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(Hypertension. 1996;27:219-227.)
© 1996 American Heart Association, Inc.

Articles

Pathophysiological Consequences of Changes in the Coupling Ratio of Na,K-ATPase for Renal Sodium Reabsorption and Its Implications for Hypertension

David E. Orosz; Ulrich Hopfer

From the Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, Cleveland, Ohio.

Correspondence to Dr Ulrich Hopfer, Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, 10900 Euclid Ave, Cleveland, OH 44106-4970. E-mail uxh@po.cwru.edu.

Abstract Recent reports indicate that 1-Na,K-ATPase from Dahl salt-sensitive (DS) rats contains a glutamine for leucine substitution associated with increased Na-K coupling at unchanged maximal velocity. Genetic analyses suggest that 1-Na,K-ATPase is a potential hypertension gene. Therefore, we investigated whether renal Na⁺ metabolism could constitute a pathophysiological link between the molecular/functional change in Na,K-ATPase and hypertension. We simulated the consequences of increased Na-K coupling on overall Na-bicarbonate reabsorption in a proximal tubular transport model that incorporates apical Na-H exchanger and basolateral Na-bicarbonate cotransporter, K⁺ channel, and Na,K-ATPase. As expected, increases in the levels of the former three transport pathways yielded higher Na⁺ reabsorption. In contrast, increases in the maximal velocity of the Na,K-ATPase with a normal 3:2 (Na-K) coupling ratio did not increase Na⁺ reabsorption when apical Na-H exchange activity was limiting overall absorption. However, an increase in the Na-K coupling from 3:2 to 3:1, reported for the mutant 1-Na,K-ATPase in DS rats, was associated with greater Na⁺ reabsorption. This increase is a consequence of lower cytosolic pH and secondary stimulation of the Na-H exchanger at its allosteric H⁺ site. Decreased pH results from activation of Na-bicarbonate cotransport by Na,K-ATPase–dependent membrane hyperpolarization due to greater charge movement in 3:1 Na-K coupling. Thus, an increase in the Na-K coupling ratio results in an altered set point for cellular Na⁺ metabolism, with higher sodium reabsorption at unchanged Na,K-ATPase levels. The simulations thereby lend support for a unifying explanation for the salt sensitivity of DS rats, which has been proposed to stem from a mutation in the 1-Na,K-ATPase.

Key Words: hypertension, genetic • hypertension, essential • kidney • rats, Dahl • Na⁺,K⁺-transporting ATPase • sodium-potassium pump

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