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首页> 外文期刊>American Journal of Physiology >Nitric oxide synthase inhibition activates L- and T-type Ca2+ channels in afferent and efferent arterioles.
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Nitric oxide synthase inhibition activates L- and T-type Ca2+ channels in afferent and efferent arterioles.

机译：一氧化氮合酶抑制激活传入和传出的小动脉中的L型和T型Ca2 +通道。

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摘要

Previous studies have shown that L-type Ca(2+) channel (LCC) blockers primarily dilate resting and ANG II-constricted afferent arterioles (AA), but do not influence either resting or ANG II-constricted efferent arterioles (EA). In contrast, blockade of T-type Ca(2+) channels (TCC) dilate EA and prevent ANG II-mediated efferent constriction. The present study determined the role of LCC and TCC in mediating the AA and EA constriction following inhibition of nitric oxide synthase (NOS) and tested the hypothesis that inhibition of NOS increases the influence of LCC on EA. With the use of an isolated blood-perfused rat juxtamedullary nephron preparation, single AA or EA were visualized and superfused with a NOS inhibitor, N-nitro-l-arginine (l-NNA), with or without concomitant treatment with an LCC blocker, diltiazem, or a TCC blocker, pimozide. In response to l-NNA (1, 10, and 100 micromol/l), AA and EA diameters decreased significantly by 6.0 +/- 0.3, 13.7 +/- 1.7, and 19.9 +/- 1.4%, and by 6.2 +/- 0.5, 13.3 +/- 1.1, and 19.0 +/- 1.9%, respectively. During TCC blockade with pimozide (10 micromol/l), l-NNA did not significantly constrict afferent (0.9 +/- 0.6, 1.5 +/- 0.5, and 1.7 +/- 0.5%) or efferent (0.4 +/- 0.1, 2.1 +/- 0.7, and 2.5 +/- 1.0%) arterioles. In contrast to the responses with other vasoconstictors, the l-NNA-induced constriction of EA, as well as AA, was reversed by diltiazem (10 micromol/l). The effects were overlapping as pimozide superimposed on diltiazem did not elicit further dilation. When the effects of l-NNA were reversed by superfusion with an NO donor, SNAP (10 micromol/l), diltiazem did not cause significant efferent dilation. As a further test of LCC activity, 55 mmol/l KCl, which depolarizes and constricts AA, caused only a modest constriction in resting EA (8.7 +/- 1.3%), but a stronger EA constriction during concurrent treatment with l-NNA (23.8 +/- 4.8%). In contrast, norepinephrine caused similar constrictions in both l-NNA-treated and nontreated arterioles. These results provide evidence that NO inhibits LCC and TCC activity and that NOS inhibition-mediated arteriolar constriction involves activation of LCC and TCC in both AA and EA. The difference in responses to high KCl between resting and l-NNA-constricted EA and the ability of diltiazem to block EA constriction caused by l-NNA contrasts with the lack of efferent effects in resting and SNAP-treated l-NNA-preconstricted arterioles and during ANG II-mediated vasoconstriction, suggesting a recruitment of LCC in EA when NOS is inhibited. These data help explain how endothelial dysfunction associated with hypertension may lead to enhanced activity of LCC in postglomerular arterioles and increased postglomerular resistance.
机译：先前的研究表明，L型Ca（2+）通道（LCC）阻滞剂主要扩张静息和ANG II收缩的传入小动脉（AA），但不影响静止或ANG II收缩的传入小动脉（EA）。相比之下，T型Ca（2+）通道（TCC）的封锁会扩张EA，并防止ANG II介导的传出收缩。本研究确定了LCC和TCC在抑制一氧化氮合酶（NOS）后介导AA和EA收缩中的作用，并验证了NOS抑制会增加LCC对EA的影响的假设。通过使用分离的血液灌输大鼠近髓肾单位制剂，可以将单个AA或EA可视化，并与NOS抑制剂N-硝基-1-精氨酸（l-NNA）融合，可以同时使用或不使用LCC阻断剂进行治疗，地尔硫卓或TCC阻断剂匹莫齐特。响应l-NNA（1、10和100 micromol / l），AA和EA直径分别显着下降6.0 +/- 0.3、13.7 +/- 1.7和19.9 +/- 1.4％，以及6.2 +/- -分别为0.5、13.3 +/- 1.1和19.0 +/- 1.9％。在用匹莫齐（10 micromol / l）进行TCC阻断期间，l-NNA并未显着收缩传入（0.9 +/- 0.6、1.5 +/- 0.5和1.7 +/- 0.5％）或传出（0.4 +/- 0.1）， 2.1 +/- 0.7和2.5 +/- 1.0％的小动脉。与其他血管收缩药的反应相反，地尔硫卓（10 micromol / l）可逆转l-NNA诱导的EA和AA收缩。由于叠加在地尔硫卓上的匹莫齐没有引起进一步的扩张，因此效果重叠。当通过与NO供体SNAP（10 micromol / l）的注解逆转l-NNA的作用时，地尔硫卓不会引起明显的传出扩张。作为对LCC活性的进一步测试，去极化和收缩AA的55 mmol / l KCl仅对静息EA产生了适度的收缩（8.7 +/- 1.3％），但在同时用l-NNA治疗期间却产生了更强的EA收缩（ 23.8 +/- 4.8％）。相反，去甲肾上腺素在l-NNA治疗和未治疗的小动脉中引起相似的收缩。这些结果提供了证据，即NO抑制LCC和TCC活性，并且NOS抑制介导的小动脉收缩涉及AA和EA中LCC和TCC的激活。静息和l-NNA收缩的小动脉对高KCl反应的差异和地尔硫卓阻止l-NNA引起的EA收缩的能力与静息和SNAP治疗的l-NNA收缩的小动脉和神经节的缺乏传出作用形成对比。在ANG II介导的血管收缩过程中，提示NOS被抑制时，EA中LCC的募集。这些数据有助于解释与高血压相关的内皮功能障碍如何导致肾小球后小动脉中LCC活性增强和肾小球后抵抗力增加。

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