Abstract
Background and PurposeProstacyclin 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 ApproachWithin 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 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 ResultsIloprost 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 ImplicationsStark 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.
Highlights
Prostacyclin (PGI2), a product cyclooxygenase-1/2 (COX-1/2) metabolism of arachidonic acid, exhibits anti-thrombotic, anti-inflammatory and potent vasodilatory properties in a process attributed to the activation of Gs-coupled IP prostanoid receptor signalling
In mesenteric arteries (MAs) from male rats stable contracted by U46619 (300 nmol-L-1), Iloprost
This phenomenon was notably absent in MAs from female rats, wherein Iloprost only evoked concentration dependent vasorelaxation (P=>0.05; Fig 1.A,B; red)
Summary
Prostacyclin (PGI2), a product cyclooxygenase-1/2 (COX-1/2) metabolism of arachidonic acid, exhibits anti-thrombotic, anti-inflammatory and potent vasodilatory properties in a process attributed to the activation of Gs-coupled IP prostanoid receptor signalling. Schubert et al, 1997, 1996; Dumas et al, 1997; Lombard et al, 1999) These diverse responses to prostacyclin mimetics remain largely uncharacterised, and few studies have considered sex as a factor when characterising prostacyclin-memetic mediated vascular responses. 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 2nd order mesenteric arteries (MAs) from male and female Wistar rats, we determined; 1.) relative mRNA transcript for EP1-4 (Ptger1-4), IP (Ptgi) and TXA2 (Tbxa) prostanoid receptors via RT-qPCR; 2.) The effect of Iloprost, MRE-269 and isoprenaline on pre-contracted arterial tone in the presence of inhibitors of prostanoid receptors, potassium channels and molecular interreference of KV7.1 via wire-myograph; 3.) Oestrus cycle stage was via histological changes in cervical cell preparations
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