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 (both P<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.
Highlights
NO is physiologically generated by endothelial and neuronal NO synthase isoforms
NO is synthesized from L-arginine and molecular oxygen by a family of 3 NO synthases (NOSs): endothelial NOS, neuronal NOS, and inducible NOS, which have distinct roles and functions.[1] eNOS and neuronal NO synthase (nNOS) are constitutively expressed isoforms named after the cell type in which they were first identified but are present in other tissues. eNOS is important in the cardiovascular system where it is involved in multiple homeostatic processes, including the endothelium-dependent regulation of vascular tone and blood flow, inhibition of platelet aggregation and adhesion, modulation of cardiac contraction, inhibition of vascular smooth muscle proliferation, and promotion of angiogenesis.[1] nNOS is found in the central nervous system, peripheral nerves, and many other tissues, including cardiac and skeletal muscle.[2]
ENOS is well established to be of significant importance in cardiovascular physiology, it is increasingly evident from animal studies that nNOS is involved in the regulation of cardiovascular function and exerts effects that in general are distinct from those of eNOS.[1,3]
Summary
NO is physiologically generated by endothelial and neuronal NO synthase (nNOS) isoforms. ENOS is well established to be of significant importance in cardiovascular physiology, it is increasingly evident from animal studies that nNOS is involved in the regulation of cardiovascular function and exerts effects that in general are distinct from those of eNOS.[1,3] Several studies using nNOS-selective inhibitors or nNOS-deficient mice suggested that nNOS-derived NO exerts central effects on blood pressure (BP) by regulating sympathetic outflow, some studies in nNOS knockout mice reported no effect on BP.[3,4] nNOS may influence BP by modulating renal renin release and fluid balance.[5] nNOS in nitrergic nerves modulates vessel tone at a local level in several vascular beds, which could potentially impact on BP.[3] Other experimental studies indicate an important role for nNOS in regulating changes in heart rate (HR) mediated by baroreflex responses.[6] nNOS regulates cardiac excitation–contraction coupling in mice, in particular influencing myocardial relaxation and the response to β-adrenergic stimulation.[7]. The aim of this study was to undertake the first direct investigation in healthy humans of the hemodynamic effects of systemic nNOS inhibition
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