Effects on kidney filtration rate by agmatine requires activation of ryanodine channels for nitric oxide generation.
Agmatine, decarboxylated arginine, is produced in the kidney and can increase nephron and kidney filtration rate via renal vasodilatation and increases in plasma flow. This increase in filtration rate after agmatine is prevented by administration of nitric oxide synthase (NOS) inhibitors. In endothelial cells, agmatine-stimulated nitrite production is accompanied by induction of cytosolic calcium. NOS activity requires calcium for activation; however, the source of this calcium remains unknown. Ryanodine receptor (RyR) calcium-activated calcium release channels are present in the kidney cortex, and we evaluated if RyR contributes to the agmatine response. Agmatine microperfused into Bowman's space reversibly increases nephron filtration rate (SNGFR) by approximately 30%. cADP-ribose (cADPR) regulates RyR channel activity. Concurrent infusion of agmatine with the cADPR blocker 8-bromo-cADPR (2 microM) prevents the increase in filtration rate. Furthermore, direct activation of the RyR channel with ryanodine at agonist concentrations (5 microM) increases SNGFR, and, like agmatine, this increase is prevented by administration of N(G)-monomethyl-l-arginine, a nonselective NOS blocker. We demonstrate that agmatine does not elicit ADPR cyclase activity in vascular smooth muscle membranes and does not directly affect RyR calcium channel responses using sea urchin egg homogenates. These results imply interplay between endothelial cell cADPR/RyR/Ca(2+)/NO and the cADPR/RyR/Ca(2+) pathways in vascular smooth muscle cells in arterioles in the regulation of kidney filtration rate. In conclusion, we show that agmatine-induced effects require activation of cADPR and RyR calcium release channels for NO generation, vasodilation, and increased filtration rate.
Satriano
Joseph
J
Division of Nephrology-Hypertension, Univ. of California, San Diego and Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Drive, M.C. 9111-H, San Diego, CA 92161, USA.
Cunard
Robyn
R
Peterson
Orjan W
OW
Dousa
Thomas
T
Gabbai
Francis B
FB
Blantz
Roland C
RC
D000376:Agmatine / Q000494:pharmacology*; D000818:Animals; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000502:physiology; D008297:Male; D009399:Nephrons / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012433:Ryanodine / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology*
D019837:Ryanodine Receptor Calcium Release Channel; D012433:Ryanodine; D009569:Nitric Oxide; D000376:Agmatine; D019001:Nitric Oxide Synthase