ABNORMAL GLOMERULAR RESPONSE TO ATRIAL-NATRIURETIC-PEPTIDE IN RATS WITH AORTOCAVAL FISTULAS

Heart failure is characterized by a blunted natriuretic and diuretic r esponse to atrial natriuretic peptide (ANP). To investigate this, a ra t model of compensated high-output heart failure was used to determine whether glomerular response to ANP differs in animals with high cardi ac output compared with control animals. An aortocaval (AC) fistula wa s made below the level of the renal arteries in male Sprague-Dawley ra ts. At 6 wk, one group of AC fistula (N = 6) and control rats (N = 6) was injected with radiolabeled microspheres for determination of hemod ynamic parameters, including cardiac output, renal blood flow, and vas cular resistance, Rats with AC fistulas had significant changes in car diac output (218 +/- 17 versus 57 +/- 11 mL/min, P less than or equal to 0.0001), renal blood flow (3.4 +/- 0.7 versus 8.4 +/- 1.9 mL/min le ft, P less than or equal to 0.05; 3.0 +/- 0.4 versus 7.2 +/- 1.9 mL/mi n Right, P less than or equal to 0.05), and fetal vascular resistance (0.6 +/- 0.1 versus 2.7 +/- 0.4 mm Hg/mL per min, P < 0.001) compared with control animals, respectively, In another group of animals, after 6 wk, glomeruli were isolated from kidneys. Extracellular (EC) and in tracellular (IC) cGMP was measured as an indication of glomerular resp onse to ANP. Early glomerular response to ANP (10(-8) mol/L) showed a similar acute 13- to 18-fold rise in IC cGMP after 30 sec exposure to ANP (P less than or equal to 0.0001 versus no ANP; N = 4 AC fistula ra ts and N = 4 control rats). During 1-h incubations with ANP, glomerula r response was characterized by a five- to sevenfold increase in EC cG MP. However, glomeruli of AC fistula rats produced significantly less EC cGMP than did those of control animals (21.3 +/- 2.5 Versus 44 +/- 4.9 fMol cGMP/2000 glomeruli, P less than or equal to 0.005; N = 5 AC fistula rats and N = 5 control rats, respectively). Probenecid sensiti ve transport of EC cGMP between AC fistula and control rats (86% decre ase versus 82% decrease) was similar. However, glomeruli from AC fistu la animals had significantly less phosphodiesterase activity compared with control animals (3.6 +/- 0.4 versus 5.4 +/- 0.7 nMol cGMP/mg prot ein per min, P less than or equal to 0.01; N = 4 AC fistula rats and N = 5 control rats, respectively), It is speculated that reduced glomer ular generation of cGMP in response to ANP contributes to sodium reten tion in heart failure, but may be compensated for in part by decreased phosphodiesterase-mediated hydrolysis of cGMP.