Stimulation of renin secretion by nitric oxide is mediated by phosphodiesterase 3.
This study aimed to characterize the cellular pathways along which nitric oxide (NO) stimulates renin secretion from the kidney. Using the isolated perfused rat kidney model we found that renin secretion stimulated 4- to 8-fold by low perfusion pressure (40 mmHg), by macula densa inhibition (100 micromol/liter of bumetanide), and by adenylate cyclase activation (3 nmol/liter of isoproterenol) was markedly attenuated by the NO synthase inhibitor nitro-L-arginine methyl ester (L-Name) (1 mM) and that the inhibition by L-Name was compensated by the NO-donor sodium nitroprusside (SNP) (10 micromol/liter). Similarly, inhibition of cAMP degradation by blockade of phosphodiesterase 1 (PDE-1) (20 micromol/liter of 8-methoxymethyl-1-methyl-3-(2-methylpropyl)xanthine) or of PDE-4 (20 micromol/liter of rolipram) caused a 3- to 4-fold stimulation of renin secretion that was attenuated by L-Name and that was even overcompensated by sodium nitroprusside. Inhibition of PDE-3 by 20 micromol/liter of milrinone or by 200 nmol/liter of trequinsin caused a 5- to 6-fold stimulation of renin secretion that was slightly enhanced by NO synthase inhibition and moderately attenuated by NO donation. Because PDE-3 is a cGMP-inhibited cAMP-PDE the role of endogenous cGMP for the effects of NO was examined by the use of the specific guanylate cyclase inhibitor 1-H-(1,2,4)oxodiazolo(4,3a)quinoxalin-1-one (20 micromol). In the presence of 1H-[1,2,4]oxodiazolo[4,3-a]quinoxalin-1-one the effect of NO on renin secretion was abolished, whereas PDE-3 inhibitors exerted their normal effects. These findings suggest that PDE-3 plays a major role for the cAMP control of renin secretion. Our findings are compatible with the idea that the stimulatory effects of endogenous and exogenous NO on renin secretion are mediated by a cGMP-induced inhibition of cAMP degradation.
Kurtz
A
A
Institut für Physiologie der Universität Regensburg, D-93040 Regensburg, Germany. armin.kutz@vkl.uni-regenburg.de
Götz
K H
KH
Hamann
M
M
Wagner
C
C
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D000818:Animals; D002034:Bumetanide / Q000494:pharmacology; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D007700:Kinetics; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology*; D009599:Nitroprusside / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000378:metabolism*; D020889:Rolipram
D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D002034:Bumetanide; D009599:Nitroprusside; D009569:Nitric Oxide; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D012083:Renin; D020889:Rolipram; D007545:Isoproterenol; D015056:1-Methyl-3-isobutylxanthine; D019331:NG-Nitroarginine Methyl Ester