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 EP(3) 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 EP(1–4) (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·L(−1) relaxing, then contracting the vessel at concentration ≥300 nmol·L(−1), a process attributed to IP and EP(3) 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.