Effects of connexin-mimetic peptides on nitric oxide synthase- and cyclooxygenase-independent renal vasodilation
Effects of connexin-mimetic peptides on nitric oxide synthase- and cyclooxygenase-independent renal vasodilation
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DOI：
10.1046/j.1523-1755.2002.00122.x
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发表时间：
2002-01-01
影响因子：
19.6
通讯作者：
Lameire, NH
中科院分区：
文献类型：
--
作者：
De Vriese, AS;Van de Voorde, J;Lameire, NH
背景内皮源性超极化因子（EDHF）的生理作用的研究受到阻碍，其性质和作用机制的持续争议，以及缺乏适用于体内使用的特异性抑制剂。最近的体外研究支持间隙连接在EDHF介导的信号传递中的作用。本研究探讨了缝隙连接通讯的贡献，EDHF介导的反应，在大鼠肾微循环在体内，并解决了EDHF的生理作用。研究肾内注射连接蛋白模拟肽对乙酰胆碱引起的L-NAME和吲哚美辛抵抗性肾血流（RBF）反应、基础RBF和全身血压的影响。（43）间隙27，一种与连接蛋白43的第二个细胞外环同源的肽，部分抑制了L-NAME和吲哚美辛抗性RBF对乙酰胆碱的反应，而（40）间隙27，与连接蛋白40的第二个细胞外环同源，消除了反应。在连接蛋白40和43的第二胞外环中存在的基序SRPTEK中替换两个氨基酸的对照肽没有效果。这些肽均不影响对β-NONOate、吡那地尔或罂粟碱的反应。肾内输注（43）Gap 27或（40）Gap 27可降低基础RBF并增加平均动脉血压，无论是否全身输注L-NAME和吲哚美辛。抑制缝隙连接通讯与连接蛋白模拟肽块EDHF介导的信号传递在体内，如废除的L-NAME和吲哚美辛耐药肾血管舒张。这些肽还降低基础RBF并增加血压，支持紧张性EDHF释放在控制组织灌注和血管阻力中的作用。
Background. Research on the physiological role of endothelium-derived hyperpolarizing factor (EDHF) is hampered by the persistent controversy on its nature and mechanisms of action, as well as by the lack of specific inhibitors that are suitable for in vivo use. Recent in vitro studies support a role for gap junctions in EDHF-mediated signal transmission. The present study examines the contribution of gap junctional communication to the EDHF-mediated responses in the rat renal microcirculation in vivo and addresses the physiological role of EDHF.Methods. The effects of intrarenal administration of connexin-mimetic peptides on the L-NAME- and indomethacin-resistant renal blood flow (RBF) response to acetylcholine, on basal RBF and on systemic blood pressure were examined.Results. (43)Gap 27, a peptide homologous to the second extracellular loop of connexin 43, partially inhibited the L-NAME- and indomethacin-resistant RBF response to acetylcholine, whereas (40)Gap 27, homologous to the second extracellular loop of connexin 40, abolished the response. A control peptide, with a replacement of two amino acids in the motif SRPTEK present in the second extracellular loop of connexins 40 and 43, was without effect. None of the peptides affected the response to DETA-NONOate, pinacidil or papaverine. Intrarenal infusion of (43)Gap 27 or (40)Gap 27 decreased basal RBF and increased mean arterial blood pressure, both in the presence and absence of systemic infusion of L-NAME and indomethacin.Conclusions. Inhibition of gap junctional communication with connexin-mimetic peptides blocks EDHF-mediated signal transmission in vivo, as suggested by the abolishment of L-NAME- and indomethacin-resistant renal vasodilation. The peptides also decrease basal RBF and increase blood pressure, supporting a role for tonic EDHF release in the control of tissue perfusion and vascular resistance.