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Selected Abstracts from Pharmacology 2019 DOI: 10.1111/bph.15035 CONFERENCE ABSTRACTS Selected Abstracts from Pharmacology 2019 Posters, Sunday 15th December, 14:00 was significantly depressed by NPS 2143, YM-254890, and removal of Ca 2+ from the medium. Ca 2+ (2 mM) induced an increase in DAF- Poster Session: Cardiovascular and Respiratory 2T fluorescence intensity, which was inhibited by NPS 2143, YM- 2+ Pharmacology 1 254890, removal of Ca from the medium, and L-NAME (a competitive eNOS inhibitor). Conclusion and Implications : Results of the present study provide evi- P027 | Involvement of Ca 2+ -sensing dence that activation of CaSR with extracellular Ca 2+ facilitates NO receptor–Gq/11 protein signalling pathway in release from human vascular endothelial cells via a G q/11 protein– NO release from human vascular endothelial eNOS-dependent pathway. cells Takahiro Horinouchi1; Yuichi Mazaki 1; Koji Terada 2; Soichi Miwa 1 P028 | Investigating the expression of purinergic receptors in arteries and associate 1Graduate School of Medicine, Hokkaido University; 2Shiga University of autonomic ganglia Medical Science Mohamed Eldaly; Samuel Fountain Background and Purpose : Ca 2+ -sensing receptor (CaSR) belongs to University of East Anglia family C of GPCRs and is activated by the endogenous agonists such as Ca 2+ . Stimulation of CaSR expressed in vascular endothelial cells 2+ 2+ through the increase in extracellular Ca concentration ([Ca ]o) is Background and Purpose: Purinergic receptors are implicated in car- reported to induce vasorelaxation via the production of NO and the diovascular disease, and P2X and P2Y are abundantly expressed by activation of intermediate conductance Ca 2+ -activated K + channels. blood vessels. In humans, local neurogenic responses mediated by The purpose of the present study is to characterize the CaSR- perivascular nerves (PVNs) contribute to normal blood flow and mediated NO production in human vascular endothelial cells. hypertension. Perivascular neurons located within the adventitia of Experimental Approach : The human endothelial cell line EA.hy926 arteries release neurotransmitters (including ATP) that influence arte- was used in the present study. Intracellular Ca 2+ concentration ([Ca2 rial tone and alter BP. ATP released by PVNs are hypothesised to + 2+ ]i) was measured using a fluorescent Ca indicator, Fura-2/ modulate release of other neurotransmitters by activating pre- acetoxymethyl ester, at 30 C using a dual-wavelength spectrofluo- junctional purinergic receptors, though the expression of such recep- rometer (CAF-110) at excitation wavelengths of 340 and 380 nm and tors is unclear. We investigate the expression and the function of pre- an emission wavelength of 500 nm. The activation of endothelial NOS junctional P2 receptors in mouse superior mesenteric arteries (SMAs), (eNOS) was estimated by Western blot analysis using anti-phospho- carotid arteries (CAs), and superior cervical ganglion (SCG), aiming to eNOS (Ser1177) antibody. NO released from EA.hy926 cells was mea- understand the role that P2X and P2Y receptors possess in peri- sured using 4,5-diaminofluorescein (DAF-2), a fluorescent NO indica- vascular nerve control function. tor that reacts with NO to produce the fluorescent triazole adduct, Experimental Approach: RT-PCR was performed using 500 ng of total triazolofluorescein (DAF-2T). The fluorescence intensity of the resul- RNA to investigate the expression patterns of all P2X and P2Y recep- tant DAF-2T was measured using a multi-mode spectroscopic reader tors in different vascular beds, SCG, and brain in mouse. To investigate (Varioskan Flash) using an excitation wavelength of 488 nm and an the distribution of perivascular nerves and detect any identified candi- emission wavelength of 515 nm. Statistically significance was deter- date P2 autoreceptors in tissue sections of SMA and CA and then mined using Student's unpaired t test or ANOVA followed by Tukey's determine the percentage of neurons expressing of each receptor multiple comparisons test. (colocalization studies with primary antibodies against P2 receptors), 2+ Key Results: Increase in the [Ca ]o from 0.2 to 2 mM induced a confocal/apotome microscopy and immunocytochemistry were per- 2+ concentration-dependent increase in [Ca ]i, which was significantly formed using antibody against the general neuronal marker PGP9.5. inhibited by NPS 2143 (a CaSR antagonist) and YM-254890 (a G q/11 Key Results: We demonstrated that many of P2X and P2Y receptors 2+ 2+ protein inhibitor). The maximum increase in [Ca ]i by 2-mM Ca was are expressed on the tissues, and this can lead us to further investi- 390.1 ± 9.9 nM ( n = 5). Stimulation with 2-mM Ca 2+ for 4 hr elicited gate the role of the expressed receptors in autonomic and sensory – an increase in the phosphorylation level of eNOS at Ser 1177, which motor nerve function. PGP immunoreactivity was present in all Br J Pharmacol. 