Inhibition of nitric oxide synthase evokes central sympatho-excitation in healthy humans

Colin N. Young, James P. Fisher, Kevin M. Gallagher, Adam Whaley-Connell, Kunal Chaudhary, Ronald G. Victor, Gail D. Thomas, Paul J. Fadel

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Abstract

Animal studies have indicated that nitric oxide is a key signalling molecule involved in the tonic restraint of central sympathetic outflow from the brainstem. Extension of these findings to humans has been difficult because systemic infusion of nitric oxide synthase (NOS) inhibitors increases blood pressure due to inhibition of endothelial NOS, resulting in activation of the arterial baroreflex and subsequent inhibition of central sympathetic outflow. To overcome this confounding inhibitory influence of the baroreflex, in the current study we directly measured skin sympathetic nerve activity (SNA), which is not under baroreceptor control. Healthy, normotensive humans were studied before, during a 60 min intravenous infusion of the NOS inhibitor NG-nitro-l-arginine methyl ester (l-NAME; 4 mg kg-1), and for 120 min following the infusion (i.e. 180 min total). Skin SNA and arterial blood pressure (BP) were continuously measured. BP was increased from baseline at the end of the l-NAME infusion (Δ14 ± 2 mmHg; P < 0.05) and remained significantly elevated for the remainder of the experiment (Δ18 ± 3 mmHg; P < 0.05). Similarly, systemic NOS inhibition produced time-dependent increases in skin SNA, such that skin SNA was elevated at the end of the l-NAME infusion (total activity, 200 ± 22% baseline; P = 0.08) and was further increased at the end of the study protocol (total activity, 350 ± 41% baseline; P < 0.05). Importantly, skin SNA remained unchanged during time and hypertensive (phenylephrine) control experiments. These findings indicate that pharmacological inhibition of NOS causes sympathetic activation and support a role of nitric oxide in central sympathetic control in humans.

Original languageEnglish (US)
Pages (from-to)4977-4986
Number of pages10
JournalJournal of Physiology
Volume587
Issue number20
DOIs
StatePublished - Oct 1 2009

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All Science Journal Classification (ASJC) codes

  • Physiology

Cite this

Young, C. N., Fisher, J. P., Gallagher, K. M., Whaley-Connell, A., Chaudhary, K., Victor, R. G., Thomas, G. D., & Fadel, P. J. (2009). Inhibition of nitric oxide synthase evokes central sympatho-excitation in healthy humans. Journal of Physiology, 587(20), 4977-4986. https://doi.org/10.1113/jphysiol.2009.177204