KCa3.1 通道在慢性抑制 NOS 后维持自发性高血压大鼠离体灌注肾脏的内皮依赖性血管舒张。
KCa 3.1 channels maintain endothelium-dependent vasodilatation in isolated perfused kidneys of spontaneously hypertensive rats after chronic inhibition of NOS.
机构信息
Institut de Recherches Servier, Suresnes, France.
出版信息
Br J Pharmacol. 2012 Oct;167(4):854-67. doi: 10.1111/j.1476-5381.2012.02062.x.
BACKGROUND AND PURPOSE
The purpose of the study was to investigate renal endothelium-dependent vasodilatation in a model of severe hypertension associated with kidney injury.
EXPERIMENTAL APPROACH
Changes in perfusion pressure were measured in isolated, perfused kidneys taken from 18-week-old Wistar-Kyoto rat (WKY), spontaneously hypertensive rats (SHR) and SHR treated for 2 weeks with N(ω) -nitro-L-arginine methyl ester in the drinking water (L-NAME-treated SHR, 6 mg·kg(-1) ·day(-1) ).
KEY RESULTS
Acetylcholine caused similar dose-dependent renal dilatation in the three groups. In vitro administration of indomethacin did not alter the vasodilatation, while the addition of N(w) -nitro-L-arginine (L-NA) produced a differential inhibition of the vasodilatation, (inhibition in WKY > SHR > L-NAME-treated SHR). Further addition of ODQ, an inhibitor of soluble guanylyl cyclase, abolished the responses to sodium nitroprusside but did not affect the vasodilatation to acetylcholine. However, the addition of TRAM-34 (or charybdotoxin) inhibitors of Ca(2+) -activated K(+) channels of intermediate conductance (K(Ca) 3.1), blocked the vasodilatation to acetylcholine, while apamin, an inhibitor of Ca(2+) -activated K(+) channels of small conductance (K(Ca) 2.3), was ineffective. Dilatation induced by an opener of K(Ca) 3.1/K(Ca) 2.3 channels, NS-309, was also blocked by TRAM-34, but not by apamin. The magnitude and duration of NS-309-induced vasodilatation and the renal expression of mRNA for K(Ca) 3.1, but not K(Ca) 2.3, channels followed the same ranking order (WKY < SHR < L-NAME-treated SHR).
CONCLUSIONS AND IMPLICATIONS
In SHR kidneys, an EDHF-mediated response, involving activation of K(Ca) 3.1 channels, contributed to the mechanism of endothelium-dependent vasodilatation. In kidneys from L-NAME-treated SHR, up-regulation of this pathway fully compensated for the decrease in NO availability.
背景与目的
本研究旨在探讨与肾损伤相关的严重高血压模型中肾脏内皮依赖性血管舒张功能。
实验方法
从 18 周龄 Wistar-Kyoto 大鼠（WKY）、自发性高血压大鼠（SHR）和 SHR 用 N（ω）-硝基-L-精氨酸甲酯处理 2 周的灌流肾中测量灌注压的变化（用 L-NAME 处理的 SHR，6mg·kg（-1）·天（-1））。
主要结果
乙酰胆碱在三组中引起类似的剂量依赖性肾舒张。体外给予吲哚美辛不会改变血管舒张作用，而加入 N（ω）-硝基-L-精氨酸（L-NA）则会产生不同程度的血管舒张抑制作用（在 WKY 中抑制作用大于 SHR 大于 L-NAME 处理的 SHR）。进一步加入可溶性鸟苷酸环化酶抑制剂 ODQ 消除了对硝普钠的反应，但不影响对乙酰胆碱的血管舒张作用。然而，加入 TRAM-34（或糜蛋白酶）中间电导钙激活钾（K(Ca)3.1）通道抑制剂阻断了对乙酰胆碱的血管舒张作用，而小电导钙激活钾（K(Ca)2.3）通道抑制剂 apamin 则无效。K(Ca)3.1/K(Ca)2.3 通道开放剂 NS-309 诱导的舒张也被 TRAM-34 阻断，但不受 apamin 影响。NS-309 诱导的舒张幅度和持续时间以及肾脏 K(Ca)3.1mRNA 的表达，与 K(Ca)3.1 而不是 K(Ca)2.3 通道的相同排序（WKY < SHR < L-NAME 处理的 SHR）。
结论和意义
在 SHR 肾脏中，涉及 K(Ca)3.1 通道激活的 EDHF 介导的反应有助于内皮依赖性血管舒张的机制。在 L-NAME 处理的 SHR 的肾脏中，该途径的上调完全补偿了 NO 可用性的降低。
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