Angiotensin II-Induced Hypertension Is Attenuated by Reduction of Sympathetic Output in NO-Sensitive Guanylyl Cyclase 1 Knockout Mice
Angiotensin II-Induced Hypertension Is Attenuated by Reduction of Sympathetic Output in NO-Sensitive Guanylyl Cyclase 1 Knockout Mice
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DOI：
10.1124/jpet.115.227728
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发表时间：
2016-01-01
影响因子：
3.5
通讯作者：
Mergia, Evanthia
中科院分区：
文献类型：
--
作者：
Broekmans, Kathrin;Stegbauer, Johannes;Mergia, Evanthia
在血管张力的调节中，扩张性一氧化氮(NO)/cGMP通路平衡肾素血管紧张素和交感神经系统诱导的血管收缩。一氧化氮诱导的cGMP形成由两种官能基环化酶（GC）催化，即一氧化氮敏感的官能基环化酶1 （NO-GC1）和NO-GC2。在血管平滑肌细胞中，NO-GC1是主要的异构体，负责90%以上的cGMP形成。尽管血管松弛减少，no - gc1缺陷小鼠没有高血压。本研究在NO-GC1缺陷小鼠中评估了NO-GC1在血管紧张素II （Ang II）和去甲肾上腺素（NE）引起的高血压中的作用。在野生型（WT）和NO-GC1基因敲除小鼠（KO）之间，慢性angii治疗诱导的高血压没有差异。此外，在两种基因型中，Ang II治疗诱导的no依赖性主动脉舒张的衰减是相似的，很可能是由于磷酸二酯酶1表达的增加。血浆NE含量（已知受Ang ii影响）分析显示，在Ang ii治疗和未治疗的情况下，NO-GC1 KO中NE含量较低。这一发现表明交感神经输出减少，并强调了NO-GC1 KO的低心率。为了找出NO-GC1 KO中缺乏较高血压是否是交感神经活动减少抵消血管松弛减少的结果，小鼠被慢性NE应用挑战。由于NO-GC1 KO的血压高于WT，我们得出结论，NO-GC1 KO中交感神经活动的减少可以预防高血压，并假设NO-GC1可能具有交感神经兴奋作用，抵消NO-GC1在血管中的扩张作用。
In the regulation of vascular tone, the dilatory nitric oxide (NO)/cGMP pathway balances vasoconstriction induced by the reninangiotensin and sympathetic nervous systems. NO-induced cGMP formation is catalyzed by two guanylyl cyclases (GC), NO-sensitive guanylyl cyclase 1 (NO-GC1) and NO-GC2, with indistinguishable enzymatic properties. In vascular smooth muscle cells, NO-GC1 is the major isoform and is responsible for more than 90% of cGMP formation. Despite reduced vaso-relaxation, NO-GC1-deficient mice are not hypertensive. Here, the role of NO-GC1 in hypertension provoked by contractile agonists angiotensin II (Ang II) and norepinephrine (NE) was evaluated in NO-GC1-deficient mice. Hypertension induced by chronic Ang II treatment did not differ between wild-type (WT) and NO-GC1 knockout mice (KO). Also, attenuation of NO-dependent aortic relaxation induced by the Ang II treatment was similar in both genotypes and was most probably attributable to an increase of phosphodiesterase 1 expression. Analysis of plasma NE content-known to be influenced by Ang II-revealed lower NE in the NO-GC1 KO under Ang II-treated- and non-treated conditions. The finding indicates reduced sympathetic output and is underlined by the lower heart rate in the NO-GC1 KO. To find out whether the lack of higher blood pressure in the NO-GC1 KO is a result of reduced sympathetic activity counterbalancing the reduced vascular relaxation, mice were challenged with chronic NE application. As the resulting blood pressure was higher in the NO-GC1 KO than in WT, we conclude that the reduced sympathetic activity in the NO-GC1 KO prevents hypertension and postulate a possible sympatho-excitatory action of NO-GC1 counteracting NO-GC1's dilatory effect in the vasculature.