EFFICIENCY OF LITHOKINETIC THERAPY IN NEPHROLITHIASIS: THE ROLE OF COMPENSATORY MECHANISMS PROVIDING TRAFFIC OF MEDIUM-SIZED STONES IN THE URETER

DOI: https://doi.org/10.29296/25877305-2022-12-12
Issue: 
12
Year: 
2022

Professor E. Barinov, MD; Yu. Malinin, Candidate of Medical Sciences;
Kh. Grigoryan, Candidate of Medical Sciences
M. Gorky Donetsk National Medical University, Donetsk, Donetsk People's Republic

Аim of the study was to analyze the activity of receptors that control contraction (α2-adrenergic receptor, purine P2X1- and P2Y receptors, angiotensin AT1 receptor, TxA2 receptor) and relaxation of smooth muscle cells (adenosine A2 receptor) while maintaining and blocking α1A-adrenoreceptor during lithokinetic therapy (LCT) in patients with medium-sized calculi in the ureter. Material and methods. The study was prospective and included 30 patients with effective (Group 1) and ineffective (Group 2) elimination of stones 11–13 mm in size. Differences in LCT related to the appointment of an α1A-adrenergic receptor antagonist. Analysis of the functional activity of receptors involved in the regulation of ureteral motility was performed in vitro on platelet suspensions. The following agonists were used: ATP, ADP, adenosine, epinephrine, angiotensin-2 (Sigma-Aldrich Chemie GmbH, Germany). Platelet aggregation was assessed by the turbidimetric method on a ChronoLog analyzer (USA). Results. Before LCT, the reactivity of receptors was revealed, signaling pathways of which can modulate the violation of the traffic medium-sized calculi in the ureter. Effective elimination of calculi after 7–9 days of LCT with the functioning of the α1A-adrenergic receptor was reproduced in a cohort of patients with the presence of: hyperreactivity of the A2A receptor, P2X1 receptor and hyporeactivity of the α2-adrenoreceptor, TxA2 receptor. Ineffective elimination of calculi in LCT with an α1A-adrenoreceptor antagonist is associated with impaired intracellular signaling due to excessive activation of the α2-adrenoreceptor, P2X1 receptor, P2Y receptors, AT1 receptor, TxA2 receptor and desensitization of the adenosine A2A receptor. The hyperreactivity of the Gq-protein-coupled receptor system (GPCR system) can neutralize the effect of the administration α1A-adrenergic receptor antagonist, since the «crosstalk» of intracellular signaling is reproduced, resulting in the preservation of an excess level of intracellular Ca2+ in smooth muscle cells. Conclusion. In vitro analysis of intracellular signaling, which regulates the entry of Ca2+ into the cell upon activation of the GPCR system and the removal of excess Ca2+ through the adenosinergic system, makes it possible to clarify the mechanisms that maintain the balance of relaxation and contraction of smooth muscle cells during the traffic of medium-sized calculi.
Keywords: 
nephrolithiasis
lithokinetic therapy
medium calculus traffic
platelet suspension
G protein-coupled receptors (GPCR system)
adenosinergic system
intracellular signaling pathways

References: 
  1. Scotland K.B., Bidnur S., Wang L. et al. Mediators of human ureteral smooth muscle contraction-a role for erythropoietin, tamsulosin and Gli effectors. Transl Androl Urol. 2021; 10 (7): 2953–61. DOI: 10.21037/tau-20-1342
  2. Gottlieb M., Long B., Koyfman A. The evaluation and management of urolithiasis in the ED: A review of the literature. Am J Emerg Med. 2018; 36 (4): 699–706. DOI: 10.1016/j.ajem.2018.01.003
  3. Shen H., Chen Z., Mokhtar A.D. еt al. Expression of β-adrenergic receptor subtypes in human normal and dilated ureter. Int Urol Nephrol. 2017; 49 (10): 1771–8. DOI: 10.1007/s11255-017-1667-y
  4. 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
  5. Parker B.M., Wertz S.L., Pollard C.M. et al. Novel Insights into the Crosstalk between Mineralocorticoid Receptor and G Protein-Coupled Receptors in Heart Adverse Remodeling and Disease. Int J Mol Sci. 2018; 19 (12): 3764. DOI: 10.3390/ijms19123764
  6. Yu W., Hill W.G., Robson S.C. et al. Role of P2X4 Receptor in Mouse Voiding Function. Sci Rep. 2018; 8 (1): 1838. DOI: 10.1038/s41598-018-20216-4
  7. Aronsson P., Andersson M., Ericsson T. et al. Assessment and characterization of purinergic contractions and relaxations in the rat urinary bladder. Basic Clin Pharmacol Toxicol. 2010; 107 (1): 603–13. DOI: 10.1111/j.1742-7843.2010.00554.x
  8. Yu W., Sun X., Robson S.C. et al. ADP-induced bladder contractility is mediated by P2Y12 receptor and temporally regulated by ectonucleotidases and adenosine signaling. FASEB J. 2014; 28 (12): 5288–98. DOI: 10.1096/fj.14-255885
  9. Silva I., Magalhães-Cardoso M.T., Ferreirinha F. et al. β3 Adrenoceptor-induced cholinergic inhibition in human and rat urinary bladders involves the exchange protein directly activated by cyclic AMP 1 favoring adenosine release. Br J Pharmacol. 2020; 177 (7): 1589–608. DOI: 10.1111/bph.14921
  10. Gopalakrishnan S.M., Buckner S.A., Milicic I. et al. Functional characterization of adenosine receptors and coupling to ATP-sensitive K+ channels in Guinea pig urinary bladder smooth muscle. J Pharmacol Exp Ther. 2002; 300 (3): 910–7. DOI: 10.1124/jpet.300.3.910
  11. 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): 4599–608. DOI: 10.1210/jc.2018-01254
  12. Harrison P., Mackie I., Mumford A. et al. Guidelines for the laboratory investigation of heritable disorders of platelet function. Br J Haematol. 2011; 155 (1): 30–44. DOI: 10.1111/j.1365-2141.2011.08793.x
  13. Patel J., Chuaiphichai S., Douglas G. et al. Vascular wall regulator of G-protein signalling-1 (RGS-1) is required for angiotensin II-mediated blood pressure control. Vascul Pharmacol. 2018; 108: 15–22. DOI: 10.1016/j.vph.2018.04.002
  14. Woszczek G., Fuerst E., Maguire T.J.A. FLIPR Calcium Mobilization Assays in GPCR Drug Discovery. Methods Mol Biol. 2021; 2268: 193–205. DOI: 10.1007/978-1-0716-1221-7_13
  15. 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
  16. Gaudry M., Vairo D., Marlinge M. et al. Adenosine and Its Receptors: An Expected Tool for the Diagnosis and Treatment of Coronary Artery and Ischemic Heart Diseases. Int J Mol Sci. 2020; 21 (15): 5321. DOI: 10.3390/ijms21155321
  17. Kishore B.K., Robson S.C., Dwyer K.M. CD39-adenosinergic axis in renal pathophysiology and therapeutics. Purinergic Signal. 2018; 14 (2): 109–20. DOI: 10.1007/s11302-017-9596-x
  18. Yu W., Sun X., Robson S.C. et al. 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): 1895–903. DOI: 10.1096/fj.12-219006
  19. Sharma P., Yadav S.K., Shah S.D. et al. Diacylglycerol Kinase Inhibition Reduces Airway Contraction by Negative Feedback Regulation of Gq-Signaling. Am J Respir Cell Mol Biol. 2021; 65 (6): 658–71. DOI: 10.1165/rcmb.2021-0106OC