MECHANISMS CONTRIBUTING TO RENAL RESISTANCE TO ATRIAL-NATRIURETIC-PEPTIDE IN RATS WITH COMMON BILE-DUCT LIGATION

Blunted volume expansion (VE) natriuresis and renal resistance to atri al natriuretic peptide (ANP) characterize states of pathological sodiu m retention, This study examined rats 1 to 3 wk after common bile-duct ligation (CBDL), at which time they had hyperbilirubinemia and hypoal buminemia, Sham-operated normal rats (Sham) showed an increased sodium excretion rate (UNaV) from 1.0 +/- 0.1 to 16.3 +/- 3.9 mu Eq/min in r esponse to acute VE (iv saline, 2 mL/100 g body wt over 5 min), wherea s CBDL rats had a blunted response that was apparent after 1 wk and be came maximal at 2 and 3 wk (0.3 +/- 0.1 to 3.2 +/- 0.4 mu Eq/min at 3 wk, P < 0.01 versus Sham response). The peak urinary cGMP excretion ra te (UcGMPV) was also blunted (37.9 +/- 3.6 versus 87.5 +/- 8.3 pmol/mi n, P < 0.01) despite an even greater increase in plasma ANP concentrat ion (Sham, 9.6 +/- 0.4 pg/mL in hydropenia to 22.8 +/- 2.6 pg/ml after VE; CBDL, 15.3 +/- 2.3 to 41.8 +/- 6.8 pg/mL). ANP-dependent cGMP acc umulation by isolated inner medullary collecting duct (IMCD) cells fro m both Sham and CBDL rat kidneys was dose-dependent; however, at highe r concentrations of ANP (>10(-8) M), accumulation by cells from CBDL r ats was significantly blunted, indicating resistance to ANP. Binding o f I-125-ANP to IMCD cells was not different in CBDL rats compared with Sham control rats, Renal denervation improved but did not completely reverse the blunted natriuresis, and ANP resistance persisted in IMCD cells from denervated kidneys of CBDL rats, Incubation of IMCD cells w ith the phosphodiesterase inhibitors isomethylbutylxanthine or Zaprina st (each at 10(-3) M) restored ANP responsiveness in both innervated a nd denervated kidneys from CBDL rats, and intrarenal infusion of Zapri nast (10 mu g/min) corrected the blunted increase in UNaV and UcGMPV a fter VE in rats with CBDL, These results suggest that ANP resistance i n a model of abnormal sodium metabolism devoid of intrinsic renal dise ase may be related to increased activity of phosphodiesterase in renal target cells for ANP as well as to heightened renal nerve activity.