Perivascular sensory nerve Ca2+ receptor and Ca2+-induced relaxation of isolated arteries
Perivascular sensory nerve Ca2+ receptor and Ca2+-induced relaxation of isolated arteries
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DOI：
10.1161/01.hyp.30.6.1431
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发表时间：
1997-12-01
期刊：
影响因子：
8.3
通讯作者：
Mupanomunda, M
中科院分区：
文献类型：
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作者：
Bukoski, RD;Bian, K;Mupanomunda, M
本研究验证了两个假设：(1)细胞外钙离子受体(CaR)位于血管周围感觉神经系统；(2)生理浓度的细胞外钙离子激活该受体导致血管扩张物质的释放，从而介导钙离子诱导的松弛。逆转录聚合酶链式反应显示，编码CAR的基因存在于背根神经节，而不存在于肠系膜阻力动脉。用抗CAR的单抗进行Western印迹分析表明，在背根神经节和完整的肠系膜阻力动脉中都存在一个与甲状旁腺CAR融合的140kD蛋白。肠系膜阻力动脉整装标本的免疫细胞化学分析表明，抗CAR染色的血管周围神经局限于外膜。肠系膜阻力动脉的生物物理分析表明，将Ca~(2+)从1增加到1.25m ol/L及以上可松弛预收缩的动脉，ED50值为2.47+/-0.17 mm o l/L(n=12)。这种松弛是非内皮依赖性的，不受一氧化氮合酶阻断的影响，但可被血管周围神经的急性和亚急性酚性破坏完全拮抗。一项生物测定进一步表明，钙离子在阻力动脉外膜表面的灌流会释放一种可扩散的血管扩张物质。药理分析表明，该松弛物质不是常见的感觉神经肽递质，而是一种磷脂酶A(2)/细胞色素P450衍生的超极化因子，我们将其归类为神经源性超极化因子。这些结果表明CAR在血管周围神经网络中表达，表明Ca~(2+)从1增加到1.25mol/L及以上可引起阻力动脉的神经依赖性松弛，并提示CAR的激活可诱导扩散性超极化血管扩张剂的释放。我们认为，该系统可以作为全动物钙平衡和动脉张力之间的分子联系。
The present study tested two hypotheses: (1) that a receptor for extracellular Ca2+ (Ca2+ receptor [CaR]) is located in the perivascular sensory nerve system and (2) that activation of this receptor by physiological concentrations of extracellular Ca2+ results in the release of vasodilator substance that mediates Ca2+-induced relaxation. Reverse transcription polymerase chain reaction using primers derived from rat kidney CaR cDNA sequence showed that mRNA encoding a CaR is present in dorsal root ganglia but not the mesenteric resistance artery. Western blot analysis using monoclonal anti-CaR showed that a 140-kD protein that comigrates with the parathyroid CaR is present in both the dorsal root ganglia and intact mesenteric resistance artery. Immunocytochemical analysis of whole mount preparations of mesenteric resistance arteries showed that the anti-CaR-stained perivascular nerves restricted to the adventitial layer. Biophysical analysis of mesenteric resistance arteries showed that cumulatively raising Ca2+ from 1 to 1.25 mol/L and above relaxes precontracted arteries with an ED50 value of 2.47+/-0.17 mmol/L (n=12). The relaxation is endothelium independent and is unaffected by blockade of nitric oxide synthase but is completely antagonized by acute and subacute phenolic destruction of perivascular nerves. A bioassay showed further that superfusion of Ca2+ across the adventitial surface of resistance arteries releases a diffusible vasodilator substance. Pharmacological analysis indicates that the relaxing substance is not a common sensory nerve peptide transmitter but is a phospholipase A(2)/cytochrome P450-derived hyperpolarizing factor that we have classified as nerve-derived hyperpolarizing factor. These data demonstrate that a CaR is expressed in the perivascular nerve network, show that raising Ca2+ from 1 to 1.25 mol/L and above causes nerve-dependent relaxation of resistance arteries, and suggest that activation of the CaR induces the release of a diffusible hyperpolarizing vasodilator. We propose that this system could serve as a molecular link between whole-animal Ca2+ balance and arterial tone.