Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA.
Department of Medicine - Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA.
Br J Pharmacol. 2021 Feb;178(3):709-725. doi: 10.1111/bph.15324. Epub 2020 Dec 27.
The TRPV cation channels have emerged as important regulators of vascular tone. TRPV1 channels and endothelin-1 are independently associated with the pathophysiology of coronary vasospasm, but the relationship between their vasomotor functions remains unclear. We characterized the vasomotor function of TRPV1 channels in human arterioles and investigated regulation of their vasomotor function by endothelin-1.
Human arterioles (mainly from adipose tissue) were threaded on two metal wires, equilibrated in a physiological buffer at 37°C and exposed to increasing concentrations of capsaicin, with or without SB366791 (TRPV1-selective inhibitor) or GF109203X (PKC-selective inhibitor). Some arterioles were pre-constricted with endothelin-1 or phenylephrine or high potassium buffer. TRPV1 mRNA and protein expression in human arteries were also assessed.
TRPV1 transcripts and proteins were detected in human resistance arteries. Capsaicin (1 μM) induced concentration-dependent constriction of endothelium-intact and endothelium-denuded human adipose arterioles (HAA), which was significantly inhibited by SB366791. Pre-constriction of HAA with endothelin-1, but not high potassium buffer or phenylephrine, significantly potentiated capsaicin (0.1 μM)-induced constriction. GF109203X significantly inhibited potentiation of capsaicin-induced constriction by endothelin-1.
TRPV1 channels are expressed in the human vasculature and affect vascular tone of human arterioles on activation. Their vasomotor function is modulated by endothelin-1, mediated in part by PKC. These findings reveal a novel interplay between endothelin-1 signalling and TRPV1 channels in human VSMC, adding to our understanding of the ion channel mechanisms that regulate human arteriolar tone and may also contribute to the pathophysiology of coronary vasospasm.
瞬时受体电位香草醛型 1（TRPV1）阳离子通道已成为血管张力的重要调节因子。TRPV1 通道和内皮素-1 与冠状动脉痉挛的病理生理学独立相关，但它们的血管运动功能之间的关系尚不清楚。我们对人小动脉中 TRPV1 通道的血管运动功能进行了特征描述，并研究了内皮素-1 对其血管运动功能的调节。
将人小动脉（主要来自脂肪组织）穿在两根金属丝上，在 37°C 的生理缓冲液中平衡，并暴露于逐渐增加浓度的辣椒素，同时或不使用 SB366791（TRPV1 选择性抑制剂）或 GF109203X（PKC 选择性抑制剂）。一些小动脉用内皮素-1、苯肾上腺素或高钾缓冲液预先收缩。还评估了人动脉中 TRPV1 mRNA 和蛋白的表达。
在人阻力血管中检测到 TRPV1 转录本和蛋白。辣椒素（1 μM）诱导内皮完整和去内皮的人脂肪小动脉（HAA）浓度依赖性收缩，这可被 SB366791 显著抑制。内皮素-1 预收缩 HAA 可显著增强辣椒素（0.1 μM）诱导的收缩，而高钾缓冲液或苯肾上腺素预收缩则不能增强。GF109203X 可显著抑制内皮素-1 对辣椒素诱导收缩的增强作用。
TRPV1 通道在人血管系统中表达，并在激活后影响人小动脉的血管张力。它们的血管运动功能受内皮素-1 的调节，部分由 PKC 介导。这些发现揭示了内皮素-1 信号与 TRPV1 通道在人血管平滑肌细胞中的新相互作用，增加了我们对调节人小动脉张力的离子通道机制的理解，也可能有助于冠状动脉痉挛的病理生理学。
