Angiotensin II AT2 receptors inhibit proximal tubular Na+-K+-ATPase activity via a NO/cGMP-dependent pathway.
Angiotensin II AT2 receptors act as a functional antagonist for the AT1 receptors in various tissues. We previously reported that activation of the renal AT2 receptors promotes natriuresis and diuresis; however, the mechanism is not known. The present study was designed to investigate whether activation of AT2 receptors affects the activity of Na+-K+-ATPase (NKA), an active tubular sodium transporter, in the proximal tubules isolated from Sprague-Dawley rats. The AT2 receptor agonist CGP-42112 (10(-10)-10(-7) M) produced a dose-dependent inhibition of NKA activity (9-38%); the inhibition was attenuated by the presence of the AT2 receptor antagonist PD-123319 (1 microM), suggesting the involvement of the AT2 receptors. The AT1 receptor antagonist losartan (1 microM) did not affect the CGP-42112 (100 nM)-induced inhibition of NKA activity. The presence of guanylyl cyclase inhibitor ODQ (10 microM) and the nitric oxide (NO) synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME; 100 microM) abolished the CGP-42112 (100 nM)-induced NKA inhibition. ANG II (100 nM), in the presence of losartan, significantly inhibited NKA activity; the inhibition was attenuated by PD-123319. CGP-42112 also, in a dose-dependent manner, stimulated NO production (approximately 0-230%) and cGMP accumulation (approximately 25-100%). The CGP-42112 (100 nM)-induced NO and cGMP increases were abolished by the AT2 receptor antagonist PD-123319, ODQ, and L-NAME. The data suggest that the activation of the AT2 receptor via stimulation of the NO/cGMP pathway causes inhibition of NKA activity in the proximal tubules. This phenomenon provides a plausible mechanism responsible for the AT2 receptor-mediated natriuresis-diuresis in rodents.
Hakam
Amer C
AC
Dept. of Pharmacological and Pharmaceutical Sciences, Science and Research Bldg. 2, Univ. of Houston, 4800 Calhoun, Houston, TX 77204-5037, USA.
Hussain
Tahir
T
D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D006152:Cyclic GMP / Q000032:analysis / Q000502:physiology* / Q000652:urine; D004231:Diuresis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007687:Kidney Tubules, Proximal / Q000737:chemistry / Q000201:enzymology*; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D009566:Nitrates / Q000032:analysis; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D009573:Nitrites / Q000032:analysis; D009842:Oligopeptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists / Q000502:physiology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism*
D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D004791:Enzyme Inhibitors; D009566:Nitrates; D009573:Nitrites; D009842:Oligopeptides; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; C060894:CGP 42112A; D009569:Nitric Oxide; D000254:Sodium-Potassium-Exchanging ATPase; D006152:Cyclic GMP