SKA-31, a novel activator of SKCa and IKCa channels, increases coronary flow in male and female rat hearts
SKA-31, a novel activator of SKCa and IKCa channels, increases coronary flow in male and female rat hearts
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DOI：
10.1093/cvr/cvs326
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发表时间：
2013-02-01
影响因子：
10.8
通讯作者：
Braun, Andrew P.
中科院分区：
文献类型：
--
作者：
Mishra, Ramesh C.;Belke, Darrell;Braun, Andrew P.
内皮SKCa和IKCa通道在血管功能和全身血压的调节中发挥重要作用。基于我们之前的研究结果，即 SKCa 和 IKCa 通道的小分子激活剂（即 NS309 和 SKA-31）可以抑制孤立阻力动脉中的肌原张力，我们假设此类化合物可能在完整的血管床（例如冠状循环）中诱导有效的血管舒张。 SKA-31（0.015 g）的给药剂量依赖性地增加了男性和女性心脏中的总冠状动脉流量（2530）；这些反应与左心室（LV）收缩压和心率的适度、继发性增加有关。 SKA-31 引起的冠状动脉血流、左心室压力和心率反应在质量上与缓激肽 (1 g) 和腺苷 (10 g) 引起的急性反应相当。在 apamin 和 TRAM-34（分别是 SKCa 和 IKCa 通道的选择性阻断剂）存在的情况下，SKA-31 和缓激肽诱导的反应被很大程度上抑制，而腺苷诱导的变化被阻断约 40；单独的 TRAM-34 产生的抑制较小。硝普钠（SNP，0.2 g 推注剂量）引起的冠状动脉血流、左心室压力和心率变化与 SKA-31 引起的变化相似，但不受 apamin TRAM-34 的影响。 NOS 抑制剂 L-NNA 减少了缓激肽和腺苷引起的变化，但不影响对 SKA-31 或 SNP 的反应。我们的研究表明，在基础血流和收缩力条件下，SKA-31 可以快速、可逆地诱导完整功能心脏的冠状循环扩张。
Endothelial SKCa and IKCa channels play an important role in the regulation of vascular function and systemic blood pressure. Based on our previous findings that small molecule activators of SKCa and IKCa channels (i.e. NS309 and SKA-31) can inhibit myogenic tone in isolated resistance arteries, we hypothesized that this class of compounds may induce effective vasodilation in an intact vascular bed, such as the coronary circulation.In a Langendorff-perfused, beating rat heart preparation, acute bolus administrations of SKA-31 (0.015 g) dose-dependently increased total coronary flow (2530) in both male and female hearts; these responses were associated with modest, secondary increases in left ventricular (LV) systolic pressure and heart rate. SKA-31 evoked responses in coronary flow, LV pressure, and heart rate were qualitatively comparable to acute responses evoked by bradykinin (1 g) and adenosine (10 g). In the presence of apamin and TRAM-34, selective blockers of SKCa and IKCa channels, respectively, SKA-31 and bradykinin-induced responses were largely inhibited, whereas the adenosine-induced changes were blocked by approximate to 40; TRAM-34 alone produced less inhibition. Sodium nitroprusside (SNP, 0.2 g bolus dose) evoked changes in coronary flow, LV pressure, and heart rate were similar to those induced by SKA-31, but were unaffected by apamin TRAM-34. The NOS inhibitor L-NNA reduced bradykinin- and adenosine-evoked changes, but did not affect responses to either SKA-31 or SNP.Our study demonstrates that SKA-31 can rapidly and reversibly induce dilation of the coronary circulation in intact functioning hearts under basal flow and contractility conditions.