2020;177:2487–2654. wileyonlinelibrary.com/journal/bph © 2020 The British Pharmacological Society 2487 2488 CONFERENCE ABSTRACTS neuronal parts of the extrinsic and intrinsic arteries innervation, male and female pro-oestrus and oestrus Wistar rats. All vessels are including different subpopulations of nerves. The results can expand insensitive to K V7.1 channel activator ML277. There were no differ- our understanding of purinergic receptor expression on the sympa- ences observed in the KCNQ/KCNE transcript expression profiles in thetic efferent neurons which could be used in the development of a arteries from male or female pro-oestrus and oestrus or female novel therapeutic target for the modulation of vascular tone, thus dioestrus and metoestrus Wistar rats. having implications for the treatment of hypertension. Conclusion and Implications : Our data indicate a sex-dependent post- Conclusion and Implications: P2 receptor expression in mouse SMA, transcriptional difference in KCNQ regulation resulting in differential CA, SCG, and brain was investigated using RT-PCR. Showing the functional responses, showing a cycle-dependent shift in the potency expression of P2X and P2Y could further be studied in autonomic and of K V7.2-5 activator to mediate vasorelaxation, sensitivity to sensory–motor nerve function. Further examination of purinergic U46619-mediated vasoconstriction, and KV7.2-5 channel modulation receptor expression on the sympathetic efferent neurons could be of vasoconstriction. ML277 was shown to be incapable of relaxing potential novel BP targets. pre-contracted arterial tone, indicating no functional role for K V7.1. REFERENCES REFERENCE 1. Ralevic, V. (2012). P2X receptors in the cardiovascular system. Wiley 1. Jepps, T. A., et al. (2011). Downregulation of Kv7.4 channel activity in Interdisciplinary Reviews: Membrane Transport and Signaling , 1(5), primary and secondary hypertension. Circulation. https://doi.org/10. 663–674. 1161/CIRCULATIONAHA.111.032136 2. Sperlágh, B., Heinrich, A., & Csölle, C. (2007). P2 receptor-mediated modulation of neurotransmitter release —An update. Purinergic Signal- ling, 3(4), 269–284. P030 | α-CGRP mediates calcium-sensing receptor-induced vasorelaxation in rat P029 | Sex-dependent differences of vascular mesenteric arteries KV7 channels Simonette Carlton-Carew; Iain Greenwood; Anthony Albert Samuel Baldwin; Vincenzo Barrese; Jennifer Stott; Iain Greenwood St George's, University of London St George's, University of London Background and Purpose: Stimulation of calcium-sensing receptors (CaSRs) expressed in the vasculature is reported to regulate vascular Background and Purpose : Vascular smooth muscle cells (VSMCs) dic- tone and is a potential novel therapeutic target for cardiovascular dis- tate arterial diameter. As VSMCs contract, blood vessels narrow, eases, such as hypertension (Schepelmann et al., 2016). Therefore, our reducing blood flow and increasing total peripheral resistance. VSMC work investigates the functional and cellular mechanisms induced by 2+ contraction is achieved by an increase in intracellular calcium. [Ca ]i activation of vascular CaSRs. is dictated by VSMC membrane potential and the opening of voltage- Experimental Approach: Wistar male rats (200 –250 g) were culled in gated calcium channels (VGCC). KCNQ-encoded KV7 channels are accordance with Animals (Scientific Procedures) Act 1986, and supe- shown to regulate VSMC membrane potential at rest, their activity rior mesenteric artery branches were dissected. mediates VSMC hyperpolarization deterring VGCC opening and vaso- Transverse arterial sections (10 μm) were fixed on microscope constriction. K V7 channels also contribute to an array of receptor- slides and incubated with anti-CaSR primary antibodies. Immunohisto- mediated responses, and in conjunction, K V7 channels are degraded in chemical distribution was detected using a confocal microscope. hypertension, contributing to a hypertensive phenotype (Jepps et al., Artery branches were mounted on a wire myograph in 1-mM 2+ 2011). Despite the known contribution of K V7 channels to VSMC CaCl2 ([Ca ]o) physiological salt solution (95% O 2/5% CO 2; 37 C). physiology and pathophysiology, the wealth of current literature Arteries were pre-contracted with the bath application of 300-nM focuses predominantly on males. U46619 (Tx receptor agonist), and CaSRs were stimulated with cumu- 2+ Experimental Approach : We have compared KCNQ expression and lative increases of [Ca ]o (1 –10 mM) in the presence and absence of function in coronary, cerebral, and renal arteries from male and female inhibitors and a functional endothelium.
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