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.
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The data supporting the results in this study are available within the paper and its Supplementary Information. The raw datasets generated during the study are available from the corresponding author on reasonable request.
The CellProfiler algorithms used for image analysis and for non-parametric drug synergy algorithms are included in the Supplementary Information.
Ye, Z. et al. Efficacy and safety of tamsulosin in medical expulsive therapy for distal ureteral stones with renal colic: a multicenter, randomized, double-blind, placebo-controlled trial. Eur. Urol. 73, 385–391 (2018).
Tharwat, M., Elsaadany, M. M., Lashin, A. M. & EL-Nahas, A. R. A randomized controlled trial evaluating sildenafil citrate in relieving ureteral stent-related symptoms. World J. Urol. 36, 1877–1881 (2018).
Koo, K. C. et al. The impact of preoperative α-adrenergic antagonists on ureteral access sheath insertion force and the upper limit of force required to avoid ureteral mucosal injury: a randomized controlled study. J. Urol. 199, 1622–1630 (2018).
Jung, H. U., Jakobsen, J. S., Mortensen, J., Osther, P. J. & Djurhuus, J. C. Irrigation with isoproterenol diminishes increases in pelvic pressure without side-effects during ureterorenoscopy: a randomized controlled study in a porcine model. Scand. J. Urol. Nephrol. 42, 7–11 (2008).
Scales, C. D., Smith, A. C., Hanley, J. M. & Saigal, C. S. Prevalence of kidney stones in the United States. Eur. Urol. 62, 160–165 (2012).
Trinchieri, A. et al. Increase in the prevalence of symptomatic upper urinary tract stones during the last ten years. Eur. Urol. 37, 23–25 (2000).
Chen, Z., Bird, V. & Prosperi, M. The latest prevalence of kidney stones in the US and its trends in different genders. Ann. Epidemiol. 27, 512 (2017).
Hollingsworth, J. M. et al. Alpha blockers for treatment of ureteric stones: systematic review and meta-analysis. BMJ 355, i6112 (2016).
Sridharan, K. & Sivaramakrishnan, G. Medical expulsive therapy in urolithiasis: a mixed treatment comparison network meta-analysis of randomized controlled clinical trials. Expert Opin. Pharmacother. 18, 1421–1431 (2017).
Dellis, A. E. et al. Tamsulosin, solifenacin, and their combination for the treatment of stent-related symptoms: a randomized controlled study. J. Endourol. 31, 100–109 (2017).
Hollingsworth, J. M. et al. Medical therapy to facilitate urinary stone passage: a meta-analysis. Lancet 368, 1171–1179 (2006).
Dauw, C. A. et al. Expulsive therapy versus early endoscopic stone removal in patients with acute renal colic: a comparison of indirect costs. J. Urol. 191, 673–677 (2014).
Rose, J. G. & Gillenwater, J. Y. Pathophysiology of ureteral obstruction. Am. J. Physiol. 225, 830–837 (1973).
Pickard, R. et al. Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. Lancet 386, 341–349 (2015).
Furyk, J. S. et al. Distal ureteric stones and tamsulosin: a double-blind, placebo-controlled, randomized, multicenter trial. Ann. Emerg. Med. 67, 86–95 (2016).
Press, Y., Punchik, B. & Freud, T. Orthostatic hypotension and drug therapy in patients at an outpatient comprehensive geriatric assessment unit. J. Hypertens. 34, 351–358 (2016).
Canda, A. E., Turna, B., Cinar, G. M. & Nazli, O. Physiology and pharmacology of the human ureter: basis for current and future treatments. Urol. Int. 78, 289–298 (2007).
Blackwell, R. H. et al. Incidence of adverse contrast reaction following nonintravenous urinary tract imaging. Eur. Urol. Focus 3, 89–93 (2017).
Cochran, S. T., Bomyea, K. & Sayre, J. W. Trends in adverse events after IV administration of contrast media. AJR Am. J. Roentgenol. 176, 1385–1388 (2001).
Horsley, H., Dharmasena, D., Malone-Lee, J. & Rohn, J. L. A urine-dependent human urothelial organoid offers a potential alternative to rodent models of infection. Sci. Rep. 8, 1238–1251 (2018).
Chen, C.-P. et al. In vivo roles for myosin phosphatase targeting subunit-1 phosphorylation sites T694 and T852 in bladder smooth muscle contraction. J. Physiol. 593, 681–700 (2015).
Komatsu, S., Kitazawa, T. & Ikebe, M. Visualization of stimulus-specific heterogeneous activation of individual vascular smooth muscle cells in aortic tissues. J. Cell. Physiol. 233, 434–446 (2018).
Monical, P. L., Owens, G. K. & Murphy, R. A. Expression of myosin regulatory light-chain isoforms and regulation of phosphorylation in smooth muscle. Am. J. Physiol. 264, C1466–C1472 (1993).
Bhadriraju, K., Elliott, J. T., Nguyen, M. & Plant, A. L. Quantifying myosin light chain phosphorylation in single adherent cells with automated fluorescence microscopy. BMC Cell Biol. 8, 43–55 (2007).
