(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
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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