Role of neuronal nitric oxide in the vasodilatory response to mental stress (360G-Wellcome-207166_Z_17_Z)

Nitric oxide (NO) is a potent regulator of vascular tone. Until relatively recently, it was assumed that the isoform of NO synthase responsible for tonic NO release was endothelial nitric oxide synthase (eNOS). However, we now know that in humans, neuronal NOS (nNOS) is the primary NOS isoform responsible for regulating vascular tone in vivo. Neuronal NOS is also activated by mental stress and contributes directly to resistance vessel vasodilatation. However, our preliminary data indicate that this response is biphasic, suggesting a second mechanism underlying the vasodilatory response to stress. We hypothesise that this additional mechanism may be mediated through agonism of beta2 adrenoceptors. This hypothesis will be tested in healthy volunteers exposed to mental stress (Stroop test), using the gold-standard technique of venous occlusion plethysmography to measure forearm blood flow, coupled with intra-arterial infusions of selective inhibitors of nNOS and beta2 adrenoceptors. The key goals of this research are (i) to better define the regulation of vascular tone in healthy humans with a view to understanding potential mechanisms underlying vascular dysfunction in disease states; and (ii) gain a broader understanding of early experimental medicine approaches in the clinical setting.