Inhibition of cGMP-phosphodiesterase restores the glomerular effects of atrial natriuretic factor in low sodium diet rats.

Abstract

It was shown that atrial natriuretic factor (ANF)-induced increase in glomerular filtration rate (GFR) is blunted in low sodium diet. We investigated whether saralasin, as an angiotensin II receptor antagonist, or verapamil, as a calcium entry blocker, or theophylline and zaprinast, as inhibitors of cGMP-phosphodiesterase activity, could restore the effect of ANF on GFR increase in low sodium diet rats. ANF alone (5 micrograms/kg bolus then 0.5 micrograms/min/kg BW maintenance) increased diuresis and natriuresis to the same extend in low and normal sodium diet rats but had no GFR-increasing effect in low sodium diet rats. Infusion of ANF in the presence of verapamil, saralasin, theophylline or zaprinast induced a significant increase in GFR and filtration fraction (FF). Administration of verapamil or saralasin alone did not alter GFR and FF whereas theophylline or zaprinast alone resulted in moderate but significant increases in both parameters. The increase of nephrogenous cGMP excretion in response to ANF infusion in low sodium diet rats was markedly lower as compared to normal sodium diet rats (243.4 +/- 43.3 vs. 444.0 +/- 35.6 pmol/min, respectively, p < 0.01). Administration of a selective inhibitor of cGMP-phosphodiesterase activity (zaprinast) abolished the differences in ANF-stimulated nephrogenous cGMP excretion in low and normal sodium diet rats. Basal and peak ANF (0.5 microM)-stimulated cGMP formation by isolated glomeruli was significantly lower in low than normal sodium diet rats (1.4 +/- 0.1 vs. 2.9 +/- 0.2 and 7.1 +/- 0.5 vs. 12.5 +/- 1.1 pmol/mg protein, for basal and ANF-stimulated cGMP formation, respectively; both p < 0.05). Zaprinast both alone and in combination with ANF, potentiated cGMP formation by glomeruli isolated from both groups of rats. In the presence of zaprinast, there were no differences in both basal and peak ANF-stimulated cGMP formation by glomeruli isolated from low and normal sodium diet rats. cGMP-phosphodiesterase activity was the same in the medulla of both groups of rats but markedly higher in the renal cortex of low sodium diet rats as compared to normal sodium diet rats (82.6 +/- 6.0 vs. 59.8 +/- 4.3, respectively; p < 0.05). These data suggest that the lack of GFR-increasing response to ANF in low sodium diet rats is primarily due to the increase of cGMP hydrolysis in glomeruli.