Abstract Body (Do not enter title and authors here): Background: Na⁺-driven extracellular fluid and blood volume expansion ostensibly causes hypertension. We tested the alternative hypothesis, namely that K⁺-driven intracellular volume contraction, initiates hypertension.
Methods: We tested the effect of deoxycorticosterone acetate (DOCA; 25 mg pellet) in mice on low Na⁺ diet (0.02-0.03%) with tap water, or with Na⁺ in their drinking water (1% NaCl or 1.44% NaHCO₃), on body Na⁺, K⁺, and water content 2, 6, and 12 days after treatment initiation. In addition, we monitored blood pressure (BP) with radio-telemetry, food and water intake, solute and water excretion, and quantified renal and cutaneous blood flow by pulse-wave/laser Doppler spectroscopy.
Results: Two days after treatment initiation, DOCA NaCl treatment reduced intracellular K⁺ and water content (Fig. 1A), and elevated BP (Fig. 2); however, without accompanying Na⁺ retention. After one week, Na⁺ solutes replaced the initially lost K⁺ (Fig. 1A), and intracellular volume increased back to control levels (Fig. 1B). For re-hydration, DOCA NaCl-treated mice also increased fluid intake, reduced renal solute-free water clearance, constricted renal blood vessels, and reduced cutaneous blood flow (Fig. 3). Normotensive DOCA NaHCO₃-treated mice similarly lost intracellular K⁺ but immediately compensated by intracellular Na⁺ accumulation and therefore experienced no body water loss (Fig. 1). Without prolonged under-hydration of their K⁺-space, DOCA NaHCO₃-treated mice neither showed augmentation of renal or cutaneous water conservation, nor dermal blood flow reduction (Fig. 3B). Without accompanying renal and dermal vasoconstriction, their BP remained normal despite body Na⁺ excess.
Conclusions: DOCA salt-sensitive hypertension initiates with a K⁺-driven under-hydration, and not with a Na⁺-driven over-hydration. The BP increase is explainable by secondary-adaptive multi-organ water conservation physiology, but not by Na⁺-driven water excretion physiology via "pressure natriuresis" (Guyton/Borst hypothesis). We conclude that dietary salt causes a Na⁺/K⁺ redistribution disorder in the K⁺-controlled intracellular volume space, which results in the hypothesis that oral K⁺ supplementation might be a causal therapy for salt-sensitive hypertension. We have transferred this hypothesis into the clinical arena (ClinicalTrials.gov; identifier NCT06569589) and report first positive study results in an accompanying clinical research presentation (Abstract ID 4391187).