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Sexual dimorphism in prostacyclin-mimetic responses within rat mesenteric arteries: A novel role for KV7.1 in shaping IP receptor-mediated relaxation

Baldwin, SN; Forrester, EA; McEwan, L; Greenwood, IA (0222) Sexual dimorphism in prostacyclin-mimetic responses within rat mesenteric arteries: A novel role for KV7.1 in shaping IP receptor-mediated relaxation. Br J Pharmacol, 179 (7). pp. 1338-1352. ISSN 1476-5381 https://doi.org/10.1111/bph.15722
SGUL Authors: Greenwood, Iain Andrew

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Abstract

Background and Purpose Prostacyclin mimetics express potent vasoactive effects via prostanoid receptors that are not unequivocally defined, as to date no study has considered sex as a factor. The aim of this study was to determine the contribution of IP and EP3 prostanoid receptors to prostacyclin mimetic iloprost-mediated responses, whether KV7.1–5 channels represent downstream targets of selective prostacyclin-IP-receptor agonist MRE-269 and the impact of the oestrus cycle on vascular reactivity. Experimental Approach Within second-order mesenteric arteries from male and female Wistar rats, we determined (1) relative mRNA transcripts for EP1–4 (Ptger1–4), IP (Ptgi) and TXA2 (Tbxa) prostanoid receptors via RT-qPCR; (2) the effect of iloprost, MRE-269, isoprenaline and ML277 on precontracted arterial tone in the presence of inhibitors of prostanoid receptors, potassium channels and the molecular interference of KV7.1 via wire-myograph; (3) oestrus cycle stage via histological changes in cervical cell preparations. Key Results Iloprost evoked a biphasic response in male mesenteric arteries, at concentrations ≤100 nmol·L−1 relaxing, then contracting the vessel at concentration ≥300 nmol·L−1, a process attributed to IP and EP3 receptors respectively. Secondary contraction was absent in the females, which was associated with a reduction in Ptger3. Pharmacological inhibition and molecular interference of KV7.1 significantly attenuated relaxations produced by the selective IP receptor agonist MRE-269 in male and female Wistar in dioestrus/metoestrus, but not pro-oestrus/oestrus. Conclusions and Implications Stark sexual dimorphisms in iloprost-mediated vasoactive responses are present within mesenteric arteries. KV7.1 is implicated in IP receptor-mediated vasorelaxation and is impaired by the oestrus cycle.

Item Type: Article
Additional Information: © 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: 1115 Pharmacology and Pharmaceutical Sciences, Pharmacology & Pharmacy
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Br J Pharmacol
ISSN: 1476-5381
Language: eng
Dates:
DateEvent
2 March 0222Published
21 January 2021Published Online
19 October 2021Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
FS/18/41/33762British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
PubMed ID: 34766649
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/113788
Publisher's version: https://doi.org/10.1111/bph.15722

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