Kurtz A, Götz K H, Hamann M, Wagner C
Institut für Physiologie der Universität Regensburg, D-93040 Regensburg, Germany.
Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4743-7. doi: 10.1073/pnas.95.8.4743.
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.
本研究旨在阐明一氧化氮（NO）刺激肾脏分泌肾素的细胞途径。使用离体灌注大鼠肾脏模型，我们发现，低灌注压力（40 mmHg）、致密斑抑制（100 μmol/L布美他尼）和腺苷酸环化酶激活（3 nmol/L异丙肾上腺素）刺激的肾素分泌增加4至8倍，被一氧化氮合酶抑制剂硝基-L-精氨酸甲酯（L-精氨酸甲酯）（1 mM）显著减弱，且L-精氨酸甲酯的抑制作用被NO供体硝普钠（SNP）（10 μmol/L）代偿。同样，通过阻断磷酸二酯酶1（PDE-1）（20 μmol/L 8-甲氧基甲基-1-甲基-3-（2-甲基丙基）黄嘌呤）或PDE-4（20 μmol/L咯利普兰）抑制cAMP降解，可使肾素分泌增加3至4倍，该作用被L-精氨酸甲酯减弱，且被硝普钠过度代偿。20 μmol/L米力农或200 nmol/L曲喹辛抑制PDE-3，可使肾素分泌增加5至6倍，一氧化氮合酶抑制对此有轻微增强作用，NO供体则有中度减弱作用。由于PDE-3是一种受cGMP抑制的cAMP磷酸二酯酶，因此使用特异性鸟苷酸环化酶抑制剂1-H-（1,2,4）恶二唑并（4,3a）喹喔啉-1-酮（20 μmol）研究了内源性cGMP对NO作用的影响。在1H-[1,2,4]恶二唑并[4,3-a]喹喔啉-1-酮存在的情况下，NO对肾素分泌的作用消失，而PDE-3抑制剂发挥其正常作用。这些发现表明，PDE-3在cAMP对肾素分泌的调控中起主要作用。我们的发现与内源性和外源性NO对肾素分泌的刺激作用由cGMP诱导的cAMP降解抑制介导这一观点相符。
