title: Inhibition of nitric oxide synthase evokes central sympatho-excitation in healthy humans.
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 N(G)-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 (14 +/- 2 mmHg; P < 0.05) and remained significantly elevated for the remainder of the experiment (18 +/- 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.
authors.affiliation: Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212, USA.
authors.forename: Colin N
authors.initials: CN
authors.lastname: Young
authors.forename: James P
authors.initials: JP
authors.lastname: Fisher
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Gallagher
authors.forename: Adam
authors.initials: A
authors.lastname: Whaley-Connell
authors.forename: Kunal
authors.initials: K
authors.lastname: Chaudhary
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Victor
authors.forename: Gail D
authors.initials: GD
authors.lastname: Thomas
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Fadel
mesh_terms: D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D006801:Humans; D006973:Hypertension / Q000201:enzymology; D007262:Infusions, Intravenous; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000294:innervation / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000201:enzymology*
chemical_list: D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester