br Conclusions In summary our results demonstrate

Conclusions In summary, our results demonstrate that in short term effect, TBT induced concentration-dependent vasorelaxation of HUA rings. Regarding the long term effects, exposure to a concentration of 100 μM TBT the human umbilical BIO-acetoxime have a dual effect, and a decrease of the 5-HT2A expression levels, suggesting that only 5-HT1B/1D receptor is responsible for the contractile effect. Regarding the histamine results the TBT induced concentration-dependent vasorelaxations of HUA rings and significantly decreased the expression of the H1 receptor gene. The genomic effects of TBT seem to not be related to the calcium or potassium channels. However, further studies are needed to better understand the effect of TBT on the expression and activity of these receptors. Since there have been an increase in the incidence of cardiovascular diseases, it is also important to study the TBT involvement in these diseases, mainly pregnancy hypertension or pre-eclampsia.
Conflict of interest
Acknowledgements The authors thank the donor mothers and the staff of the Gynaecology–Obstetrics Department of the Centro Hospitalar da Cova da Beira (Covilhã, Portugal) for their collaboration. The authors also acknowledge that TBT was generous gift from Ana Sousa (Department of Biology & Centre for Environmental and Marine Studies (CESAM), University of Aveiro (Ref. FCT UID/CTM/50011/2013)). This work is supported by FEDER funds through the POCI - COMPETE 2020 - Operational Programme Competitiveness and Internationalisation in Axis I - Strengthening research, technological development and innovation (Project POCI-01-0145-FEDER-007491) and National Funds by FCT - Foundation for Science and Technology (Project UID/Multi/00709/2013). We also thank to FCT for supporting the grant SFRH/BD/131665/2017.
Introduction Histamine is involved in the immune and inflammatory response, and it also plays a role of a neurotransmitter in the central nervous system. The cell bodies of histamine neurons are found in the posterior hypothalamus, in the tuberomammillary nuclei; they send projections to various brain areas [1], [2], [3]. Action of histamine is mediated by H1-H4 histamine receptors. These metabotropic receptors regulate numerous physiological functions and are involved in many CNS pathologies such as epilepsy, Alzheimer's disease, narcolepsy, attention-deficit hyperactivity disorder, schizophrenia, multiple sclerosis [4], [5], [6]. A large number of ligands was developed for histamine receptors H1-H4 [7]. They are rather small molecules that can potentially affect other targets, thus leading to the non-specific interactions, which in turn may result in the side effects of histamine receptor ligands. For instance, diphenhydramine also acts as an intracellular sodium channel blocker, which is responsible for its action as a local anesthetic [8]. Recently we found that synthetic amine-containing compounds affect the proton-gated ion channels of ASIC family [9]. Structure of some of these compounds, which contain an aromatic or hydrophobic moiety connected to amino group, is markedly similar to those of histamine receptor ligands [10]. This similarity has inspired the idea, that histamine and synthetic ligands of histamine receptors can target ASICs. Subsequent study demonstrated that histamine selectively potentiates recombinant homomeric ASIC1a [11]. Histamine shifts the activation curve of ASIC1a to less acidic values, thus allowing for the receptor activation even by modest acidifications. Under such conditions even 10 μM histamine produces significant potentiation. This finding seems important for understanding of physiological mechanism of ASIC function, because these channels generate transient response to pH drops, while slow long-lasting acidifications result in steady-state desensitization. The pH drops can take place during synaptic transmission since the content of synaptic vesicles is acidic. However, ASIC-mediated component of synaptic responses revealed in recent studies [12], [13] is very small. It is possible that some endogenous ligand(s) potentiates ASICs in physiological conditions of weak synaptic acidifications.