Sex influence on serotonergic modulation of the vascular noradrenergic drive in rats.

IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY British Journal of Pharmacology Pub Date : 2024-11-03 DOI:10.1111/bph.17380
Anaïs Clara Terol-Úbeda, Juan Francisco Fernández-González, Carlos Andrés Roldán-Hernández, María Luisa Martín, Asunción Morán, Mónica García-Domingo, José Ángel García-Pedraza
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Abstract

Background and purpose: In male rats, the serotonergic system modulates sympathetic outflow at vascular levels, causing sympatho-inhibition and sympatho-excitation, mainly via 5-HT1D/1A and 5-HT3 receptors, respectively. However, sex influence on vascular serotonergic regulation has not yet been elucidated. This study aimed to analyse the 5-HT sympatho-modulatory role in female rats, characterising the 5-HT receptors involved.

Experimental approach: Female Wistar (14- to 16-week-old) rats were prepared for sympathetic stimulation. Mean blood pressure (MBP) and heart rate (HR) were continuously measured. Vasopressor responses were obtained by electrical stimulation of the sympathetic outflow (0.1-5 Hz) or i.v. noradrenaline (0.01-0.5 μg·kg-1). 5-HT-related drug effects on adrenergic system were determined. Age-matched male rats were used as control.

Key results: Basal MBP in females was lower than in male rats, whereas electrical-induced increases in MBP were similar. In females, 5-HT exerted a dose-dependent inhibition on the sympathetic-evoked vasoconstrictions, that was reproduced by some agonists; 5-CT (5-HT1/5/7) and L-694,247 (5-HT1D), whereas the selective 5-HT2A/2B/2C (α-methyl-5-HT) and 5-HT3 agonist (1-PBG) increased the electrically-produced vasopressor responses. None of the other drugs tested (targeting 5-HT1A/1B/1F, 5-HT2B/2C, 5-HT4, 5-HT5A or 5-HT7) modified these vasoconstrictions. Only 1-PBG (5-HT3) modified the vasoconstrictions induced by exogenous noradrenaline.

Conclusions and implications: In female rats, vascular serotonergic sympatholytic effects are due to prejunctional 5-HT1D receptor activation, whereas pre and/or postjunctional 5-HT3 and prejunctional 5-HT2A receptor activation is involved in the potentiating effect of vascular sympathetic neurotransmission. These findings may open novel sex-differential therapeutic strategies for treating cardiovascular conditions.

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性别对血清素能调节大鼠血管去甲肾上腺素能驱动力的影响
背景和目的:在雄性大鼠体内,5-羟色胺能系统主要通过 5-HT1D/1A 和 5-HT3 受体调节血管水平的交感神经外流,引起交感抑制和交感兴奋。然而,性别对血管血清素能调节的影响尚未阐明。本研究旨在分析 5-HT 对雌性大鼠交感神经的调节作用,并确定参与其中的 5-HT 受体的特征:实验方法:准备对雌性 Wistar(14 至 16 周大)大鼠进行交感神经刺激。连续测量平均血压(MBP)和心率(HR)。通过电刺激交感神经外流(0.1-5 Hz)或静脉注射去甲肾上腺素(0.01-0.5 μg-kg-1)获得血管加压反应。测定5-HT相关药物对肾上腺素能系统的影响。将年龄匹配的雄性大鼠作为对照:主要结果:雌性大鼠的基础 MBP 低于雄性大鼠,而电诱导的 MBP 升高与雄性大鼠相似。在雌性大鼠中,5-HT 对交感神经诱发的血管收缩有剂量依赖性抑制作用,一些激动剂(5-CT(5-HT1/5/7)和 L-694,247(5-HT1D))可再现这种作用,而选择性 5-HT2A/2B/2C(α-甲基-5-HT)和 5-HT3 激动剂(1-PBG)可增加电引起的血管加压反应。其他测试药物(靶向 5-HT1A/1B/1F、5-HT2B/2C、5-HT4、5-HT5A 或 5-HT7)均未改变这些血管收缩反应。只有 1-PBG(5-HT3)能改变外源性去甲肾上腺素诱导的血管收缩:在雌性大鼠中,血管5-羟色胺能交感神经溶解作用是由功能前5-HT1D受体激活引起的,而功能前和/或功能后5-HT3和功能前5-HT2A受体激活参与了血管交感神经传递的增效作用。这些发现可能为治疗心血管疾病开辟新的性别差异治疗策略。
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来源期刊
CiteScore
15.40
自引率
12.30%
发文量
270
审稿时长
2.0 months
期刊介绍: The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
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