Influence of the α α_1а-adrenoreceptor blocker on the mechanisms of limination of small stones from the middle third of the ureter

   BACKGROUND. To date, the mechanisms of small stone elimination by lithokinetic therapy (LCT) have not been elucidated.
   THE AIM of this investigation was to estimate the activity of receptors controlling the contraction and relaxation of smooth muscle cells (SMC) against the background of α_1A-adrenoreceptor blockade during LCT in patients with small stones localization in the middle third of ureter.

   PATIENTS AND METHODS. The study was prospective and included 40 patients in whom standard LCT was done for localization of small concrements (≤6 mm) in the middle third of ureter. The functional activity of receptors modulating ureteric peristalsis was analyzed in vitro using platelet suspension. The agonists used were ATP, ADP, adenosine, epinephrine, angiotensin-2 (Sigma-Aldrich Chemie GmbH, Germany) at EC₅₀ concentrations causing aggregation at 50 % in healthy subjects. Platelet aggregation was assessed by turbidimetric method on ChronoLog analyzer (USA).

   RESULTS. No differences in the rate of small concrements elimination from the middle third of ureter was found in presence and absence of α_1A-adrenoreceptor blocker in LCT. Before LCT, α₂-adrenoreceptor hyperresponsiveness, normoreponsiveness of purine P2X1- and P2Y-receptors, adenosine A2-receptor and angiotensin AT1-receptor were found. After 9 days of LCT with verified elimination of concrements, an increase in P2X1-receptor and AT1-receptor activity (p < 0.001) was found regardless of the administration of α_1A-adrenoceptor blocker. P2Y-receptor hyperresponsiveness was seen in the presence and normoreponsiveness in the absence of α1A-adrenoreceptor blocker in LCT.

   CONCLUSION. At the lithokinetic therapy irrespective of α_1A-adrenoreceptor blocker prescription, compensatory mechanisms, aimed at enhancement of contractile activity and preservation of smooth muscle cell relaxation take part in the traffics of small concrements from the middle third of ureter.

1. Chung B. I., Aron M., Hegarty N. J., Desai M. M. Ureteroscopic versus percutaneous treatment for medium-size (1-2-cm) renal calculi. J Endourol 2008; 22 (2): 43–46. doi: 10.1089/end.2006.9865

2. Guan N. N., Gustafsson L. E., Svennersten K. Inhibitory Effects of Urothelium-related Factors. Basic Clin Pharmacol Toxicol 2017; 121 (4): 220–224. doi: 10.1111/bcpt.12785

3. Bobalova J., Mutafova-Yambolieva V. N. Presynaptic alpha2-adrenoceptor-mediated modulation of adenosine 5' triphosphate and noradrenaline corelease: differences in canine mesenteric artery and vein. J Auton Pharmacol 2001; 21 (1): 47–55. doi: 10.1046/j.1365-2680.2001.00207.x

4. Skolarikos A., Grivas N., Kallidonis P. Members of RISTA Study Group. The Efficacy of Medical Expulsive Therapy (MET) in Improving Stone-free Rate and Stone Expulsion Time, After Extracorporeal Shock Wave Lithotripsy (SWL) for Upper Urinary Stones: A Systematic Review and Meta-analysis. Urology 2015; 86 (6): 1057–1064. doi: 10.1016/j.urology.2015.09.004

5. Harrison P., Mackie I., Mumford A. British. Guidelines for the laboratory investigation of heritable disorders of platelet function. Brit Journal of Haematology 2011; 155 (1): 30–44. doi: 10.1111/j.1365-2141.2011.08793.x

6. Al-Sofiani M. E., Yanek L. R., Faraday N. еt al. Diabetes and Platelet Response to Low-Dose Aspirin. J Clin Endocrinol Metab 2018; 103 (12): 4599–4608. doi: 10.1210/jc.2018-01254

7. Chaignat V., Danuser H., Stoffel M. H. еt al. Effects of a non-selective COX inhibitor and selective COX-2 inhibitors on contractility of human and porcine ureters in vitro and in vivo. Br J Pharmacol 2008; 154 (6): 1297–1307. doi: 10.1038/bjp.2008.193

8. Nørregaard R., Jensen B. L., Topcu S. O. еt al. Cyclooxygenase type 2 is increased in obstructed rat and human ureter and contributes to pelvic pressure increase after obstruction. Kidney Int 2006; 70 (5): 872–881. doi: 10.1038/sj.ki.5001616

