Abnormal glomerular response to atrial natriuretic peptide in rats with aortocaval fistulas

Heart failure is characterized by a blunted natriuretic and diuretic response to atrial natriuretic peptide (ANP). To investigate this, a rat model of compensated high-output heart failure was used to determine whether glomerular response to ANP differs in animals with high cardiac output compared with control animals. An aortocaval (AC) fistula was made below the level of the renal arteries in male Sprague-Dawley rats. At 6 wk, one group of AC fistula (N = 6) and control rats (N = 6) was injected with radiolabeled microspheres for determination of hemodynamic parameters, including cardiac output, renal blood flow, and vascular resistance. Rats with AC fistulas had significant changes in cardiac output (218 +/- 17 versus 57 +/- 11 mL/min, P < or = 0.0001), renal blood flow (3.4 +/-0.7 versus 8.4 +/- 1.9 mL/min Left, P < or = 0.05; 3.0 +/- 0.4 versus 7.2 +/- 1.9 mL/min Right, P < or = 0.05), and total 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 intracellular (IC) cGMP was measured as an indication of glomerular response 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 < or = 0.0001 versus no ANP; N = 4 AC fistula rats and N = 4 control rats). During 1-h incubations with ANP, glomerular response was characterized by a five- to sevenfold increase in EC cGMP. 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 < = 0.005; N = 5 AC fistula rats and N = 5 control rats, respectively). Probenecid-sensitive transport of EC cGMP between AC fistula and control rats (86% decrease versus 82% decrease) was similar. However, glomeruli from AC fistula animals had significantly less phosphodiesterase activity compared with control animals (3.6 +/- 0.4 versus 5.4 +/- 0.7 nMol cGMP/mg protein per min, P < or = 0.01; N = 4 AC fistula rats and N = 5 control rats, respectively). It is speculated that reduced glomerular generation of cGMP in response to ANP contributes to sodium retention in heart failure, but may be compensated for in part by decreased phosphodiesterase-mediated hydrolysis of cGMP.