Nitric oxide synthase and cGMP-mediated stimulation of renin secretion

The interaction between nitric oxide (NO) and renin is controversial. cAMP is a stimulating messenger for renin, which is degraded by phosphodiesteras e (PDE)-3. PDE-3 is inhibited by cGMP, whereas PDE-5 degrades cGMP. We hypo thesized that if endogenous cGMP was increased by inhibiting PDE-5, it coul d inhibit PDE-3, increasing endogenous cAMP, and thereby stimulate renin. W e used the selective PDE-5 inhibitor zaprinast at 20 mg/kg body wt ip, whic h we determined would not change blood pressure (BP) or renal blood flow (R BF). In thiobutabarbital (Inactin)-anesthetized rats, renin secretion rate (RSR) was determined before and 75 min after administration of zaprinast or vehicle. Zaprinast increased cGMP excretion from 12.75 +/- 1.57 to 18.67 /- 1.87 pmol/min (P< 0.003), whereas vehicle had no effect. Zaprinast incre ased RSR sixfold (from 2.95 +/- 1.74 to 17.62 +/- 5.46 ng ANG I . h(-1) . m in(-1), P< 0.024), while vehicle had no effect (from 4.08 +/- 2.02 to 3.87 +/- 1.53 ng ANG I . h(-1) . min(-1)). There were no changes in BP or RBF. W e then tested whether the increase in cGMP could be partially due to the ac tivity of the neuronal isoform of NO synthase (nNOS). Pretreatment with the nNOS inhibitor 7-nitroindazole (7-NI; 50 mg/kg body wt) did not change BP or RBF but attenuated the renin-stimulating effect of zaprinast by 40% comp ared with vehicle. In 7-NI-treated animals, zaprinast-stimulated cGMP excre tion was attenuated by 48%, from 9.17 +/- 1.85 to 13.60 +/- 2.15 pmol/min, compared with an increase from 10.94 +/- 1.90 to 26.38 +/- 3.61 pmol/min wi th zaprinast without 7-NI (P< 0.04). This suggests that changes in endogeno us cGMP production at levels not associated with renal hemodynamic changes are involved in a renin-stimulatory pathway. One source of this cGMP may be nNOS generation of NO in the kidney.