Interaction between nitric oxide and oxygen radicals in regulation of tubuloglomerular feedback.
NADPH oxidase, nitric oxide synthase (NOS) and cyclooxygenase are oxidases that are expressed in the juxtaglomerular apparatus (JGA) or blood vessels and can generate oxygen radicals (O-2) during partial reduction of molecular oxygen. O-2 interacts rapidly and irreversibly with nitric oxide (NO) to yield peroxynitrite (ONOO-), thereby restricting the half-life, diffusion distance and bioactivity of NO in tissues. NO generated by a neuronal (n) NOS isoform that is heavily expressed in macula densa (MD) cells, is generated during NaCl reabsorption at the MD and blunts the expression of the tubuloglomerular feedback (TGF) response. Therefore, we tested the hypothesis that O-2 formed in the JGA of the normal rat limits NO signalling. Tempol is a membrane-permeable superoxide dismutase (SOD) mimetic. Maximal TGF responses were assessed from the fall in proximal stop flow pressure during orthograde perfusion of artificial tubular fluid (ATF) into the loop of Henle. Microperfusion of tempol (10-4 M) into the efferent arteriole (EA) of Wistar-Kyoto rats blunted maximal TGF response (8. 2 +/- 0.4 vs. 6.4 +/- 0.4 mmHg; n=8; P < 0.05). Graded doses of the NO donor compound, S-nitroso-acetylpenicillamine (SNAP; 10-7-10-4 M) microperfused into the lumen of the MD produces graded buffering of TGF. During EA microperfusion of tempol, responses to luminal SNAP at 10-6 M and greater were enhanced significantly (P < 0.05 or <0. 01). In conclusion, O-2 generated in the JGA can be metabolized by a membrane-permeable SOD mimetic. O-2 enhances the basal TGF response and limits NO signalling from the macula densa. Therefore, O-2 and NO interact in the JGA to modulate the TGF response.
Wilcox
C S
CS
Division of Nephrology and Hypertension, Georgetown University Medical Center, Washington, DC 20007, USA.
Welch
W J
WJ
D000818:Animals; D003497:Cyclic N-Oxides / Q000494:pharmacology; D005246:Feedback / Q000187:drug effects / Q000502:physiology; D016166:Free Radical Scavengers / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000502:physiology*; D007684:Kidney Tubules / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D017382:Reactive Oxygen Species / Q000502:physiology*; D026423:S-Nitroso-N-Acetylpenicillamine; D015398:Signal Transduction / Q000502:physiology; D013113:Spin Labels
D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D013113:Spin Labels; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D010396:Penicillamine; C001803:tempol