Tsymbaliuk O. Biophysical mechanisms of action of nanoscale materials on the mechanokinetics of visceral smooth muscles

It has been established that suspensions of nano-sized material TiO2 of three size groups, which contain different ratios of mixtures of rutile polymorphs and anatase under non-cumulative and cumulative effects, are effective modulators of spontaneous and evoked contractions of visceral smooth muscles (SM). In particular, TiO2 modulates the presynaptic and postsynaptic mechanisms of regulation of the gastrointestinal SM contraction with the participation of the acetylcholine, histamine and GABA receptors. The absence of the influence of TiO2 nanoparticles on the processes of excitation-contraction conjugation, which are induced by endogenous acetylcholine upon activation of its release by the depolarization of SM tissue, is shown. At the same time, it was revealed that these nanomaterials modulate contractions activated by exogenous acetylcholine and inhibit their tonic component by the ionotropic acetylcholine receptor agonist nicotine. The TiO2 induced activation of the influx of Ca2+ ions through L-type Ca2+-channels. It has been proven that the nano-sized TiO2 does not change the mobilization of Ca2+ ions with inositol-1,4,5-triphosphate- and ryanodine-sensitive pools of the sarcoplasmic reticulum of antrum myocytes. It was revealed that blocking the work of the mitochondrial respiratory chain eliminates the effects of TiO2 on acetylcholine-induced contractions. In the myometrium, TiO2 eliminates the effects of blocking ATP-sensitive K+ channels. In silico studies have established that the nano-sized material TiO2 is able to interact with different affinity with several sites of the extracellular part of the metabotropic GABAB and M2 and M3 acetylcholine and H1 receptors. By elemental analysis, it was shown that in vivo intragastric administration, nano-TiO2 penetrates tissues and unevenly accumulates in various organs: the greatest amount of Ti is accumulated by visceral smooth muscle tissue (stomach> colon> uterus) and kidneys. By tensometric studies and mechanokinetics analysis, it was established that chronic (30 and 100 days) body loads in vivo of TiO2 cause a non-uniform (time-dependent and tissue-dependent) effect on the contractile activity of visceral smooth muscles. Thermodynamic analysis established that under the conditions of the chronic action of TiO2 causes significant changes in the processes of highly elastic deformation in the smooth muscle tissue of the stomach with large deformations. Acetylcholine-induced smooth muscle contractions of caecum were found to be sensitive to the action of calix[4]arene C-99 under conditions of pre-blocking of Na+, K+-ATP-ases of ouabain. It was established that this calix[4]arene under conditions of chronic in vivo exposure causes inhibition of ouabain-sensitive Na+, K+-ATP-ase activity of plasmalemma preparations. Using mechanokinetic analysis of K+-depolarization and acetylcholine-induced contractions, it has been established that the results of ouabain, calix[4]arene C-107 and M-3 under chronic in vivo conditions predominantly reproduce the trends when they are applied in vitro. The increase in the tonic component of the myometrium smooth muscle K+-contraction under the action of calix[4]arene C-716 (previous blocking of the exchange of Ca ions in intracellular Ca2+-depot) is associated with an increased concentration of Ca2+ ions in myocytes, while an increase in the normalized speed relaxation under these conditions is probably due to the substantial activation of nitric oxide synthesis by constitutive forms of NO-synthase. Obtained in the case of preincubation of the smooth muscle preparations of the myometrium with calix[4]arene C-90, a significant decrease in the normalized maximum relaxation rate of spontaneous and oxytocin-induced contractions is associated with a directed inhibition of the plasma membrane Ca2+ pump. Against the background of the action of the nitric oxide synthase blocke, L-NAME, calix[4]arene C-90 is not capable of suppressing the tonic phase of K+ - and oxytocin-induced contractions, but leads to a decrease in the maximum relaxation rate.