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Increased Oxidative Stress Underlies Impaired Endothelial Function and Vascular Reactivity with High Salt Dietary Intake, Independently of Blood Pressure Changes – Translational Studies

Introduction: High salt dietary intake (HS) is known causal factor of endothelial dysfunction, even without increases in arterial blood pressure. The aim of this study was to present our current work on the underlying mechanisms of endothelial dysfunction occurring in HS diet, related to increased oxidative stress, in healthy animals and young healthy humans. Methods: Functional studies on the mechanisms of microvessel’s reactivity (endothelium- dependent and endothelium-independent) as well as molecular (mRNA ; protein expression) and biochemical analyses (enzymatic activity, flow- cytometry, direct fluorescence) on the biomarkers of vascular and systemic oxidative stress were performed in healthy normotensive young men and women (N = 10–15 (per set ; average age 21 yrs) and healthy normotensive Sprague-Dawley male rats 11-weeks old (N = 7–10/per group) on a HS and low-salt (LS) diet. Results: Human:HS diet impairs endothelium- dependent, but not endothelium-independent vasodilation in skin microcirculation (post-occlusive reactive hyperemia (PORH) ; ACH vs. SNP) and increases TXA2 production in healthy women (J Physiol 2015 ; 593(24):5313–24). HS diet significantly increased basal ROS production in monocytes. HS diet significantly increased oxidative stress level (TBARS) and decreased antioxidant capacity (FRAP). PORH and FRAP positively correlated, while PORH and TBARS negatively correlated. There was negative correlation between salt intake and FRAP and between salt intake and PORH. 7-day HS diet did not induce significant change in arterial blood pressure, or in body composition or fluid status in young healthy population. Plasma renin activity (PRA) and serum aldosterone level in humans are suppressed by HS diet. Animals: Attenuated flow-induced dilation of cerebral resistance arteries (MCA) is related to increased vascular oxidative stress and NO pathway in rats on a short-term HS diet (J Physiol 2016 ; 594(17):4917–31). HS diet suppresses flow- induced NO production in MCA, which is restored by superoxide scavenging (AJP 2018 ; 315(3):H718-H730). Brain blood vessels antioxidant enzyme expression is decreased in HS diet (Gpx4), while HIF-1alpha and COX-2 protein levels are increased, possibly related to increased oxidative stress caused by HS diet and reversed by TEMPOL in vivo. Oxidative stress in leukocytes isolated from blood and peripheral lymph nodes is increased. Conclusions: HS diet significantly alters microvascular reactivity in young healthy normotensive women, without changes in blood pressure and in animal model of normotensive SpragueDawley rat. HS diet significantly reduces antioxidant capacity and increases oxidative stress markers, leading to switch in pathways mediating vasodilation, which can be associated with microvascular dysfunction, confirmed in both types of studies. Microvascular dysfunction precedes changes in blood pressure. Funded by grants from Croatian Science Fundation: RAS-AdrenOX (IP-2016-06- 8744, PI Ana Stupin) and VELI-Athero (IP-2014- 09-6380, PI Ines Drenjancevic.

high salt intake ; arterial blood pressure ; endothelium ; vascular function ; oxidative stress

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