Kaliuretic peptide: the most potent inhibitor of Na(+)-K+ ATPase of the atrial natriuretic peptides

The present investigation was designed to determine whether atrial natriuretic peptides consisting of amino acids 1-30 (i.e. long-acting natriuretic peptide), 31-67 (vessel dilator), 79-98 (kaliuretic peptide), and 99-126 [atrial natriuretic factor (ANF)] of the 126 amino acid ANF prohormone inhibit sodium-potassium-ATPase as part of their mechanism(s) of action for producing a natriuresis and/or kaliuresis. Kaliuretic peptide, long-acting natriuretic peptide, vessel dilator and ANF at their 10(-11) M concentrations inhibited Na(+)-K(+)-ATPase 39.5%, 27.8%, 19.2%, and 4% respectively, in bovine renal medulla, whereas their inhibition in renal cortical membranes was 37.5%, 27.5%, 20%, and 0%, respectively. Ouabain (0.5 mM) inhibited kidney medullary Na(+)-K(+)-ATPase 45% and in the cortex, 38%. There was no additive effect of any of these peptides with ouabain suggesting that they are interacting with the same site on the Na(+)-K(+)-ATPase as ouabain. To help elucidate the mechanism of these peptides' interaction with Na(+)-K(+)-ATPase, naproxen (0.5 mM), an inhibitor of prostaglandin synthesis, and direct measurement of prostaglandin E2 by RIA were used. Naproxen completely blocked the inhibition of Na(+)-K(+)-ATPase by kaliuretic peptide, long-acting natriuretic peptide, and vessel dilator suggesting that their inhibition of Na(+)-K(+)-ATPase in both the kidney medulla and cortex are mediated by prostaglandins. Direct measurement of prostaglandin E2 revealed that kaliuretic peptide > long-acting natriuretic peptide > vessel dilator increased prostaglandin E2 synthesis, whereas ANF did not have any effect. Of interest, angiotensin II and ouabain inhibition of Na(+)-K(+)-ATPase were also completely blocked by naproxen.