Ex vivo imaging in acute cortical brain slices is a valuable tool to assess neurovascular coupling and is particularly useful for studying active, local changes in microvascular compartments in isolation from upstream or downstream changes in flow. However, the lack of vascular perfusion pressure ex vivo results in loss of vascular tone, which must be restored prior to experiments to unmask dilatory signals. The thromboxane A2 receptor agonist U46619 is a widely used preconstrictor, yet its dose-response properties and kinetics of action on different vascular segments are not fully known. Here, we characterize the effects of U46619 on cortical arterioles and capillaries in ex vivo slices from rats and mice. Dose response curves tested in acute rat brain slices using 0 to 1000 nM U46619 showed that maximal constriction is reached at ∼300 nM in both arterioles and capillaries. Extended application of 200 nM U46619 (∼66 % maximal dose) over 2 h revealed that, on average, capillaries constrict faster than arterioles in rat brain slices. Cross-species examination in mouse tissue showed that vessels in mouse brain slices respond faster and constrict stronger on average than in rat brain slices, and that mouse capillaries also constrict faster than mouse arterioles. Our observations suggest that near-maximal preconstriction can be achieved in ex vivo experiments using 200-300 nM U46619, with a minimum incubation time of 20 min for studies involving capillaries and at least 30 min for studies involving arterioles.

2025-09-01·EUROPEAN JOURNAL OF PHARMACOLOGY

Morin ameliorates coronary artery relaxation by activating TRPV4-eNOS-NO signalling in high-salt diet-fed rats

Article

作者: Li, Jianwei ; Ye, Yang ; Gu, Xin ; Zhang, Zhixuan ; Liu, Qian ; Xie, Yifei ; Zhang, Xiaodong ; Liu, Fengqi ; Sun, Runfeng ; Wang, Xiaoyan ; Wang, Fen ; Zhang, Xiaotian

Morin has been shown to be beneficial for cardiovascular disease. A high-salt diet induces dysfunction of coronary artery endothelial cells (CAECs), leading to altered regulation of coronary artery tone and increasing the risk of coronary artery diseases. In the present study, the protective effect of morin on the coronary artery was investigated in high-salt diet-induced hypertensive rats. Initially, morin pre-treatment of isolated rat coronary artery depressed the contraction induced by U46619, and morin induced endothelium-dependent relaxation of isolated rat coronary artery in a concentration-dependent manner. Moreover, the TRPV4 inhibitor HC067047, the nitric oxide (NO) synthase (eNOS) inhibitor L-NAME and a Ca²⁺-free solution significantly reduced morin-induced coronary artery vasodilation. In primary CAECs, morin induced NO production; however, NO production was significantly reduced by HC067047 and L-NAME pre-treatment. Furthermore, the dose-dependent attenuating effect of morin was tested at doses of 50 and 100 mg/kg/day in high-salt diet-fed rats, and morin decreased blood pressure and significantly improved the relaxation response of the coronary arteries. Morin administration increased NO production in the coronary artery of high-salt diet-fed rats by activating TRPV4-eNOS signalling. In addition, oxidative stress levels were diminished by morin treatment in high-salt diet-fed rats. Western blot analyses confirmed that morin downregulated NOX2 expression. Thus, we demonstrate that morin induces endothelium-dependent relaxation in the rat coronary artery by activating TRPV4-eNOS-NO signalling, attenuates blood pressure, improves coronary artery vasodilation, and reduces coronary artery oxidative stress levels in individuals with high-salt diet-induced hypertension, highlighting the beneficial effect of morin in high-salt-induced coronary artery disease.

2025-08-01·AIDS

Fetoplacental arteriolar dysfunction in placentas of HIV-exposed, small for gestational age birthweight neonates

Article

作者: Michel, Katherine G. ; Scott, Rachel K. ; Wilcox, Christopher S. ; Wang, Dan ; Moriarty, Patricia ; Dalby, Sean ; Hanson, Tranessa ; Umans, Jason G.

Objective(s)::

Individuals with HIV are more likely to deliver small-for-gestational-age (SGA) neonates. We evaluated the associations between fetoplacental arteriolar function and HIV-exposure and SGA.

Design::

Case–control study of fetoplacental arteriolar function from placentas with/without HIV exposure and with/without SGA birthweight delivered between 36 and 41 weeks of gestation.

Methods::

Fetoplacental arterioles were harvested from the intervillous space of fresh placental specimens. We assessed arteriolar function by myograph. We measured dose-dependent contraction to U-46,619 (a thromboxane-prostanoid receptor agonist), endothelin (ET-1), as well as relaxation to AdipoRon (ApR, an adiponectin receptor agonist). ET-1-induced reactive oxygen species (ROS) were measured by DHE fluorescence and ApR-induced nitric oxide (NO) activity by DAF-FM fluorescence using a RatioMaster system. Comparisons across groups were determined using two-way ANOVA.

Results::

We analyzed specimens from 9 placentas of HIV-unexposed appropriate for gestational age (AGA)-birthweight neonates, 6 placentas of HIV-unexposed SGA neonates, 11 placentas of HIV-exposed AGA neonates, and 4 placentas of HIV-exposed SGA neonates. Contractions to ET-1 and U-46 619 were greater in placentas with HIV-exposure or of SGA neonates compared to AGA controls, and greatest in the setting of both HIV-exposure and SGA. Impaired arteriolar relaxation to ApR was associated with HIV-exposure, SGA, and combined HIV-exposure with SGA. Likewise, ApR-induced NO was decreased and ET-1-induced ROS was increased with HIV-exposure and SGA.

Conclusions::

Fetoplacental arteriolar relaxation was impaired and contraction was enhanced among placentas of HIV-exposed and SGA neonates.

100 项与 U-46619 相关的药物交易

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