Mishra Ramesh C, Wulff Heike, Hill Michael A, Braun Andrew P
*Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada; †Department of Pharmacology, University of California Davis, Davis, CA; and ‡Department of Medical Pharmacology and Physiology, Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO.
J Cardiovasc Pharmacol. 2015 Jul;66(1):118-27. doi: 10.1097/FJC.0000000000000252.
Endothelial KCa2.3 and KCa3.1 channels contribute to the regulation of myogenic tone in resistance arteries by Ca(2+)-mobilizing vasodilatory hormones. To define further the functional role of these channels in distinct vascular beds, we have examined the vasodilatory actions of the KCa channel activator SKA-31 in myogenically active rat cremaster and middle cerebral arteries. Vessels pressurized to 70 mm Hg constricted by 80-100 μm (ie, 25%-45% of maximal diameter). SKA-31 (10 μM) inhibited myogenic tone by 80% in cremaster and ∼65% in middle cerebral arteries, with IC50 values of ∼2 μM in both vessels. These vasodilatory effects were largely prevented by the KCa2.3 blocker UCL1684 and the KCa3.1 blocker TRAM-34 and abolished by endothelial denudation. Preincubation with N(G) nitro L-arginine methyl ester (L-NAME, 0.1 mM) did not affect the inhibitory response to SKA-31, but attenuated the ACh-evoked dilation by ∼45%. Penitrem-A, a blocker of BK(Ca) channels, did not alter SKA-31 evoked vasodilation but did reduce the inhibition of myogenic tone by ACh, the BKCa channel activator NS1619, and sodium nitroprusside. Collectively, these data demonstrate that SKA-31 produces robust inhibition of myogenic tone in resistance arteries isolated from distinct vascular beds in an endothelium-dependent manner.
内皮KCa2.3和KCa3.1通道通过动员Ca(2+)的血管舒张激素参与对阻力动脉肌源性张力的调节。为了进一步明确这些通道在不同血管床中的功能作用，我们研究了KCa通道激活剂SKA-31对具有肌源性活性的大鼠提睾肌动脉和大脑中动脉的血管舒张作用。将血管压力升至70 mmHg时，血管收缩80 - 100 μm（即最大直径的25% - 45%）。SKA-31（10 μM）在提睾肌动脉中抑制肌源性张力达80%，在大脑中动脉中约为65%，两种血管的IC50值均约为2 μM。KCa2.3阻滞剂UCL1684和KCa3.1阻滞剂TRAM-34在很大程度上可阻止这些血管舒张作用，而内皮剥脱则可消除这些作用。用N(G)硝基-L-精氨酸甲酯（L-NAME，0.1 mM）预孵育不影响对SKA-31的抑制反应，但使乙酰胆碱诱发的舒张减弱约45%。BK(Ca)通道阻滞剂青霉震颤素A不改变SKA-31诱发的血管舒张，但确实降低了乙酰胆碱、BKCa通道激活剂NS1619和硝普钠对肌源性张力的抑制作用。总体而言，这些数据表明，SKA-31以内皮依赖的方式对从不同血管床分离出的阻力动脉的肌源性张力产生强烈抑制作用。
