Cyclic GMP mediates influence of macula densa nitric oxide over tubuloglomerular feedback.
BACKGROUND
Tubuloglomerular feedback (TGF) stabilizes nephron function by eliciting reciprocal changes in single-nephron glomerular filtration rate in response to changes in salt reaching the macula densa. Nitric oxide (NO) modulates TGF, making it less reactive. NO could come from NO synthase (NOS) in mesangium or microvessels (NOS III) or from neuronal NOS (NOS I) in the macula densa. Cyclic GMP is second messenger for many NO functions.


METHODS
Rat micropuncture was performed to confirm that macula densa NOS I makes the NO which modulates TGF and that cyclic GMP is a second messenger for this. The range of TGF was determined by measuring the single-nephron glomerular filtration rate while perfusing Henle's loop. The TGF slope was calculated from the response to flow perturbations in free-flowing nephrons using a noninvasive optical technique to measure flow. The NO-cyclic GMP axis was manipulated by tubular microperfusion of the antagonists S-methyl-thiocitrulline (SMTC) and 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ) and NO donor (spermine NONOate).


RESULTS
SMTC and ODQ each increased slope and range of TGF and tended to shift it leftward. NONOate reversed the effects of SMTC, but not of ODQ.


CONCLUSIONS
Cyclic GMP mediates desensitization of TGF by macula densa NOS I.
Thomson
Scott C
SC
Department of Medicine, Veterans Affairs Medical Center and University of California, San Diego, CA 92161-9151, USA. sthompson@ucsd.edu
Deng
Aihua
A
D000818:Animals; D002956:Citrulline / Q000031:analogs & derivatives* / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D025461:Feedback, Physiological; D005919:Glomerular Filtration Rate / Q000502:physiology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007606:Juxtaglomerular Apparatus / Q000502:physiology*; D008297:Male; D009399:Nephrons / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D010069:Oxadiazoles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D011810:Quinoxalines; D002956:Citrulline; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D006162:Guanylate Cyclase; D013890:Thiourea; D006152:Cyclic GMP; C086717:S-methylthiocitrulline