Figure 5.

Endothelial responses to high salt intake affect arteriolar vasodilation and BP. Endothelium-specific responses are shown in red. Increased salt intake expands extracellular fluid (ECF) volume and increases CO. In response, normally functioning endothelium increases NO production to promote arteriolar vasodilation, which reduces PVR, and the net effect is unchanged BP. A decrease in renal vascular resistance (RVR) facilitates natriuresis and subsequent return to salt balance. The increase in NO production is facilitated by production and activation of TGF-β. However, TGF-β–dependent ALK5 signaling also increases endothelial NADPH oxidase-4 (NOX4),⁴⁵ an enzyme that produces hydrogen peroxide, which limits NO bioavailability and ultimately promotes increased BP.⁴⁸ As reviewed in detail by Laffer et al.,⁵³ the recently described extravascular storage of sodium may mitigate the hemodynamic effects of higher salt intake by increasing effective vascular capacity and limiting expansion of ECF volume. This paradigm partially shows the complexity of the pathophysiology of high salt intake and potentially how disruption of any of the pathways may result in salt sensitivity.