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Identification and local delivery of vasodilators for the reduction of ureteral contractions.
Nature Biomedical Engineering ( IF 26.8 ) Pub Date : 2019-12-02 , DOI: 10.1038/s41551-019-0482-4 Christopher X Lee 1, 2 , Jaime H Cheah 2 , Christian K Soule 2 , Huiming Ding 3 , Charles A Whittaker 3 , Kyle Karhohs 4 , Aurora A Burds 2 , Kriti S Subramanyam 1, 2 , Anne E Carpenter 4 , Brian H Eisner 5 , Michael J Cima 1, 2, 6
Nature Biomedical Engineering ( IF 26.8 ) Pub Date : 2019-12-02 , DOI: 10.1038/s41551-019-0482-4 Christopher X Lee 1, 2 , Jaime H Cheah 2 , Christian K Soule 2 , Huiming Ding 3 , Charles A Whittaker 3 , Kyle Karhohs 4 , Aurora A Burds 2 , Kriti S Subramanyam 1, 2 , Anne E Carpenter 4 , Brian H Eisner 5 , Michael J Cima 1, 2, 6
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Kidney stones and ureteral stents can cause ureteral colic and pain. By decreasing contractions in the ureter, clinically prescribed oral vasodilators may improve spontaneous stone passage rates and reduce the pain caused by ureteral stenting. We hypothesized that ureteral relaxation can be improved via the local administration of vasodilators and other smooth muscle relaxants. Here, by examining 18 candidate small molecules in an automated screening assay to determine the extent of ureteral relaxation, we show that the calcium channel blocker nifedipine and the Rho-kinase inhibitor ROCKi significantly relax human ureteral smooth muscle cells. We also show, by using ex vivo porcine ureter segments and sedated pigs that, with respect to the administration of a placebo, the local delivery of a clinically deployable formulation of the two drugs reduced ureteral contraction amplitude and frequency by 90% and 50%, respectively. Finally, we show that standard oral vasodilator therapy reduced contraction amplitude by only 50% and had a minimal effect on contraction frequency. Locally delivered ureteral relaxants therefore may improve ureter-related conditions.
中文翻译：
确定和局部输送血管舒张剂以减少输尿管收缩。
肾结石和输尿管支架可引起输尿管绞痛和疼痛。通过减少输尿管的收缩，临床上规定的口服血管舒张药可以提高自发性结石通过率，并减轻由输尿管支架置入引起的疼痛。我们假设可以通过局部使用血管扩张药和其他平滑肌松弛剂来改善输尿管松弛。在这里，通过在自动筛选测定中检查18个候选小分子以确定输尿管松弛的程度，我们表明钙通道阻滞剂硝苯地平和Rho激酶抑制剂ROCKi可以显着松弛人输尿管平滑肌细胞。我们还显示，通过使用离体猪输尿管段和镇静猪，就安慰剂的使用而言，两种药物的临床可部署制剂的局部递送分别使输尿管收缩幅度和频率分别降低了90％和50％。最后，我们证明了标准的口服血管扩张剂治疗仅可将收缩幅度降低50％，并且对收缩频率的影响最小。因此，局部输送输尿管松弛剂可以改善与输尿管有关的状况。
更新日期：2019-12-02
中文翻译：
确定和局部输送血管舒张剂以减少输尿管收缩。
肾结石和输尿管支架可引起输尿管绞痛和疼痛。通过减少输尿管的收缩，临床上规定的口服血管舒张药可以提高自发性结石通过率，并减轻由输尿管支架置入引起的疼痛。我们假设可以通过局部使用血管扩张药和其他平滑肌松弛剂来改善输尿管松弛。在这里，通过在自动筛选测定中检查18个候选小分子以确定输尿管松弛的程度，我们表明钙通道阻滞剂硝苯地平和Rho激酶抑制剂ROCKi可以显着松弛人输尿管平滑肌细胞。我们还显示，通过使用离体猪输尿管段和镇静猪，就安慰剂的使用而言，两种药物的临床可部署制剂的局部递送分别使输尿管收缩幅度和频率分别降低了90％和50％。最后，我们证明了标准的口服血管扩张剂治疗仅可将收缩幅度降低50％，并且对收缩频率的影响最小。因此，局部输送输尿管松弛剂可以改善与输尿管有关的状况。
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