Renal interstitial guanosine cyclic 3', 5'-monophosphate mediates pressure-natriuresis via protein kinase G.
Pressure-natriuresis is the physiological protective mechanism whereby elevation of blood pressure induces a rapid increase in renal sodium (Na+) excretion. Pressure-natriuresis abnormalities are common to all forms of hypertension. We tested the hypothesis that pressure-natriuresis is mediated by renal interstitial (RI) cGMP and protein kinase G (PKG). We used anesthetized, uninephrectomized Sprague-Dawley rats and a standard pressure-natriuresis model in which bilateral adrenalectomy and renal denervation was done on rats. Renal perfusion pressure (RPP) was adjusted by manipulating clamps above and below the renal artery, and RI cGMP was quantified by microdialysis. RI cGMP increased from 3.1+/-0.5 to 5.5+/-0.4 fmol/min (P<0.05) when RPP was raised from 100 to 140 mm Hg. This increase in RI cGMP was eliminated by RI infusion of soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,2-alpha]quinoxalin-1-one (ODQ). Raising RPP from 100 to 140 mm Hg increased urinary sodium excretion from 0.2+/-0.1 to 0.8+/-0.1 micromol/min, fractional sodium excretion from 0.2+/-0.1% to 0.8+/-0.1%, and fractional lithium excretion from 20.1+/-3.0% to 62.7+/-3.7% (all P<0.05). These responses were eliminated by RI infusion of nitric oxide synthase inhibitor N-nitro-l-arginine methyl ester, ODQ, and PKG inhibitors Rp-8-pCPT-cGMP and Rp-8-Br-cGMP. Increasing RPP from 100 to 140 mm Hg decreased fractional proximal sodium reabsorption without influencing fractional distal Na+ reabsorption or glomerular filtration rate. In conclusion, pressure-natriuresis is mediated by RI cGMP and a PKG signaling pathway in target renal proximal tubule cells.
Jin
Xiao-Hong
XH
Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908-1414, USA.
McGrath
Helen E
HE
Gildea
John J
JJ
Siragy
Helmy M
HM
Felder
Robin A
RA
Carey
Robert M
RM
D000315:Adrenalectomy; D000818:Animals; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D003714:Denervation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006162:Guanylate Cyclase; D006973:Hypertension / Q000503:physiopathology*; D017136:Ion Transport / Q000187:drug effects; D007668:Kidney / Q000294:innervation; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009318:Natriuresis / Q000187:drug effects / Q000502:physiology*; D009392:Nephrectomy; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010069:Oxadiazoles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D012964:Sodium / Q000378:metabolism; D000071756:Soluble Guanylyl Cyclase; D013873:Thionucleotides / Q000494:pharmacology
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D011810:Quinoxalines; D018160:Receptors, Cytoplasmic and Nuclear; D013873:Thionucleotides; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; C055656:8-((4-chlorophenyl)thio)cyclic-3',5'-GMP; D012964:Sodium; D019001:Nitric Oxide Synthase; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester