Stimulation of renin secretion by nitric oxide is mediated by phosphodiesterase 3

Abstract

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.

Figures

Figure 1

Effect of l-Name and SNP on renin secretion from isolated rat kidneys perfused at 100 mmHg. Samples were taken in 5-min intervals during the different experimental periods, the duration of which is indicated in the upper part of the figure. For determination of significant differences renin secretion rates obtained within a certain experimental period of each kidney were taken together and averaged. The experimental protocols were run with five different kidneys. Data are means +/− SEM.

Figure 2

Effect of l-Name and SNP in the presence of lower (3 nmol/liter) and higher (10 nmol/liter) concentrations of isoproterenol on renin secretion from isolated rat kidneys perfused at 100 mmHg. Samples were taken in 5-min intervals during the different experimental periods, the duration of which is indicated in the upper part of the figure. For determination of significant differences renin secretion rates obtained within a certain experimental period of each kidney were taken together and averaged. The experimental protocols were run with five different kidneys. Data are means +/− SEM.

Figure 3

Effect of l-Name and SNP in the presence of 8-methoxymethyl-1-methyl-3-(2-methylpropyl)xanthine (8-MM-IBMX) (Upper) and in the presence of rolipram (Lower) on renin secretion from isolated rat kidneys perfused at 100 mmHg. Samples were taken in 5-min intervals during the different experimental periods, the duration of which are indicated in the upper parts of each panel. For determination of significant differences renin secretion rates obtained within a certain experimental period of each kidney were taken together and averaged. The experimental protocols were run with five different kidneys. Data are means +/− SEM.

Figure 4

(Upper) Effect of l-Name and SNP in the presence of trequinsin (200 nmol/liter) on renin secretion from isolated rat kidneys perfused at 100 mmHg. (Lower) Effect of l-Name and ANGI in the presence of 20 μmol/liter of milrinone on renin secretion from isolated rat kidneys perfused at 100 mmHg. Samples were taken in 5-min intervals during the different experimental periods, the duration of which is indicated in the upper parts of the panels. For determination of significant differences renin secretion rates obtained within a certain experimental period of each kidney were taken together and averaged. The experimental protocols were run with five different kidneys. Data are means +/− SEM.

Figure 5

Effect of SNP and milrinone in the absence (○) and in the presence (•) of 20 μmol/liter of ODQ on renin secretion from isolated rat kidneys perfused at 100 mmHg. Samples were taken in 5-min intervals during the different experimental periods, the duration of which is indicated in the upper part of the figure. For determination of significant differences renin secretion rates obtained within a certain experimental period of each kidney were taken together and averaged. The experimental protocols were run with five different kidneys. Data are means +/− SEM.

Figure 6

Effect of l-Name and SNP at low perfusion pressure (Upper) and in the presence of 100 μmol/liter of bumetanide (Lower) on renin secretion from isolated perfused rat kidneys. Samples were taken in 5-min intervals during the different experimental periods, the duration of which is indicated in the upper panel of the figure. For determination of significant differences renin secretion rates obtained within a certain experimental period of each kidney were taken together and averaged. The experimental protocols were run with five different kidneys. Data are means +/− SEM.