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Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Michigan 48202
The interaction between nitric oxide (NO) and renin is
controversial. cAMP is a stimulating messenger for renin, which is degraded by phosphodiesterase (PDE)-3. PDE-3 is inhibited by cGMP, whereas PDE-5 degrades cGMP. We hypothesized that if endogenous cGMP
was increased by inhibiting PDE-5, it could inhibit PDE-3, increasing
endogenous cAMP, and thereby stimulate renin. We used the selective
PDE-5 inhibitor zaprinast at 20 mg/kg body wt ip, which we determined
would not change blood pressure (BP) or renal blood flow (RBF). 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 increased RSR sixfold (from 2.95 ± 1.74 to 17.62 ± 5.46 ng ANG
I · h
1 · min1, P
< 0.024), while vehicle had no effect (from 4.08 ± 2.02 to 3.87 ± 1.53 ng ANG
I · h1 · min1). There were
no changes in BP or RBF. We then tested whether the increase in cGMP
could be partially due to the activity 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% compared with vehicle. In
7-NI-treated animals, zaprinast-stimulated cGMP excretion 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 with zaprinast without 7-NI
(P < 0.04). This suggests that changes in endogenous
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.
phosphodiesterase; zaprinast; cyclic nucleotides
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