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    • serial dilution calculator Our results demonstrated that mos

    2021-10-20

    Our results demonstrated that most of the HUA rings incubated with 100 μM TBT do not have the capacity to contract in the presence of 5-HT or exhibit very low contractions in comparison to the control. Only 23.3% of the HUA rings were able to contract. These results seem to indicate that there may be a change in the 5-HT2A receptor, in which the only active receptor is the 5-HT1B/1D receptor which corresponds to a dual effect as described previously by other authors in non-incubated HUA (Lovren et al., 1999; Santos-Silva, 2009). Moreover, these authors observed with two different 5-HT1B/1D agonists a HUA contraction, even though these effects are dual because in most of the serial dilution calculator there was a small contractile effect but in some cases a bigger contraction was obtained (Lovren et al., 1999; Santos-Silva, 2009). The HUA incubated with 0.1 nM TBT and 0.1 μM TBT demonstrated a different result being able to contract in the presence of 5-HT. Thus, the observed effect of contractile incapacity caused by TBT is associated with concentrations higher than 0.1 μM. Facing these results, mRNA expression levels of 5-HT2A were analyzed in order to confirm the reduction of these levels. According to the obtained results, a decrease in gene expression at concentrations of 0.1 nM, 10 nM and 0.1 μM was observed. Thus, we can conclude that TBT modifies the contractile effect of serotonin due to decreased gene expression of the 5-HT2A receptor. Concerning the HUA rings contracted with histamine, its contractile effect is similar to the control. Subsequently for the addition of different concentrations of TBT (0.1 nM-100 μM), this compound induced concentration-dependent vasorelaxation on HUA rings in the three TBT incubations (0.1 nM, 0.1 μM and 100 μM) tested and this relaxation is higher than the control. As previously described by our group, the H2 receptor causes relaxation of HUA through adenylyl cyclase stimulation and through cAMP increase (Cairrao et al., 2008; Santos-Silva, 2009), so given our results (higher vasorelaxation after pre-incubation with TBT) it is expected that TBT may cause a possible alteration in this receptor or in its mechanism of action, leading to the vasodilatation of HUA. Another possible explanation for this mechanism is a change/decrease in the contractile effect, similar to a genomic change in the H1 receptor. In order to further understand these effects, we also analyzed the mRNA expression levels of H1 receptor. Our results show that TBT significantly decreased the H1 receptor gene expression in comparison with the control. According to our results (Nath, 2008) also observed vasodilation in arteries of rabbits exposed to alkyltins suffered and demonstrated that organotin complexes could act as direct vasodilators in smooth muscle cells in animal model. Dos Santos et al. (2012) investigated the influence of TBT on the coronary function of female rats and it has been shown that this compound impairs the coronary vasodilation induced by 17β-estradiol in isolated rat heart (dos Santos et al., 2012). Regarding our results with MTT tests, it has been found that when exposed to concentrations of 1 μM, 10 μM and 100 μM, cells have a low viability, ranging from about 20% to 30%, in which we can conclude that the TBT has a small toxic effect in smooth muscle cells. Studies by Rohl et al. (2001) demonstrated that TBT was able to induce a concentration-dependent cytotoxicity in primary cultures of rat cortical astrocytes performed by the MTT method (Rohl et al., 2001). However, the organ bath results have shown that TBT is non-toxic to the arteries, since they were responsive to the contractile agent. Overall our results concerning the genomic effect of TBT, demonstrated clearly that TBT can change the sensitivity of the HUA to 5-HT and to histamine, which can lead to changes in vascular resistance. Some authors associated the increased sensitivity of HUA to 5-HT and to histamine with the development of pre-eclampsia (Brew and Sullivan, 2006; Feinberg, 2006; Gupta et al., 2006; Redman and Sargent, 2005). On the contrary, other studies demonstrated that the decrease in the sensitivity of HUA to 5-HT may also induce pre-eclampsia (Ishii et al., 1993). The increase of hypertensive disorders of pregnancy is associated with adverse maternal and neonatal outcomes, including perinatal death, while severe foetal growth restriction has short and long-term adverse consequences for new-borns (Feinberg, 2006; Redman and Sargent, 2005).