Role of neuronal nitric oxide synthase in human vascular tone and systemic haemodynamics in vivo

• Main Author: Shabeeh, Husain
• Other Authors: Shah, Ajay Manmohan; Chowienczyk, Philip Jan
• Published: King's College London (University of London) 2014
• Subjects: 616.1
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.669559

Endothelial and neuronal nitric oxide synthase (eNOS and nNOS respectively) are constitutively expressed in vivo. Recent data showed 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. This thesis aimed to investigate the role of nNOS-derived nitric oxide (NO) in the regulation of skeletal blood flow during exercise and myocardial blood flow during increased cardiac workload. At a systemic level, the role of nNOS on blood pressure and haemodynamics was investigated in a first-in-man study. We used the non-selective NOS inhibitor, NG-monomethyl-Larginine (L-NMMA), and selective nNOS inhibitor, S-methyl-L-thiocitrulline (SMTC), to determine the role of eNOS and nNOS in opposing an increase in sympathetically mediated increases in arteriolar tone in the human forearm during handgrip exercise. We found that despite reducing basal forearm blood flow (FBF), intra-brachial L-NMMA or SMTC had no significant effect on the increase in FBF or conduit artery diameter induced by local handgrip exercise, even in the face of increased sympathetic stimulation with lower body negative pressure. We investigated the relative contribution of eNOS and nNOS in the regulation of coronary vascular tone during increasing metabolic demand as achieved through incremental cardiac pacing. We found that the pacing induced increase in coronary blood flow and artery diameter was blunted by intra-coronary L-NMMA but not so by SMTC. We then undertook the first investigation in humans of the effects of systemic nNOS inhibition on haemodynamics. We found that intravenous SMTC increased systemic vascular resistance and blood pressure, whilst stroke volume, cardiac output and heart rate were reduced. Importantly, there was no effect on flow-mediated dilatation, an effect mediated by eNOS. These results suggest that nNOS has a major contribution to basal regulation of systemic vascular resistance in humans.