Abstract 11569: First-In-Man Study of the Effects of Neuronal Nitric Oxide Synthase on Systemic Haemodynamics
Introduction: Endothelial and neuronal nitric oxide synthase (eNOS and nNOS respectively) are constitutively expressed in vivo. Non-selective NOS inhibition with L-NMMA in healthy humans in vivo causes an increase in arterial blood pressure (BP) that has been assumed to be mediated through inhibition of eNOS. However, we previously found that selective local inhibition of nNOS reduced basal blood flow without affecting endothelial-mediated vasodilatation induced by acetylcholine or increased shear stress - suggesting that eNOS and nNOS have distinct roles in vasoregulation. We have now undertaken the first investigation in humans of the effects of systemic nNOS inhibition on haemodynamics.
Methods: Seventeen healthy normotensive men were studied after regulatory and ethical approval. The nNOS-selective inhibitor S-methyl-L-thiocitrulline (SMTC) was first infused intravenously in a dose-escalation safety study (n=9 subjects). We then undertook a randomised crossover study with blinded haemodynamic assessment in which either SMTC (3.0 μ mol/Kg over 10 min) or saline vehicle were infused on separate occasions (n=8 subjects). BP and heart rate (HR) were measured by an oscillometric method whereas stroke volume (SV) was measured using 3D echocardiography. Systemic vascular resistance (SVR) was calculated from the mean BP (MAP) and cardiac output (CO). Brachial flow-mediated dilatation (FMD) was measured as an index of eNOS activity.
Results: There were no adverse events or changes in biochemical or haematological safety profiles during the study. SMTC induced dose-dependent changes in systemic haemodynamics as compared to saline. At the highest dose of SMTC (3.0 μ mol/Kg), there was a significant increase in diastolic BP (67.6±1.4 to 77.3±2.6 mmHg; P<0.001) and SVR (by 42.2±6.4%, P<0.001) whereas systolic BP did not change (n=8, P=NS). Both HR (60.2±3.6 to 51.0±3.4 bpm) and SV (59.4±5.8 to 55.1±5.8 mL) decreased significantly (P<0.01 vs. saline for both). SMTC infusion had no significant effect on FMD (6.24±1.50 to 6.84±1.41 %; n=8, P=NS), consistent with a lack of effect on eNOS activity.
Conclusion: These data suggest that nNOS contributes to the basal physiological regulation of SVR and BP in healthy humans.
- © 2012 by American Heart Association, Inc.