9. Lee S. Y., Lee M. Y., Park S. H. et al. NS-398 (a selective cyclooxygenase-2 inhibitor) decreases agonist-induced contraction of the human ureter via calcium channel inhibition. J Endourol 2010; 24 (11): 1863–868. doi: 10.1089/end.2009.0461

10. Campschroer T., Zhu X., Vernooij R. W. M., Lock T. M. T. W. α-blockers as medical expulsive therapy for ureteric stones: a Cochrane systematic review. BJU Int 2018; 122 (6): 932–945. doi: 10.1111/bju.14454

11. Oestreich M. C., Vernooij R. W., Sathianathen N. J. et al. Alphablockers after shock wave lithotripsy for renal or ureteral stones in adults. Cochrane Database Syst Rev 2020; 11 (11): CD013393. doi: 10.1002/14651858.CD013393.pub2

12. Aslam M., Gündüz D., Troidl C. et al. Purinergic Regulation of Endothelial Barrier Function. Int J Mol Sci 2021; 22 (3): 1207. doi: 10.3390/ijms22031207

13. Gonzalez-Montelongo M. D. C., Fountain S. J. Neuropeptide Y facilitates P2X1 receptor-dependent vasoconstriction via Y1 receptor activation in small mesenteric arteries during sympathetic neurogenic responses. Vascul Pharmacol 2021; 136: 106810. doi: 10.1016/j.vph.2020.106810

14. Billaud M., Chiu Y. H., Lohman A. et al. A molecular signature in the pannexin1 intracellular loop confers channel activation by the α1 adrenoreceptor in smooth muscle cells. Sci Signal 2015; 8 (364): ra 17. doi: 10.1126/scisignal.2005824

15. Yu W., Hill W. G., Robson S. C., Zeidel M. L. Role of P2X 4 Receptor in Mouse Voiding Function. Sci Rep 2018; 8 (1): 1838. doi: 10.1038/s41598-018-20216-4

16. Aronsson P., Andersson M., Ericsson T., Giglio D. Assessment and characterization of purinergic contractions and relaxations in the rat urinary bladder. Basic Clin Pharmacol Toxicol 2010; 107 (1): 603–613. doi: 10.1111/j.1742-7843.2010.00554.x

17. Stenqvist J., Carlsson T., Winder M., Aronsson P. Functional atropine sensitive purinergic responses in the healthy rat bladder. Auton Neurosci 2020; 227: 102693. doi: 10.1016/j.autneu.2020.102693

18. Cho S. T., Park E. Y., Kim J. C. Effect of angiotensin II receptor antagonist telmisartan on detrusor overactivity in rats with bladder outlet obstruction. Urology 2012; 80 (5): 1163.e1–7. doi: 10.1016/j.urology.2012.05.002

19. Nguyen M. J., Hashitani H., Lang R. J. Angiotensin receptor-1A knockout leads to hydronephrosis not associated with a loss of pyeloureteric peristalsis in the mouse renal pelvis. Clin Exp Pharmacol Physiol 2016; 43 (5): 535–542. doi: 10.1111/1440-1681.12560

20. Aikawa K., Sakai T., Ishibashi K. et al. Involvement of angiotensin II type 1 receptor on pathological remodeling and dysfunction in obstructed bladder. Int J Urol 2012; 19 (5): 457–464. doi: 10.1111/j.1442-2042.2012.02965.x

21. Kulthinee S., Nernpermpisooth N., Poomvanicha M. et al. Cold Pressor Test Influences the Cardio-Ankle Vascular Index in Healthy Overweight Young Adults. Pulse (Basel) 2021; 9 (1–2): 30–37. doi: 10.1159/000517617

22. Yu W., Sun X., Robson S. C., Hill W. G. Extracellular UDP enhances P2X-mediated bladder smooth muscle contractility via P2Y(6) activation of the phospholipase C/inositol trisphosphate pathway. FASEB J 2013; 27 (5): 1895–1903. doi: 10.1096/fj.12-219006

23. Hao Y., Wang L., Chen H. et al. Targetable purinergic receptors P2Y12 and A2b antagonistically regulate bladder function. JCI Insight 2019; 4 (16): e122112. doi: 10.1172/jci.insight.122112