Beierwaltes William H
Hypertension and Vascular Research Division, 7121 E&R Bldg., Henry Ford Hospital, Wayne State University, 2799 West Grand Blvd., Detroit, MI 48202, USA.
Am J Physiol Renal Physiol. 2006 Jun;290(6):F1376-81. doi: 10.1152/ajprenal.00209.2005. Epub 2006 Jan 31.
The interaction between renin, nitric oxide (NO), and its second messenger cGMP is controversial. cAMP is the stimulatory second messenger for renin but is degraded by phosphodiesterases (PDEs). We previously reported that increasing endogenous cGMP in rats by inhibiting its breakdown by PDE-5 stimulated renin secretion rate (RSR). This could be reversed by selective inhibition of neuronal nitric oxide synthase (nNOS). PDE-3 metabolizes cAMP, but this can be inhibited by cGMP, suggesting that renal cGMP could stimulate RSR by diminishing PDE-3 degradation of cAMP. Rats were anesthetized with Inactin before determination of blood pressure (BP), renal blood flow (RBF), and sampling of renal venous and arterial blood to determine RSR. In 13 rats, basal BP was 104 +/- 2 mmHg, RBF was 6.1 ml x min(-1) x g kidney wt(-1) and RSR was 2.9 +/- 1.4 ng ANG I x h(-1) x min(-1). Inhibiting PDE-5 with 20 mg/kg body wt i.p. Zaprinast did not change hemodynamic parameters but increased RSR fivefold to 12.2 +/- 4.9 ng ANG I x h(-1) x min(-1) (P < 0.05). Renal venous cAMP was increased by Zaprinast from 93.8 +/- 27.9 to 149.2 +/- 36.0 pM x min(-1) x g kidney wt(-1) (P < 0.05). When another 10 rats were treated with the PDE-3 inhibitor Milrinone (0.4 microg/min over 30 min, which did not affect hemodynamics), RSR was elevated to 10.4 +/- 4.4 ng ANG I x h(-1) x min(-1). Milrinone also increased renal venous cAMP from 212 +/- 29 to 304 +/- 29 pM x min(-1) x g kidney wt(-1) (P < 0.025). Administration of Zaprinast to rats pretreated with Milrinone (n = 10) did not further increase in RSR (7.5 +/- 3.3 ng ANG I x h(-1) x min(-1)). These results are consistent with endogenous renal cGMP inhibiting PDE-3, which diminishes renal metabolism of cAMP. The resulting increase in cAMP serves as an endogenous stimulus for renin secretion. This suggests a pathway by which NO can indirectly stimulate RSR through its second messenger cGMP.
肾素、一氧化氮（NO）及其第二信使环磷酸鸟苷（cGMP）之间的相互作用存在争议。环磷酸腺苷（cAMP）是肾素的刺激性第二信使，但会被磷酸二酯酶（PDEs）降解。我们之前报道过，通过抑制磷酸二酯酶5（PDE-5）对cGMP的分解来增加大鼠体内的内源性cGMP，会刺激肾素分泌率（RSR）。这可以通过选择性抑制神经元型一氧化氮合酶（nNOS）来逆转。PDE-3可代谢cAMP，但cGMP可抑制PDE-3，这表明肾脏中的cGMP可能通过减少PDE-3对cAMP的降解来刺激RSR。在测定血压（BP）、肾血流量（RBF）以及采集肾静脉和动脉血样以测定RSR之前，用安泰酮麻醉大鼠。在13只大鼠中，基础血压为104±2 mmHg，RBF为6.1 ml·min⁻¹·g肾重⁻¹，RSR为2.9±1.4 ng血管紧张素I·h⁻¹·min⁻¹。腹腔注射20 mg/kg体重的扎普司特抑制PDE-5，并未改变血流动力学参数，但使RSR增加了五倍，达到12.2±4.9 ng血管紧张素I·h⁻¹·min⁻¹（P<0.05）。扎普司特使肾静脉cAMP从93.8±27.9增加到149.2±36.0 pM·min⁻¹·g肾重⁻¹（P<0.05）。当另外10只大鼠用PDE-3抑制剂米力农（30分钟内以0.4微克/分钟给药，这不会影响血流动力学）治疗时，RSR升高到10.4±4.4 ng血管紧张素I·h⁻¹·min⁻¹。米力农还使肾静脉cAMP从212±29增加到304±29 pM·min⁻¹·g肾重⁻¹（P<0.025）。对预先用米力农处理的大鼠（n = 10）给予扎普司特，RSR没有进一步增加（7.5±3.3 ng血管紧张素I·h⁻¹·min⁻¹）。这些结果与内源性肾脏cGMP抑制PDE-3一致，PDE-3的抑制减少了cAMP的肾脏代谢。由此导致的cAMP增加作为肾素分泌的内源性刺激。这提示了一条途径，通过该途径NO可以通过其第二信使cGMP间接刺激RSR。
