Normal rat pregnancy is characterized by plasma volume expansion due to renal sodium retention and is associated with a blunted response to natriuretic stimuli, such as atrial natriuretic peptide (ANP). ANP signals via cGMP, and phosphodiesterases (PDE) inactivate cGMP and terminate the natriuretic response. We previously reported that increased medullary PDE-5 activity occurs in normal rat pregnancy which may be the mechanism of the blunted natriuretic effect of ANP. Here we used anesthetized 16-day pregnant and virgin rats to investigate if intrarenal infusion of a selective PDE-5 inhibitor, sildenafil would reverse the blunted response to ANP in pregnancy. We measured blood pressure, renal clearances using inulin and p-aminohippuric acid and electrolyte excretion, at baseline and during an ANP infusion. ANP caused a fall in MAP in all groups and sildenafil induced a further reduction. We observed an increase in sodium excretion with ANP in all rats but this was blunted in the vehicle infused pregnant rats. This could not be explained by differences in renal hemodynamics and was of tubular origin as reflected by the reduced rise in fractional excretion of sodium (FE_Na) with ANP in the pregnant rat given vehicle (45±11 vs. 204±49%; p<0.05). However, intrarenal sildenafil increased the natriuretic response and the rise in FE_Na to the virgin value (226±23 vs. 245±73%; ns) while the blunting persisted in the contralateral kidney. This demonstrates that increased intrarenal PDE-5 mediates the blunted natriuretic response to ANP during pregnancy and may contribute to the physiologic volume expansion.