Assessment of vascular function in systemic sclerosis: Indications of the development of nitrate tolerance as a result of enhanced endothelial nitric oxide production

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Abstract
Objective To investigate the relationship between endothelium‐dependent and endothelium‐independent functions and the stiffness of conduit arteries as well as levels of endothelial activation markers in patients with systemic sclerosis (SSc). Methods Endothelium‐dependent (i.e., flow‐mediated) and endothelium‐independent (i.e., nitroglycerin‐induced) dilation of the brachial artery was measured as the percentage of change from baseline (FMD% and NTG%, respectively) in 24 SSc patients and 24 age‐ and sex‐matched healthy controls by high‐resolution ultrasound imaging. The maximum increase in systolic pressure per unit of time (dP/dtmax), as a measure of arterial wall stiffness, was assessed in the radial artery by pulse applanation tonometry. Plasma nitrate, the most important metabolite of nitric oxide, and 24‐hour urinary excretion of nitrate were measured by gas chromatography mass spectrometry. Soluble E‐selectin and soluble vascular cell adhesion molecule 1 (sVCAM‐1) were measured by enzyme‐linked immunosorbent assay. Results Brachial artery FMD% and NTG% did not differ between SSc patients and controls. Radial artery dP/dtmax was significantly increased in the patients and correlated significantly with elevated levels of plasma nitrate and sVCAM‐1. Twenty‐four‐hour urinary nitrate excretion tended to be elevated. Brachial artery NTG% was significantly inversely correlated with levels of plasma nitrate and soluble endothelial adhesion molecules. Conclusion The ability of the brachial arteries to dilate in response to hyperemia and nitroglycerin challenge is preserved in SSc. Stiffness of the radial artery is increased, however. Endothelial activation seems to determine the extent of the brachial artery NTG% and the radial artery dP/dtmax. The data are compatible with the hypothesis that nitrate tolerance is present in the vascular smooth muscle cells of the brachial artery wall in SSc.
Funding Information
  • Swedish Heart and Lung Foundation, the Faculty of Medicine, University of Umea
  • Swedish Medical Research Council (K99-04RM-13192-01, K2002-71X-4231-01)
  • Swedish Medical Society (98020555)