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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Smooth muscle-selective deletion of guanylyl cyclase-A prevents the acute but not chronic effects of ANP on blood pressure
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Smooth muscle-selective deletion of guanylyl cyclase-A prevents the acute but not chronic effects of ANP on blood pressure

机译：鸟苷酰环化酶A的平滑肌选择性缺失可预防ANP对血压的急性而非慢性影响

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摘要

Atrial natriuretic peptide (ANP) is an important regulator of arterial blood pressure. The mechanisms mediating its hypotensive effects are complex and involve the inhibition of the sympathetic and renin-angiotensin-aldosterone (RAA) systems, increased diuresisa-triuresis, vasodilation, and enhanced vascular permeability. In particular, the contribution of the direct vasodilating effect of ANP to the hypotensive actions remains controversial, because variable levels of the ANP receptor, guanylyl cyclase A (GC-A), are expressed in different vascular beds. The objective of our study was to determine whether a selective deletion of GC-A in vascular smooth muscle would affect the hypotensive actions of ANP. We first created a mutant allele of mouse GC-A by flanking a required exon with IoxP sequences. Crossing floxed GC-A with SM22-Cre transgene mice expressing Cre recombinase in smooth muscle cells (SMC) resulted in mice in which vascular GC-A mRNA expression was reduced by ≈80%. Accordingly, the relaxing effects of ANP on isolated vessels from these mice were abolished; despite this fact, chronic arterial blood pressure of awake SMC GC-A KO mice was normal. Infusion of ANP caused immediate decreases in blood pressure in floxed GC-A but not in SMC GC-A knockout mice. Furthermore, acute vascular volume expansion, which causes release of cardiac ANP, did not affect resting blood pressure of floxed GC-A mice, but rapidly and significantly increased blood pressure of SMC GC-A knockout mice. We conclude that vascular GC-A is dispensable in the chronic and critical in the acute moderation of arterial blood pressure by ANP.
机译：心钠素（ANP）是动脉血压的重要调节剂。介导其降压作用的机制很复杂，涉及抑制交感和肾素-血管紧张素-醛固酮（RAA）系统，利尿/利尿钠增多，血管舒张和血管通透性增强。尤其是，ANP的直接血管舒张作用对降压作用的作用仍然存在争议，因为在不同的血管床中表达了不同水平的ANP受体鸟苷酰环化酶A（GC-A）。我们研究的目的是确定血管平滑肌中GC-A的选择性缺失是否会影响ANP的降压作用。我们首先通过将所需的外显子与IoxP序列连接在一起，创建了小鼠GC-A的突变等位基因。用平滑肌细胞（SMC）中表达Cre重组酶的SM22-Cre转基因小鼠与浮选的GC-A杂交，导致小鼠的血管GC-A mRNA表达降低约80％。因此，消除了ANP对这些小鼠分离的血管的松弛作用；尽管有这个事实，但清醒的SMC GC-A KO小鼠的慢性动脉血压是正常的。注入ANP会导致浮游的GC-A的血压立即下降，但不会导致SMC GC-A敲除小鼠的血压下降。此外，引起心脏ANP释放的急性血管体积扩张并不影响浮游GC-A小鼠的静息血压，而是迅速且显着增加SMC GC-A敲除小鼠的血压。我们得出的结论是，血管AGC在慢性中是必不可少的，而在ANP引起的动脉血压的急性减轻中则至关重要。

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