Deoxycorticosterone-acetate salt-sensitive hypertension initiates with intracellular K+ and water loss

Abstract

Background: Textbook teaching pretends that Na+-driven extracellular fluid and blood volume expansion may cause hypertension. We tested the alternative hypothesis, namely that K+ loss-driven intracellular volume contraction causes hypertension. Methods: We tested the effect of deoxycorticosterone acetate (DOCA; 25 mg pellet) in mice on low Na+ diet (0.02-0.03%) without (tap water), or with Na+ in their drinking water (1% NaCl or 1.44% NaHCO3). We measured BP with radio-telemetry, and analysed body Na+, K+, and water content 2, 6, and 12 days after initiation of DOCA treatment. We monitored food intake, solute and water excretion in urine and stool, and quantified renal and cutaneous blood flow by pulse-wave/laser Doppler spectroscopy. Results: DOCA NaCl treatment initially reduced intracellular K+ and water content, and elevated BP without accompanying Na+ retention. To re-hydrate the intracellular volume space, hypertensive DOCA NaCl−treated mice secondarily replaced lost intracellular K+ by Na+ solutes, increased fluid intake, reduced renal solute-free water clearance, constricted renal blood vessels, and reduced dermal blood flow. Normotensive DOCA NaHCO3-treated mice similarly lost intracellular K+, but immediately compensated by intracellular Na+ accumulation, and therefore experienced no intracellular volume contraction. Without prolonged under-hydration of their K+-space, DOCA NaHCO3-treated mice neither showed augmentation of renal or dermal water conservation, nor vasoconstriction and blood flow reduction, and their BP remained normal despite body Na+ excess. Conclusions: DOCA salt-sensitive hypertension is caused by K+-driven under-hydration, and not by 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. National Medical Research Council (NMRC) of Singapore to the Duke-NUS Medical School, the German Federal Ministry for Economics and Technology/DLR Forschung unter Weltraumbedingungen (Mars500-III; 50WB2024). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.