Baumann, F. et al. Increasing evidence of mechanical force as a functional regulator in smooth muscle myosin light chain kinase. eLife 6, e26473 (2017).
Kamentsky, L. et al. Improved structure, function and compatibility for CellProfiler: modular high-throughput image analysis software. Bioinformatics 27, 1179–1180 (2011).
Pan, W., Lin, J. & Le, C. T. A mixture model approach to detecting differentially expressed genes with microarray data. Funct. Integr. Genomics 3, 117–124 (2003).
Pick, D. L. et al. First prize: chitosan and the urothelial barrier: effects on ureteral intraluminal drug penetration and peristalsis. J. Endourol. 25, 385–390 (2011).
Özel, B. Z., Sun, V., Pahwa, A., Nelken, R. & Dancz, C. E. Randomized controlled trial of 2% lidocaine gel versus water-based lubricant for multi-channel urodynamics. Int. Urogynecol. J. 9, 1297–1302 (2018).
Rowe, R.C., Sheskey, P. J., et al. Handbook of Pharmaceutical Excipients 4th edn (Pharmaceutical Press, 2004).
Raemsch, K. D. & Sommer, J. Pharmacokinetics and metabolism of nifedipine. Hypertension 5, II18–II24 (1983).
Shimokawa, H., Sunamura, S. & Satoh, K. RhoA/Rho-Kinase in the cardiovascular system. Circ. Res. 118, 352–366 (2016).
Dellabella, M., Milanese, G. & Muzzonigro, G. Efficacy of tamsulosin in the medical management of juxtavesical ureteral stones. J. Urol. 170, 2202–2205 (2003).
Pickard, R. et al. Use of drug therapy in the management of symptomatic ureteric stones in hospitalised adults: a multicentre, placebo-controlled, randomised controlled trial and cost-effectiveness analysis of a calcium channel blocker (nifedipine) and an alpha-blocker (tamsulosin) (the SUSPEND trial). Health Technol. Assess. 19, 1–171 (2015).
Renwick, A. G. et al. The pharmacokinetics of oral nifedipine‐a population study. Br. J. Clin. Pharmacol. 25, 701–708 (1988).
Saigal, C. S., Joyce, G. & Timilsina, A. R. Direct and indirect costs of nephrolithiasis in an employed population: opportunity for disease management? Kidney Int. 68, 1808–1814 (2005).
Gershman, B., Eisner, B. H., Sheth, S. & Sacco, D. E. Ureteral stenting and retrograde pyelography in the office: clinical outcomes, cost effectiveness, and time savings. J. Endourol. 27, 662–666 (2013).
Wang, J. et al. The role of solifenacin, as monotherapy or combination with tamsulosin in ureteral stent-related symptoms: a systematic review and meta-analysis. World J. Urol. 35, 1669–1680 (2017).
Franco-Salinas, G., de la Rosette, J. J. M. C. H. & Michel, M. C. Pharmacokinetics and pharmacodynamics of tamsulosin in its modified-release and oral controlled absorption system formulations. Clin. Pharmacokinet. 49, 177–188 (2010).
Wang, X.-D. et al. Rapid and simultaneous determination of nifedipine and dehydronifedipine in human plasma by liquid chromatography-tandem mass spectrometry: Application to a clinical herb-drug interaction study. J. Chromatogr. B 852, 534–544 (2007).
Vignoli, G. Urodynamics: A Quick Pocket Guide 175–184 (Springer, 2017).
We thank A. LaRochelle and K. Wood of CBSET, Inc. for providing discarded porcine ureters used for experimentation; F. McGovern, A. Feldman and D. Dahl of Massachusetts General Hospital Department of Urology for providing human ureteral tissue samples intraoperatively; C. Beale, L. Reyelt, C. Bogins and M. Hull of Tufts Surgical Research for providing discarded porcine ureters and assisting with in vivo surgical validation and protocol design; N. Enzer, K. Cormier and G. Ekchian of the Koch Institute for primary cell line, histopathological consultations and lubricant mixing equipment, respectively; C. Lewis of the Whitehead Institute Metabolomics Core for LCMS validation; L. Richey of Tufts Comparative Pathology Services for histopathological verification and consultation related to in vivo studies; D. Logan and M. Bray of the Broad Institute for CellProfiler assistance; N. Hawes (Nicola Hawes Design) for all figure schematics. We acknowledge funding support from M. Cima, the MIT Institute of Medical Engineering and Science Broshy Fellowship (C.X.L.) and the MIT Deshpande Center for Technological Innovation (C.X.L., M.J.C. and B.H.E.). This work was also supported in part by the Koch Institute Support (core) Grant P30-CA14051 from the National Cancer Institute and the National Institutes of Health (R35 GM122547 to A.E.C.).
The authors declare no competing interests.
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Lee, C.X., Cheah, J.H., Soule, C.K. et al. Identification and local delivery of vasodilators for the reduction of ureteral contractions. Nat Biomed Eng 4, 28–39 (2020). https://doi.org/10.1038/s41551-019-0482-4
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