Suvorava Tatsiana, Stegbauer Johannes, Thieme Manuel, Pick Stephanie, Friedrich Sebastian, Rump Lars C, Hohlfeld Thomas, Kojda Georg
Institute of Pharmacology and Clinical Pharmacology, Heinrich-Heine-University, Universitätsstr. 1, 40225 Düsseldorf, Germany.
Department of Nephrology, University Hospital, Heinrich-Heine-University, Universitätsstr. 1, 40225 Düsseldorf, Germany.
Biochem Biophys Res Commun. 2015 Mar 13;458(3):576-583. doi: 10.1016/j.bbrc.2015.01.152. Epub 2015 Feb 11.
The aim of the study was to evaluate the possible contribution of non-endothelial eNOS to the regulation of blood pressure (BP). To accomplish this, a double transgenic strain expressing eNOS exclusively in the vascular endothelium (eNOS-Tg/KO) has been generated by endothelial-specific targeting of bovine eNOS in eNOS-deficient mice (eNOS-KO). Expression of eNOS was evaluated in aorta, myocardium, kidney, brain stem and skeletal muscle. Organ bath studies revealed a complete normalization of aortic reactivity to acetylcholine, phenylephrine and the NO-donors in eNOS-Tg/KO. Function of eNOS in resistance arteries was demonstrated by acute i.v. infusion of acetylcholine and the NOS-inhibitor L-NAME. Acetylcholine decreased mean arterial pressure in all strains but eNOS-KO responded significantly less sensitive as compared eNOS-Tg/KO and C57BL/6. Likewise, acute i.v. L-NAME application elevated mean arterial pressure in C57BL/6 and eNOS-Tg/KO, but not in eNOS-KO. In striking contrast to these findings, mean, systolic and diastolic BP in eNOS-Tg/KO remained significantly elevated and was similar to values of eNOS-KO. Chronic oral treatment with L-NAME increased BP to the level of eNOS-KO only in C57BL/6, but had no effect on hypertension in eNOS-KO and eNOS-Tg/KO. Taken together, functional reconstitution of eNOS in the vasculature of eNOS-KO not even partially lowered BP. These data suggest that the activity of eNOS expressed in non-vascular tissue might play a role in physiologic BP regulation.
本研究的目的是评估非内皮型内皮一氧化氮合酶（eNOS）对血压（BP）调节的可能作用。为实现这一目标，通过在eNOS基因缺陷小鼠（eNOS-KO）中对牛eNOS进行内皮特异性靶向，构建了一种仅在血管内皮中表达eNOS的双转基因品系（eNOS-Tg/KO）。在主动脉、心肌、肾脏、脑干和骨骼肌中评估了eNOS的表达。器官浴研究显示，eNOS-Tg/KO中主动脉对乙酰胆碱、去氧肾上腺素和一氧化氮供体的反应性完全恢复正常。通过急性静脉注射乙酰胆碱和一氧化氮合酶抑制剂L-NAME，证实了阻力动脉中eNOS的功能。乙酰胆碱使所有品系的平均动脉压降低，但与eNOS-Tg/KO和C57BL/6相比，eNOS-KO的反应明显不敏感。同样，急性静脉注射L-NAME使C57BL/6和eNOS-Tg/KO的平均动脉压升高，但对eNOS-KO无效。与这些发现形成鲜明对比的是，eNOS-Tg/KO的平均、收缩压和舒张压仍显著升高，与eNOS-KO的值相似。仅在C57BL/6中，用L-NAME进行慢性口服治疗可使血压升高至eNOS-KO的水平，但对eNOS-KO和eNOS-Tg/KO的高血压无影响。综上所述，在eNOS-KO的脉管系统中对eNOS进行功能重建甚至不能部分降低血压。这些数据表明，在非血管组织中表达的eNOS的活性可能在生理性血压调节中起作用。
