Cardiovascular benefits associated with higher dietary K+ vs. lower dietary Na+: evidence from population and mechanistic studies

Abstract

The World Health Organization ranks hypertension the leading global risk factor for disease, specifically, cardiovascular disease. Blood pressure (BP) is higher in Westernized populations consuming Na⁺-rich processed foods than in isolated societies consuming K⁺-rich natural foods. Evidence suggests that lowering dietary Na⁺ is particularly beneficial in hypertensive individuals who consume a high-Na⁺ diet. Nonetheless, numerous population studies demonstrate a relationship between higher dietary K⁺, estimated from urinary excretion or dietary recall, and lower BP, regardless of Na⁺ intake. Interventional studies with K⁺ supplementation suggest that it provides a direct benefit; K⁺ may also be a marker for other beneficial components of a "natural" diet. Recent studies in rodent models indicate mechanisms for the K⁺ benefit: the distal tubule Na⁺-Cl^- cotransporter (NCC) controls Na⁺ delivery downstream to the collecting duct, where Na⁺ reabsorbed by epithelial Na⁺ channels drives K⁺ secretion and excretion through K⁺ channels in the same region. High dietary K⁺ provokes a decrease in NCC activity to drive more K⁺ secretion (and Na⁺ excretion, analogous to the actions of a thiazide diuretic) whether Na⁺ intake is high or low; low dietary K⁺ provokes an increase in NCC activity and Na⁺ retention, also independent of dietary Na⁺ Together, the findings suggest that public health efforts directed toward increasing consumption of K⁺-rich natural foods would reduce BP and, thus, cardiovascular and kidney disease.

Keywords: ENaC; NCC; dietary potassium; dietary sodium; hypertension.

Fig. 1.

Angiotensin II (ANG II) infusion (400 ng·kg⁻¹·min⁻¹) in rats fed 1% K⁺ diet activates the epithelial Na⁺ channel (ENaC), evident as increased abundance of the cleaved γ-subunit, and increases distal convoluted tubule (DCT1 and DCT2) Na⁺-Cl⁻ cotransporter (NCC) abundance (ANG II, 1% K) compared with control 1% K⁺ diet-fed rats (65). Rats fed 1% K⁺ also presented with higher urinary K⁺ and lower plasma K⁺ concentration after an overnight fast (not shown), leading to the hypothesis that the increased NCC abundance was secondary to K⁺ depletion, a response that decreases Na⁺ delivery to ENaC, which drives K⁺ secretion via K⁺ channels such as the renal outer medullary K⁺ (ROMK) channel. This hypothesis (top) was supported by data from the study of Vieras et al. (65) of rats fed a diet in which K⁺ was doubled during ANG II infusion (ANG II, 2%K) to prevent K⁺ depletion (bottom): NCC was unchanged, and γENaC cleavage was elevated. CNT, connecting tubule, CCD, cortical collecting duct.

Fig. 2.

Raising dietary K⁺ counteracts hypertension in spontaneously hypertensive rats (SHR). A: at baseline, with dietary electrolytes at 0.2% NaCl and 0.5% K⁺, blood pressure (BP) is 148 mmHg. Raising dietary NaCl to 8% increases BP to 182 mmHg if K⁺ is kept at 0.5%, but BP does not increase if K⁺ is also raised to 2% (146 mmHg). [Redrawn from results of Ganguli and Tobian (18).] B: dietary K⁺ intake, under conditions of normokalemia, inhibits Na⁺ reabsorption via DCT NCC, which increases Na⁺ delivery downstream to ENaC, where Na⁺ reabsorption drives increased K⁺ secretion. Net result is increased excretion of Na⁺ and K⁺. C: summary of results from a small study of SHR fed 2% NaCl + 1% KCl or 2% NaCl + 4% KCl from 6 to 13 wk of age (37). Tail cuff BP [mean arterial pressure (MAP), mean of weekly measurements from weeks 11–14 after 3 wk of adaptation] was 24 mmHg lower in SHR fed 4% KCl; overnight urine Na⁺ (U_NaV) was marginally increased by 25%; NCC total abundance, measured by immunoblotting, was decreased ~15%, and ENaC activation, estimated from abundance of the cleaved (clvd) γ-subunit, was increased ~20%, supporting the model linking increased K⁺ secretion to decreased Na⁺ reabsorption.