Phosphodiesterase inhibitors correct resistance to natriuretic peptides in rats with Heymann Nephritis.
Experimental nephrotic syndrome is characterized by abnormal sodium metabolism, reflected in a blunted natriuretic response both to volume expansion and to infused atrial natriuretic peptide (ANP). The studies presented here examined the relationships among plasma ANP concentration and urinary sodium (VNaV) and cyclic GMP excretion (UcGMPV) in vivo, and the responsiveness of isolated glomeruil and inner medullary collecting duct (IMCD) cells to ANP and urodilatin (renal natriuretic peptide; RNP) in vitro in rats with Heymann nephritis, an immunologically mediated model of nephrotic syndrome. Nine to 14 days after Ip injection of anti-Fx1A antiserum, rats were proteinuric and had a blunted natriuretic response to intravenous infusion of isotonic saline (2% body weight, given over 5 min). Thirty min after the onset of the infusion, plasma ANP concentration was increased to the same extent in both normal and nephritic rats, compared with their respective hydropenic controls. Despite this increase, UcGMPV was significantly less in nephritic rats after the saline infusion. Accumulation of cGMP by isolated glomeruil and IMCD cells from nephritic rats after incubation with ANP and RNP was also significantly reduced, compared with normal rats. This difference was not related to differences in either density or affinity of renal ANP receptors, but was abolished when accumulation of cGMP was measured in the presence of 10(-3) M isobutylmethylxanthine or Zaprinast, two different inhibitors of cyclic nucleotide phosphodiesterases (PDE). Infusion of Zaprinast into one renal artery in nephritic rats normalized both the natriuretic response to volume expansion and the increase in UcGMPV from the infused, but not the contralateral, kidney. Furthermore, cGMP-PDE activity was increased in IMCD cell homogenates from nephritic compared with normal rats (388 +/- 32 versus 198 +/- 93 pmol/min per mg protein, P < 0.03). These results indicate that blunted volume expansion natriuresis accompanied by cellular resistance to ANP in vitro occurs in an immunologic model of renal injury. The resistance is not related to an alteration in ANP release or binding to its renal receptors, but is suppressed by PDE inhibitors and is associated with increased renal cGMP. PDE activity, thus suggesting that enhanced cGMP-PDE activity may account for resistance to the natriuretic actions of ANP observed in vivo. This defect may represent the intrinsic sodium transport abnormality linked to sodium retention in nephrotic syndrome.
Valentin
J P
JP
Division of Nephrology, San Francisco General Hospital, University of California 94143, USA.
Ying
W Z
WZ
Sechi
L A
LA
Ling
K T
KT
Qiu
C
C
Couser
W G
WG
Humphreys
M H
MH
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006152:Cyclic GMP / Q000096:biosynthesis*; D004232:Diuretics / Q000494:pharmacology; D005919:Glomerular Filtration Rate; D005921:Glomerulonephritis / Q000378:metabolism* / Q000652:urine; D066298:In Vitro Techniques; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D007685:Kidney Tubules, Collecting / Q000378:metabolism / Q000473:pathology; D008297:Male; D009318:Natriuresis / Q000187:drug effects*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011688:Purinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017461:Receptors, Atrial Natriuretic Factor / Q000378:metabolism
D004232:Diuretics; D010446:Peptide Fragments; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; C056452:Ularitide; D009320:Atrial Natriuretic Factor; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D017461:Receptors, Atrial Natriuretic Factor; C011145:zaprinast; D006152:Cyclic GMP; D015056:1-Methyl-3-isobutylxanthine