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

Abstract

Key points: 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. 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. 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. The present study demonstrates the important role of COX-1 derived vasoconstrictor metabolites in regulation of microvascular blood flow during a HS diet. 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.

Abstract: The 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 A2 (TXA2 ) and prostaglandin F2α (PGF2α ), 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) (∼14 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 TXB2 (stable TXA2 metabolite) and PGF2α , 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 TXA2 but did not change PGF2α levels. Indomethacin restored microcirculatory blood flow and reduced TXA2 . By contrast, celecoxib decreased TXA2 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.

© 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

Figures

Figure 1. LDF measurement of skin microvascular blood flow

Microcirculatory blood flow in a given time was expressed in arbitrary perfusion units and determined by software calculating the area under the curve (AUC) during baseline flow, occlusion and reperfusion (AUC is denoted by the shaded portions of the trace). Because the flow does not reach the value of zero even when perfusion is absent, flow values are expressed as a quotient of a standard comparator – baseline flow. The final result was expressed as the difference between the quotients of flow change during reperfusion and occlusion in relation to baseline (ΔR‐O). Source: original trace, Laboratory for Vascular Physiology, Department of Physiology and Immunology, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek).

Figure 2. Changes of PORH

Relative changes of PORH before and after HS, A and LS diet, B, protocols.

Figure 3. Changes of peripheral blood flow

Relative changes of peripheral blood flow between occlusion and reperfusion before and after the HS diet protocol with indomethacin, A or celecoxib, B, administration.

Figure 4. Effect of the HS diet on vasoconstrictor prostaglandins TXB2 and PGF2α plasma levels

Significant increase of TXB2, A, with no changes in PGF2α, B, 1 week after HS dietary intake compared to control levels.

Figure 5. Effect of the HS diet and the non‐selective COX‐1 and COX–2 inhibitor indomethacin and the selective COX–2 inhibitor celecoxib on TXB2 plasma levels

Significant decrease of TXB2 plasma levels in HS diet groups after indomethacin, A and celecoxib, B, administration.