The role of mechanosensitive TRPV4 channels in the regulation of myometrium spontaneous and oxytocin- induced contractility under normal and pathophysiologically relevant conditions

Abstract

Pharmacological modulators of TRPV4 activity were examined in the rat and human myometrial tissue as the potential drugs with the perspective of attenuation of premature uterine contractions or for strengthening them in case of their insufficiency. Changes in myometrium contractility under hypotonic stress, which often occurs in patients with preeclampsia, hypertension and diabetes and may lead to the activation of mechanosensitive TRPV4 channels were explored. Using the tissue bath system with force transducers for recording of isometric contraction of isolated human and rat pregnant myometrium strips, the amplitude of contraction, duration of contraction at 50% of maximal peak amplitude (T1/2) and integral force of contractions were measured and analyzed. Pharmacological activation of TRPV4 ion channels by its selective agonist GSK1016790A (0.3 µМ) caused an increase of the tone of human myometrium strips at term that was abolished by the TRPV4 selective antagonist HC067047 (1 µM). Under hypotonic stress the amplitude of force significantly decreased for human strips (p < 0.05) but in rat myometrium it was up to 60% higher (p < 0.05). During oxytocin-stimulated myometrium contractions TRPV4 channels were found to play the role of a limiting factor likely contributing to the reduction of excitability of uterine myocytes. We propose that the effect of activation of TRPV4 channels depends on both certain species-specific features, as well as the functional state of the myometrium. The effect of TRPV4 agonist in the presence of oxytocin opens new avenues to look for similar patterns and interactions in the regulation of uterine contractility.