Effectiveness of α1A-adrenoreceptor antagonist in the passage of middle stones from the ureter: the role of receptors coupled with G-protein

The study aims to analyze the dependence of an α1A-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 α1A-adrenergic receptor antagonist (α1A-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 α1A-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.