The role of cyclo‐oxygenase‐1 in high‐salt diet‐induced microvascular dysfunction in humans

Abstract

Key pointsr Recent studies have shown that some of the deleterious effects of a high-salt (HS) diet are independent of elevated blood pressure and are associated with impaired endothelial function.r Increased generation of cyclo-oxygenase (COX-1 and COX-2)-derived vasoconstrictor factors and endothelial activation may contribute to impaired vascular relaxation during HS loading.r The present study aimed to assess the regulation of microvascular reactivity and to clarify the role of COX-1 and COX-2 in normotensive subjects on a short-term HS diet.r The present study demonstrates the important role of COX-1 derived vasoconstrictor metabolites in regulation of microvascular blood flow during a HS diet.r These results help to explain how even short-term HS diets may impact upon microvascular reactivity without changes in blood pressure and suggest that a vasoconstrictor metabolite of COX-1 could play a role in this impaired tissue blood flow. AbstractThe present study aimed to assess the effect of a 1-week high-salt (HS) diet on the role of cyclo-oxygenases (COX-1 and COX-2) and the vasoconstrictor prostaglandins, thromboxane A 2 (TXA 2 ) and prostaglandin F 2α (PGF 2α ), on skin microcirculatory blood flow, as well as to detect its effect on markers of endothelial activation such as soluble cell adhesion molecules. Young women (n = 54) were assigned to either the HS diet group (N = 30) (ß14 g day -1 NaCl ) or low-salt (LS) diet group (N = 24) (<2.3 g day -1 NaCl ) for 7 days. Post-occlusive reactive hyperaemia (PORH) in the skin microcirculation was assessed by laser Doppler flowmetry. Plasma renin activity, plasma aldosterone, plasma and 24 h urine sodium and potassium, plasma concentrations of TXB 2 (stable TXA 2 metabolite) and PGF 2α , soluble cell adhesion molecules and blood pressure were measured before and after the diet protocols. One HS diet group subset received 100 mg of indomethacin (non-selective COX-1 and COX-2 inhibitor), and another HS group subset received 200 mg of celecoxib (selective COX-2 inhibitor) before repeating laser Doppler flowmetry measurements. Blood pressure was unchanged after the HS diet, although it significantly reduced after the LS diet. Twenty-four hour urinary sodium was increased, and plasma renin activity and plasma aldosterone levels were decreased after the HS diet. The HS diet significantly impaired PORH and increased TXA 2 but did not change PGF 2α levels. Indomethacin restored microcirculatory blood flow and reduced TXA 2 . By contrast, celecoxib decreased TXA 2 levels but had no significant effects on blood flow. Restoration of of PORH by indomethacin during a HS diet suggests an important role of COX-1 derived vasoconstrictor metabolites in the regulation of microvascular blood flow during HS intake.

Sildenafil (Viagra®) Prevents Cox-1/ TXA2 Pathway-Mediated Vascular Hypercontractility in ApoE-/- Mice

“…Therefore, using different protocols, our data indicate that Cox-1, but not Cox-2 is an important contributor to the endothelium-dependent hypercontractility observed in the apoE -/- mouse model of AT, which is in agreement with other studies [40]. The present data is also corroborated by other studies that show that activation of TP is of high relevance for vasoconstriction [26, 43-46], and that the pharmacological antagonism of TXA 2 can delay the progression of AT [47, 48]. This could be explained by the fact that the activation of TP lead to the increase in [Ca +2 ] c , a critical step for vasoconstriction and the atherosclerotic process [18, 49, 50].…”

Activation of protease‐activated receptor 2 mediates cutaneous vasodilatation but not sweating: roles of nitric oxide synthase and cyclo‐oxygenase

“…Nitric oxide synthase (NOS) and cyclo-oxygenase (COX) are two key enzymes that can modulate cutaneous vascular tone (Holowatz et al 2005;Kellogg et al 2005;McCord et al 2006;Lenasi & Strucl, 2008;McNamara et al 2014;Cavka et al 2015) as well as sweating (Lee & Mack, 2006;Welch et al 2009;Fujii et al 2014;Stapleton et al 2014). To the best of our knowledge, no study has investigated whether these enzymes contribute to cutaneous vasodilatation and sweating in response to PAR2 activation.…”

Blood Pressure Reduction is Associated With the Changes in Oxidative Stress and Endothelial Activation in Hypertension, Regardless of Antihypertensive Therapy

“…Conversely, suppression of ANGII during increased dietary salt intake or pharmacological inhibition of the renin-angiotensin system by ACE and AT 1 receptor blockers have been shown to increase vascular oxidative stress [13] by affecting superoxide dismutase (SOD) activity, leading to a similar increase of ROS levels [14,15]. In a recent study healthy normotensive volunteers subjected to a short period of high salt intake exhibited impaired endothelium dependent vasodilatation in response to reactive hyperaemia and acetylcholine infusion [16,17]. In addition, low renin activity has been linked to higher mortality of cardiovascular events in salt sensitive individuals [18].…”