ACTIVATION DEACTIVATION OF RENAL NA+,K+-ATPASE - A FINAL COMMON PATHWAY FOR REGULATION OF NATRIURESIS/

Renal sodium metabolism, a major determinant of blood pressure, is reg ulated with great precision by a variety of endocrine, autocrine, and neuronal factors. Although these factors are known to regulate sodium metabolism by affecting the rate of tubular sodium reabsorption, the m olecular mechanisms by which they act are poorly understood. Na+,K+-AT Pase plays a pivotal role for sodium reabsorption in all tubular segme nts. The activity of this enzyme can be dynamically regulated by phosp horylation and dephosphorylation. Here we summarize both old and new e vidence that several major substances believed to be involved in the r egulation of sodium metabolism and blood pressure, i.e., the antidiure tic agents angiotensin II and norepinephrine, and the diuretic agents dopamine and atrial natriuretic peptide (ANP), may achieve their effec ts through a common pathway that involves reversible activation/deacti vation of renal tubular Na+,K+-ATPase. Regulation of Na+,K+-ATPase act ivity was studied using a preparation of single proximal tubule (PT) s egments, dissected from rat kidneys. Na+,K+-ATPase activity was stimul ated by angiotensin II and the alpha-adrenergic agonist, oxymetazoline , at physiological, nonsaturating Nai concentrations. These stimulator y effects were blocked by dopamine and ANP as well as by their respect ive second messengers, cAMP and cGMP. They were also blocked by the sp ecific protein phosphatase 2B inhibitor FK506. These results indicate that regulation of sodium excretion by norepinephrine, angiotensin II, dopamine, and ANP can be accounted for by a bidirectionally regulated intracellular protein phosphorylation cascade that modulates the acti vity of renal tubular Na+,K+-ATPase.