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 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 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 KV 7.1 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 KV 7.1 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. KV 7.1 is implicated in IP receptor-mediated vasorelaxation and is impaired by the oestrus cycle.
Keywords: GPCR; Iloprost; Kv7; MRE-269; Prostacyclin; Sex; Vascular.
© 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.