Reinforcing feedback loop of renal cyclic guanosine 3' 5' -monophosphate and interstitial hydrostatic pressure in pressure-natriuresis.
This study addresses the hypothesis that renal interstitial (RI) cGMP, a modulator of pressure-natriuresis, exerts its effect through a relationship with renal interstitial hydrostatic pressure (RIHP). Increasing renal perfusion pressure in Sprague-Dawley rats led to increases in RIHP (5.2+/-0.6 to 10.9+/-1.6 mm Hg; P<0.01), urine sodium excretion (0.062+/-0.009 to 0.420+/-0.068 micromol/min per gram; P<0.01), and RI cGMP (3.5+/-0.8 to 9.5+/-1.7 fmol/min; P<0.01), and these effects were blocked by partial renal decapsulation. Infusion of cGMP into the RI compartment of decapsulated animals restored natriuresis (0.067+/-0.010 to 0.310+/-0.061 micromol/min per gram; P<0.01). These changes were independent of changes in glomerular filtration rate . Artificially increasing RIHP in normotensive animals increased RI cGMP (4.1+/-0.6 to 6.9+/-0.7 fmol/min; P<0.01) and urine sodium excretion (0.071+/-0.013 to 0.179+/-0.039 micromol/min per gram; P<0.05). Coinfusion of organic anion transport-inhibitor probenecid, or soluble guanylyl cyclase inhibitor 1-H(1,2,4) oxadiazolo-(4,2)quinoxalin-1-one, abolished these effects. Infusion of cGMP into the RI compartment of normotensive animals increased RIHP (6.7+/-0.4 to 10.3+/-0.9 mm Hg; P<0.001). Exogenous RI cGMP delivery did not affect total, cortical, or medullary renal blood flow. These studies suggest that extracellular RI cGMP is required for the natriuresis observed after increases in renal perfusion pressure and RIHP and that cGMP acts via a tubule mechanism. The results support an intrarenal positive-feedback loop wherein RI cGMP increases RIHP, which, in turn, increases RI cGMP, contributing to the reinforcement of pressure-natriuresis.
Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA, USA. liebdc@evms.edu
David C
DC
Lieb
Brandon A
BA
Kemp
Nancy L
NL
Howell
John J
JJ
Gildea
Robert M
RM
Carey
D000418:Albumins / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D006152:Cyclic GMP / Q000378:metabolism* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D006874:Hydrostatic Pressure; D006977:Hypertension, Renal / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects / Q000502:physiology*; D009318:Natriuresis / Q000187:drug effects / Q000502:physiology*; D010069:Oxadiazoles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects / Q000502:physiology; D014556:Urine
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000418:Albumins; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D011810:Quinoxalines; D006152:Cyclic GMP