EFFECTIVENESS OF α1А-ADRENORECEPTOR ANTAGONIST IN THE PASSAGE OF MIDDLE STONES FROM THE URETER: THE ROLE OF RECEPTORS COUPLED WITH G-PROTEIN

DOI: https://doi.org/10.29296/24999490-2022-05-05

E.F. Barinov, Y.Yu. Malinin, H.V. Grigoryan
State educational organization of higher professional education «M. Gorky Donetsk National Medical University»,
DNR, 283003, Donetsk, 16 Ilyich Ave

The study aims to analyze the dependence of an α1А-adrenoreceptor antagonist effectiveness on G-protein-coupled receptors (GPCRs) intracellular signaling in the passage of medium-sized calculi from the ureter. Material and methods. The study was prospective and included 30 patients divided into two groups: with effective (Group 1) and ineffective (Group 2) passage of stones 11–13 mm in size during 9 days of standard lithokinetic therapy (LCT), including an α1А-adrenergic receptor antagonist (α1А-A). The following antogonists 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 the study started, the reactivity of receptors coupled with Gi-, Gq-proteins was revealed, as their signaling can cause a disturbance of medium-sized calculi movement in the ureter. After 7–9 days of LCT, the passage of calculi occurred with the normoreactivity of the purine P2X1 receptor and P2Y receptors, hyperreactivity of the α2-adrenoreceptor and A2A receptor, and desensitization of the AT1 receptor and TXA2 receptor. With ineffective passage after 7–9 days of LCT, there was hyperreactivity of receptors coupled to Gi-protein (α2-adrenoreceptor), Gq-protein (P2Y receptors, AT1 receptor and TxA2 receptor), as well as the receptor, which is a ligand-dependent. Excessive stimulation of the Gq protein-coupled receptor system can neutralize the effect of an α1А-adrenergic receptor antagonist administration by reproducing “crosstalk” of intracellular signaling resulting in the maintenance of an excess level of intracellular Ca2+. Hyporeactivity of the A2A receptor ruled out the possibility of achieving the required level of relaxation of smooth muscle tissue in the ureter. Conclusion. An in vitro analysis of intracellular signaling that regulates the entry of Ca2+ ions into the cell upon activation of the GPCR system and the passage of excess Ca2+ (adenosinergic system) makes it possible to clarify the mechanisms that maintain the balance of relaxation and contraction of SCMs during the movement of medium-sized calculi.
Keywords: 
nephrolithiasis, lithokinetic therapy, medium calculus traffic, G protein-coupled receptors (GPCR system), intracellular signaling pathways
Список литературы: 
  1. Fry C.H., McCloskey K.D. Purinergic signalling in the urinary bladder – When function becomes dysfunction. Auton Neurosci. 2021; 235: 102852. DOI: 10.1016/j.autneu.2021.102852.
  2. Patel J., Chuaiphichai S., Douglas G., Gorvin C.M., Channon K.M. 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.
  3. Kostenis E., Pfeil E.M., Annala S. Heterotrimeric Gq proteins as therapeutic targets? J. Biol. Chem. 2020; 295 (16): 5206–15. DOI: 10.1074/jbc.REV119.007061.
  4. 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.
  5. Wang J., Gareri C., Rockman H.A. G-Protein-Coupled Receptors in Heart Disease. Circ Res. 2018; 123 (6): 716–35. DOI: 10.1161/CIRCRESAHA.118.311403.
  6. Mohamed R., Janke R., Guo W., Cao Y., Zhou Y., Zheng W., Babaahmadi-Rezaei H., Xu S., Kamato D., Little P.J. GPCR transactivation signalling in vascular smooth muscle cells: role of NADPH oxidases and reactive oxygen species Vasc Biol. 2019; 1 (1): 1–11. DOI: 10.1530/VB-18-0004.
  7. Micucci M., Chiarini A., Budriesi R. Neutral/negative α1-AR antagonists and calcium channel blockers at comparison in functional tests on guinea-pig smooth muscle and myocardium. Pharmacol Rep. 2019; 71 (1): 128–32. DOI: 10.1016/j.pharep.2018.10.007.
  8. 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): 1863–8. DOI: 10.1089/end.2009.0461.
  9. Gopalakrishnan S.M., Buckner S.A., Milicic I., Groebe D.R., Whiteaker K.L., Burns D.J., Warrior U., Gopalakrishnan M. 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.
  10. Parker B.M., Wertz S.L., Pollard C.M., Desimine V.L., Maning J., McCrink K.A., Lymperopoulos A. 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.
  11. Harrison P., Mackie I., Mumford A. British. Guidelines for the laboratory investigation of heritable disorders of platelet function. Brit J. of Haematology. 2011; 155 (1): 30–44. DOI: 10.1111/j.1365-2141.2011.08793.x
  12. Savio L.E.B., Leite-Aguiar R., Alves V.S., Coutinho-Silva R., Wyse A.T.S. Purinergic signaling in the modulation of redox biology. Redox Biol. 2021; 47: 102137. DOI: 10.1016/j.redox.2021.102137.
  13. Sharma P., Yadav S.K., Shah S.D., Javed E., Lim J.M., Pan S., Nayak A.P., Panettieri R.A.Jr., Penn R.B., Kambayashi T., Deshpande D.A. 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.
  14. Matthey M., Roberts R., Seidinger A., Simon A., Schröder R., Kuschak M., Annala S., König G.M., Müller C.E., Hall I.P., Kostenis E., Fleischmann B.K., Wenzel D. Targeted inhibition of Gq signaling induces airway relaxation in mouse models of asthma. Sci Transl Med. 2017; 9 (407): eaag2288. DOI: 10.1126/scitranslmed.aag2288.
  15. Yadav S.K., Sharma P., Shah S.D., Panettieri R.A., Kambayashi T., Penn R.B., Deshpande D.A. Autocrine regulation of airway smooth muscle contraction by diacylglycerol kinase. J. Cell Physiol. 2022; 237 (1): 603–16. DOI: 10.1002/jcp.30528.
  16. Meinel S., Gekle M., Grossmann C. Mineralocorticoid receptor signaling: crosstalk with membrane receptors and other modulators. Steroids. 2014; 91: 3–10. DOI: 10.1016/j.steroids.2014.05.017.
  17. Shi Q., Li M., Mika D., Fu Q., Kim S., Phan J., Shen A., Vandecasteele G., Xiang Y.K. Heterologous desensitization of cardiac β-adrenergic signal via hormone-induced βAR/arrestin/PDE4 complexes. Cardiovasc Res. 2017; 113 (6): 656–70. DOI: 10.1093/cvr/cvx036.
  18. Kim D., Tokmakova A., Woo J.A., An S.S., Goddard W.A., Liggett S.B. Selective Signal Capture from Multidimensional GPCR Outputs with Biased Agonists: Progress Towards Novel Drug Development. Mol Diagn Ther. 2022. DOI: 10.1007/s40291-022-00592-4. Online ahead of print.