Sexual dimorphism in prostacyclin-mimetic responses within rat mesenteric arteries: A novel role for K(V)7.1 in shaping IP receptor-mediated relaxation

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 K(V)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 (Ptger(1-4)), IP (Ptgi) and TXA(2) (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 K(V)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 center dot L-1 relaxing, then contracting the vessel at concentration >= 300 nmol center dot 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 K(V)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. K(V)7.1 is implicated in IP receptor-mediated vasorelaxation and is impaired by the oestrus cycle.