuronal NOS (nNOS). S-methyl-L-thiocitrulline (SMTC) specifically inhibits nNOS, whereas NG-monomethyl-L-arginine (L-NMMA) nonspecifically inhibits all NOS isoforms. Although nNOS is known to contribute to basal tone, its relative contribution compared to eNOS has not been elucidated. Furthermore, the role of nNOS versus eNOS in mediating vasodilation due to bradykinin (BK) remains unknown. We assessed the hypothesis that nNOS contributes to BK mediated vasodilation.
METHODS: In 10 healthy volunteers, we measured forearm blood flow (FBF) by venous occlusion plethysmography at rest and during intra-arterial infusion of BK and acetylcholine in sequential doses of 100, 200, and 400 ng/min and 7.5, 15, and 30 μg/min, respectively. FBF responses were repeated after nNOS blockade with SMTC (0.2mmol/min) and after combined infusion of SMTC and L-NMMA, a non-specific NOS inhibitor at 8 umol/min. Responses were compared using mixed model analysis.
RESULTS: SMTC reduced resting FBF by 24±5% (±SEM), p=0.008 with a further 11±2% decrease after L-NMMA co-infusion, p=0.002, indicating an important contribution of both nNOS and eNOS to resting vasodilator tone. BK infusion produced a dose-dependent increase in FBF that was significantly inhibited by SMTC (p <0.001), with a 21±8% reduction in FBF, indicating a significant contribution of nNOS to BK-mediated vasodilation. Co-infusion of L-NMMA with SMTC resulted in an additional drop in BK-mediated vasodilation (p <0.001) with a further 18±8% decrease in FBF. Acetylcholine increased FBF but SMTC did not inhibit acetylcholine-induced vasodilation.
CONCLUSIONS: Both nNOS and eNOS play a crucial role in mediating NO dependent, bradykinin-induced vasodilation and maintenance of resting vasomotor tone in the human forearm. Interestingly, nNOS does not contribute to acetylcholine-induced vasodilation. In conclusion, these data demonstrate substantial heterogeneity in the source of NO mediated vasodilatation in response to endothelium-dependent pharmacologic stimuli in humans. Further work is needed to elucidate the role of nNOS signaling in disease states.
- © 2012 by American Heart Association, Inc.