Atrial natriuretic peptide modulates sodium and potassium-activated adenosine triphosphatase through a mechanism involving cyclic GMP and cyclic GMP-dependent protein kinase.
Prior studies indicate that the natriuretic effects of atrial natriuretic peptide (ANP) are due, in part, to an inhibition of the passive movement of sodium ions from tubular lumen through apical cation channels into renal tubular epithelium. The present work demonstrates that ANP also exerts a potent inhibitory effect on the active pumping of sodium ions by renal tubular sodium and potassium-activated adenosine triphosphatase (Na, K-ATPase). This action of ANP is relatively long lasting, is due to a change in enzyme Vmax and is specific for ouabain-sensitive activity. Enzyme modulation occurs with an EC50 for ANP of 0.1 nM, is independent of intracellular [Na+] and is associated with an increase in tissue cyclic GMP (cGMP), but not cyclic AMP (cAMP). Modulation of Na, K-ATPase by ANP is mimicked by 8-bromo-cGMP and okadaic acid (OA) and is blocked by KT 5823, a selective inhibitor of cGMP-dependent protein kinase (PKG), but not by KT 5720, a selective inhibitor of cyclic AMP-dependent protein kinase (PKA), which suggests that the action of ANP on the sodium pump involves cGMP-mediated changes in protein phosphorylation. Regulation of renal Na, K-ATPase activity also occurs with nitric oxide-generating compounds, such as nitroglycerin and sodium nitroprusside (SNP). However, the ability of ANP to modulate Na, K-ATPase does not appear to involve this latter pathway because the effects of ANP on the sodium pump cannot be blocked by either N omega-nitro-L-arginine, an inhibitor of NO synthase, or hemoglobin, which blocks NO through binding.(ABSTRACT TRUNCATED AT 250 WORDS)
Scavone
C
C
Department of Neurology, Harvard Medical School, Boston, Massachusetts.
Scanlon
C
C
McKee
M
M
Nathanson
J A
JA
D000470:Alkaloids / Q000494:pharmacology; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D002227:Carbazoles; D006152:Cyclic GMP / Q000502:physiology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D007679:Kidney Medulla / Q000201:enzymology; D008297:Male; D009569:Nitric Oxide / Q000502:physiology; D010042:Ouabain / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*
D000470:Alkaloids; D002227:Carbazoles; D007211:Indoles; D011758:Pyrroles; C073601:KT 5823; D009569:Nitric Oxide; C057416:KT 5720; D010042:Ouabain; D000584:Amiloride; D009320:Atrial Natriuretic Factor; D012964:Sodium; D017869:Cyclic GMP-Dependent Protein Kinases; D000254:Sodium-Potassium-Exchanging ATPase; D006152:Cyclic GMP