title: Blood Pressure in Healthy Humans Is Regulated by Neuronal NO Synthase.
abstract: NO is physiologically generated by endothelial and neuronal NO synthase (nNOS) isoforms. Although nNOS was first identified in brain, it is expressed in other tissues, including perivascular nerves, cardiac and skeletal muscle. Increasing experimental evidence suggests that nNOS has important effects on cardiovascular function, but its composite effects on systemic hemodynamics in humans are unknown. We undertook the first human study to assess the physiological effects of systemic nNOS inhibition on basal hemodynamics. Seventeen healthy normotensive men aged 24±4 years received acute intravenous infusions of an nNOS-selective inhibitor, S-methyl-l-thiocitrulline, and placebo on separate occasions. An initial dose-escalation study showed that S-methyl-l-thiocitrulline (0.1-3.0 µmol/kg) induced dose-dependent changes in systemic hemodynamics. The highest dose of S-methyl-l-thiocitrulline (3.0 µmol/kg over 10 minutes) significantly increased systemic vascular resistance (+42±6%) and diastolic blood pressure (67±1 to 77±3 mm Hg) when compared with placebo (bothP<0.01). There were significant decreases in heart rate (60±4 to 51±3 bpm;P<0.01) and left ventricular stroke volume (59±6 to 51±6 mL;P<0.01) but ejection fraction was unaltered. S-methyl-l-thiocitrulline had no effect on radial artery flow-mediated dilatation, an index of endothelial NOS activity. These results suggest that nNOS-derived NO has an important role in the physiological regulation of basal systemic vascular resistance and blood pressure in healthy humans.
authors.affiliation: From the King's College London British Heart Foundation Centre, Cardiovascular Division, United Kingdom (H.S., S.K., B.J., S.B., N.M., P.J.C., A.M.S.); and Department of Cardiovascular Medicine, University of Oxford, United Kingdom (B.C.).
authors.forename: Husain
authors.initials: H
authors.lastname: Shabeeh
authors.affiliation: From the King's College London British Heart Foundation Centre, Cardiovascular Division, United Kingdom (H.S., S.K., B.J., S.B., N.M., P.J.C., A.M.S.); and Department of Cardiovascular Medicine, University of Oxford, United Kingdom (B.C.).
authors.forename: Sitara
authors.initials: S
authors.lastname: Khan
authors.affiliation: From the King's College London British Heart Foundation Centre, Cardiovascular Division, United Kingdom (H.S., S.K., B.J., S.B., N.M., P.J.C., A.M.S.); and Department of Cardiovascular Medicine, University of Oxford, United Kingdom (B.C.).
authors.forename: Benyu
authors.initials: B
authors.lastname: Jiang
authors.affiliation: From the King's College London British Heart Foundation Centre, Cardiovascular Division, United Kingdom (H.S., S.K., B.J., S.B., N.M., P.J.C., A.M.S.); and Department of Cardiovascular Medicine, University of Oxford, United Kingdom (B.C.).
authors.forename: Sally
authors.initials: S
authors.lastname: Brett
authors.affiliation: From the King's College London British Heart Foundation Centre, Cardiovascular Division, United Kingdom (H.S., S.K., B.J., S.B., N.M., P.J.C., A.M.S.); and Department of Cardiovascular Medicine, University of Oxford, United Kingdom (B.C.).
authors.forename: Narbeh
authors.initials: N
authors.lastname: Melikian
authors.affiliation: From the King's College London British Heart Foundation Centre, Cardiovascular Division, United Kingdom (H.S., S.K., B.J., S.B., N.M., P.J.C., A.M.S.); and Department of Cardiovascular Medicine, University of Oxford, United Kingdom (B.C.).
authors.forename: Barbara
authors.initials: B
authors.lastname: Casadei
authors.affiliation: From the King's College London British Heart Foundation Centre, Cardiovascular Division, United Kingdom (H.S., S.K., B.J., S.B., N.M., P.J.C., A.M.S.); and Department of Cardiovascular Medicine, University of Oxford, United Kingdom (B.C.).
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Chowienczyk
authors.affiliation: From the King's College London British Heart Foundation Centre, Cardiovascular Division, United Kingdom (H.S., S.K., B.J., S.B., N.M., P.J.C., A.M.S.); and Department of Cardiovascular Medicine, University of Oxford, United Kingdom (B.C.). ajay.shah@kcl.ac.uk.
authors.forename: Ajay M
authors.initials: AM
authors.lastname: Shah
mesh_terms: D000328:Adult; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D001795:Blood Pressure Determination; D002956:Citrulline / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D004791:Enzyme Inhibitors / Q000494:pharmacology; D064368:Healthy Volunteers; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008297:Male; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000502:physiology*; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D055815:Young Adult
chemical_list: D004791:Enzyme Inhibitors; D002956:Citrulline; D052248:Nitric Oxide Synthase Type I; D013890:Thiourea; C086717:S-methylthiocitrulline
keywords: blood pressure; brain; humans; nitric oxide; stroke