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 molec ular oxygen. O-2(-) interacts rapidly and irreversibly with nitric oxide (N O) to yield peroxynitrite (ONOO-), thereby restricting the half-life, diffu sion 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 ge nerated during NaCl reabsorption at the MD and blunts the expression of the tubuloglomerular feedback (TGF) response. Therefore, we tested the hypothe sis that O-2(-) formed in the JGA of the normal rat limits NO signalling. T empol is a membrane-permeable superoxide dismutase (SOD) mimetic. Maximal T GF responses were assessed from the fall in proximal stop flow pressure dur ing 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-nitr oso-acetylpenicillamine (SNAP; 10(-7)-10(-4) M) microperfused into the lume n of the MD produces graded buffering of TGF. During EA microperfusion of t empol, responses to luminal SNAP at 10(-6) M and greater were enhanced sign ificantly (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. Therefo re, O-2(-) and NO interact in the JGA to modulate the TGF response.