一氧化氮 - 环磷酸鸟苷途径在大鼠肾上腺髓质素诱导的血管舒张中的作用。

Role of nitric oxide-cGMP pathway in adrenomedullin-induced vasodilation in the rat.

作者信息

Hayakawa H, Hirata Y, Kakoki M, Suzuki Y, Nishimatsu H, Nagata D, Suzuki E, Kikuchi K, Nagano T, Kangawa K, Matsuo H, Sugimoto T, Omata M

机构信息

The Third Department of Internal Medicine, Kanto Central Hospital, Tokyo, Japan.

出版信息

Hypertension. 1999 Feb;33(2):689-93. doi: 10.1161/01.hyp.33.2.689.

DOI:10.1161/01.hyp.33.2.689

PMID:10024329

Abstract

We previously reported that adrenomedullin (AM), a potent vasodilator peptide discovered in pheochromocytoma cells, stimulates nitric oxide (NO) release in the rat kidney. To further investigate whether the NO-cGMP pathway is involved in the mechanisms of AM-induced vasodilation, we examined the effects of E-4021, a cGMP-specific phosphodiesterase inhibitor, on AM-induced vasorelaxation in aortic rings and perfused kidneys isolated from Wistar rats. We also measured NO release from the kidneys using a chemiluminescence assay. AM (10(-10) to 10(-7) mol/L) relaxed the aorta precontracted with phenylephrine in a dose-dependent manner. Denudation of endothelium (E) attenuated the vasodilatory action of AM (10(-7) mol/L AM: intact (E+) -25.7+/-5.2% versus denuded (E-) -7. 8+/-0.6%, P<0.05). On the other hand, pretreatment with 10(-8) mol/L E-4021 augmented AM-induced vasorelaxation in the intact aorta (-49. 0+/-7.9%, P<0.05) but not in the denuded one. E-4021 also enhanced acetylcholine (ACh)-induced vasorelaxation in the rat intact aorta (10(-7) mol/L ACh -36.6+/-8.4% versus 10(-8) mol/L E-4021+10(-7) mol/L ACh -62.7+/-3.1%, P<0.05). In perfused kidneys, AM-induced vasorelaxation was also augmented by preincubation with E-4021 (10(-9) mol/L AM -15.4+/-0.6% versus 10(-8) mol/L E-4021+10(-9) mol/L AM -23.6+/-1.2%, P<0.01). AM significantly increased NO release from rat kidneys (DeltaNO: +11.3+/-0.8 fmol. min-1. g-1 kidney at 10(-9) mol/L AM), which was not affected by E-4021. E-4021 enhanced ACh-induced vasorelaxation (10(-9) mol/L ACh -9.7+/-1.7% versus 10(-8) mol/L E-4021+10(-9) mol/L ACh -18.8+/-2.9%, P<0.01) but did not affect ACh-induced NO release from the kidneys. In the aorta and the kidney, 10(-4) mol/L of NG-nitro-L-arginine methyl ester, an NO synthase inhibitor, and 10(-5) mol/L of methylene blue, a guanylate cyclase inhibitor, reduced the vasodilatory effect of AM. These results suggest that the NO-cGMP pathway is involved in the mechanism of AM-induced vasorelaxation, at least in the rat aorta and kidney.

摘要

我们之前报道过，肾上腺髓质素（AM）是一种在嗜铬细胞瘤细胞中发现的强效血管舒张肽，可刺激大鼠肾脏释放一氧化氮（NO）。为了进一步研究NO - cGMP途径是否参与AM诱导的血管舒张机制，我们检测了cGMP特异性磷酸二酯酶抑制剂E - 4021对从Wistar大鼠分离的主动脉环和灌注肾脏中AM诱导的血管舒张的影响。我们还使用化学发光分析法测量了肾脏释放的NO。AM（10⁻¹⁰至10⁻⁷mol/L）以剂量依赖性方式使预先用去氧肾上腺素收缩的主动脉舒张。内皮剥脱（E）减弱了AM的血管舒张作用（10⁻⁷mol/L AM：完整（E⁺）-25.7±5.2% 对比剥脱（E⁻）-7.8±0.6%，P<0.05）。另一方面，用10⁻⁸mol/L E - 4021预处理可增强完整主动脉中AM诱导的血管舒张（-49.0±7.9%，P<0.05），但在剥脱的主动脉中则不然。E - 4021还增强了大鼠完整主动脉中乙酰胆碱（ACh）诱导的血管舒张（10⁻⁷mol/L ACh -36.6±8.4% 对比 10⁻⁸mol/L E - 4021 + 10⁻⁷mol/L ACh -62.7±3.1%，P<0.05）。在灌注肾脏中，用E - 4021预孵育也增强了AM诱导的血管舒张（10⁻⁹mol/L AM -15.4±0.6% 对比 10⁻⁸mol/L E - 4021 + 10⁻⁹mol/L AM -23.6±1.2%，P<0.01）。AM显著增加大鼠肾脏释放的NO（在10⁻⁹mol/L AM时，ΔNO：+11.3±0.8 fmol·min⁻¹·g⁻¹肾脏），这不受E - 4021影响。E - 4021增强了ACh诱导的血管舒张（10⁻⁹mol/L ACh -9.7±1.7% 对比 10⁻⁸mol/L E - 4021 + 10⁻⁹mol/L ACh -18.8±2.9%，P<0.01），但不影响ACh诱导的肾脏NO释放。在主动脉和肾脏中，10⁻⁴mol/L的NO合酶抑制剂NG - 硝基 - L - 精氨酸甲酯和10⁻⁵mol/L的鸟苷酸环化酶抑制剂亚甲蓝降低了AM的血管舒张作用。这些结果表明，NO - cGMP途径至少在大鼠主动脉和肾脏中参与了AM诱导的血管舒张机制。