title: Neuronal nitric oxide synthase: its role and regulation in macula densa cells.
abstract: Macula densa (MD) cells detect changes in distal tubular sodium chloride concentration ([NaCl](L)), at least in part, through an apical Na:2Cl:K co-transporter. This co-transporter may be a site for regulation of tubuloglomerular feedback (TGF), and recently angiotensin II (Ang II) was shown to regulate the MD Na:2Cl:K co-transporter. In addition, nitric oxide (NO) produced via neuronal NO synthase (nNOS) in MD cells attenuates MD-TGF signaling. This study investigated [NaCl](L)-dependent MD-NO production, the regulation of co-transporter activity by NO, and the possible interaction of NO with Ang II. MD cell Na(+) concentration ([Na(+)](i)) and NO production were measured using sodium-binding benzofuran isophthalate and 4-amino-5-methylamino-2',7'-difluorescein diacetate, respectively, using fluorescence microscopy. Na:2Cl:K co-transport activity was assessed as the initial rate of increase in [Na(+)](i) when [NaCl](L) was elevated from 25 to 150 mM. 10(-4) M 7-nitroindazole, a specific nNOS blocker, significantly increased by twofold the initial rate of rise in [Na(+)](i) when [NaCl](L) was increased from 25 to 150 mM, indicating co-transporter stimulation. There was no evidence for an interaction between the stimulatory effect of Ang II and the inhibitory effect of NO on co-transport activity, and, furthermore, Ang II failed to alter MD-NO production. NO production was sensitive to [NaCl](L) but increased only when [NaCl](L) was elevated from 60 to 150 mM. These studies indicate that MD-NO directly inhibits Na:2Cl:K co-transport and that NO and Ang II independently alter co-transporter activity. In addition, generation of MD-NO seems to occur only at markedly elevated [NaCl](L), suggesting that NO may serve as a buffer against high rates of MD cell transport and excessive TGF-mediated vasoconstriction.
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology; D007606:Juxtaglomerular Apparatus / Q000166:cytology / Q000201:enzymology*; D008138:Loop of Henle / Q000166:cytology / Q000201:enzymology*; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I; D011817:Rabbits; D012965:Sodium Chloride / Q000493:pharmacokinetics; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D007191:Indazoles; D020030:Nitric Oxide Donors; D028021:Sodium-Potassium-Chloride Symporters; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D009569:Nitric Oxide; D012965:Sodium Chloride; D001120:Arginine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C080122:7-nitroindazole