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BACKGROUND AND PURPOSE Prostacyclin mimetics express potent vsoactive effects via prostanoid receptors which are not defined unequivocally, 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 KV 7.1-5 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 2nd order mesenteric arteries (MAs) 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 pre-contracted arterial tone in the presence of inhibitors of prostanoid receptors, potassium channels and molecular interreference of KV 7.1 via wire-myograph; 3.) Oestrus cycle stage via histological changes in cervical cell preparations. KEY RESULTS Iloprost evoked a bi-phasic response in male MAs, at concentrations ≤100nmol-L-1 relaxing, then contracting the vessel at concentration ≥300nmol-L-1 in 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 KV 7.1 significantly attenuated relaxations produced by the selective IP-receptor agonist MRE-269 in male and female Wistar in Diestrus /Metoestrous, but not Pro-oestrus/Oestrus. CONCLUSIONS AND IMPLICATIONS Stark sexual dimorphisms in Iloprost mediated vasoactive responses are present within MAs. KV 7.1 is implicated in IP-receptor mediated vasorelaxation and is impaired by the Oestrus cycle.

Kcnq-encoded KRT-qPCR, immunocytochemistry, proximity ligation assay and wire myography were performed in renal and mesenteric arteries. Circulating sex hormone concentrations were determined by liquid chromatography-tandem mass spectrometry. Whole-cell electrophysiology was undertaken on cells expressing KThe KGPER1 signalling decreased K

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 EPWithin second-order mesenteric arteries from male and female Wistar rats, we determined (1) relative mRNA transcripts for EPIloprost evoked a biphasic response in male mesenteric arteries, at concentrations ≤100 nmol·LStark sexual dimorphisms in iloprost-mediated vasoactive responses are present within mesenteric arteries. K