Dataset Information

Sexual dimorphism in prostacyclin-mimetic responses within rat mesenteric arteries: A novel role for K_V 7.1 in shaping IP receptor-mediated relaxation.

ABSTRACT:

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 EP_1-4 (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 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 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.

SUBMITTER: Baldwin SN

PROVIDER: S-EPMC9340493 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Publications

Sexual dimorphism in prostacyclin-mimetic responses within rat mesenteric arteries: A novel role for K<sub>V</sub> 7.1 in shaping IP receptor-mediated relaxation.

Baldwin Samuel N SN Forrester Elizabeth A EA McEwan Lauren L Greenwood Iain A IA

British journal of pharmacology 20220121 7

<h4>Background and purpose</h4>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<sub>3</sub> prostanoid receptors to prostacyclin mimetic iloprost-mediated responses, whether K<sub>V</sub> 7.1-5 channels represent downstream targets of selective prostacyclin-IP-receptor agonist MRE-269 and the impact of the oes ...[more]

PMID: 34766649

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Project description:Hyperalgesic priming, a model of pain chronification in the rat, is mediated by ryanodine receptor-dependent calcium release. Although ryanodine induces priming in both sexes, females are 5 orders of magnitude more sensitive, by an estrogen receptor α (EsRα)-dependent mechanism. An inositol 1,4,5-triphosphate (IP3) receptor inhibitor prevented the induction of priming by ryanodine. For IP3 induced priming, females were also more sensitive. IP3-induced priming was prevented by pretreatment with inhibitors of the sarcoendoplasmic reticulum calcium ATPase and ryanodine receptor. Antisense to EsRα prevented the induction of priming by low-dose IP3 in females. The induction of priming by an EsRα agonist was ryanodine receptor-dependent and prevented by the IP3 antagonist. Thus, an EsRα-dependent bidirectional interaction between endoplasmic reticulum IP3 and ryanodine receptor-mediated calcium signaling is present in the induction of hyperalgesic priming, in females. In cultured male DRG neurons, IP3 (100 μm) potentiated depolarization-induced transients produced by extracellular application of high-potassium solution (20 mm, K20), in nociceptors incubated with β-estradiol. This potentiation of depolarization-induced calcium transients was blocked by the IP3 antagonist, and not observed in the absence of IP3 IP3 potentiation was also blocked by ryanodine receptor antagonist. The application of ryanodine (2 nm), instead of IP3, also potentiated K20-induced calcium transients in the presence of β-estradiol, in an IP3 receptor-dependent manner. Our results point to an EsRα-dependent, reciprocal interaction between IP3 and ryanodine receptors that contributes to sex differences in hyperalgesic priming.SIGNIFICANCE STATEMENT The present study demonstrates a mechanism that plays a role in the marked sexual dimorphism observed in a model of the transition to chronic pain, hyperalgesic priming. This mechanism involves a reciprocal interaction between the endoplasmic reticulum receptors, IP3 and ryanodine, in the induction of priming, regulated by estrogen receptor α in the nociceptor of female rats. The presence of this signaling pathway modulating the susceptibility of nociceptors to develop plasticity may contribute to our understanding of sex differences observed clinically in chronic pain syndromes.

Project description:We recently reported sex differences in mesenteric arterial function of the UC Davis type-2 diabetes mellitus (UCD-T2DM) rats as early as the prediabetic state. We reported that mesenteric arteries (MA) from prediabetic male rats exhibited a greater impairment compared to that in prediabetic females. However, when females became diabetic, they exhibited a greater vascular dysfunction than males. Thus, the aim of this study was to investigate whether the female sex hormone, estrogen preserves mesenteric arterial vasorelaxation in UCD-T2DM female rats at an early prediabetic state. Age-matched female Sprague Dawley and prediabetic (PD) UCD-T2DM rats were ovariectomized (OVX) and subcutaneously implanted with either placebo or 17β-estradiol (E2, 1.5 mg) pellets for 45 days. We assessed the contribution of endothelium-derived relaxing factors (EDRF) to acetylcholine (ACh)-induced vasorelaxation, using pharmacological inhibitors. Responses to sodium nitroprusside (SNP) and phenylephrine (PE) were also measured. Additionally, metabolic parameters and expression of some targets associated with vascular and insulin signaling were determined. We demonstrated that the responses to ACh and SNP were severely impaired in the prediabetic state (PD OVX) rats, while E2 treatment restored vasorelaxation in the PD OVX + E2. Moreover, the responses to PE was significantly enhanced in MA of PD OVX groups, regardless of placebo or E2 treatment. Overall, our data suggest that 1) the impairment of ACh responses in PD OVX rats may, in part, result from the elevated contractile responses to PE, loss of contribution of endothelium-dependent hyperpolarization (EDH) to vasorelaxation, and a decreased sensitivity of MA to nitric oxide (NO), and 2) the basis for the protective effects of E2 may be partly attributed to the elevation of the NO contribution to vasorelaxation and its interaction with MA as well as potential improvement of insulin signaling. Here, we provide the first evidence of the role of E2 in protecting MA from early vascular dysfunction in prediabetic female rats.

Dataset Information

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

Experimental approach

Key results

Conclusions and implications

Publications

Sexual dimorphism in prostacyclin-mimetic responses within rat mesenteric arteries: A novel role for K<sub>V</sub> 7.1 in shaping IP receptor-mediated relaxation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Sexual dimorphism in prostacyclin-mimetic responses within rat mesenteric arteries: A novel role for KV 7.1 in shaping IP receptor-mediated relaxation.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Sexual dimorphism in prostacyclin-mimetic responses within rat mesenteric arteries: A novel role for K<sub>V</sub> 7.1 in shaping IP receptor-mediated relaxation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Sexual dimorphism in prostacyclin-mimetic responses within rat mesenteric arteries: A novel role for K_V 7.1 in shaping IP receptor-mediated relaxation.