Department of Pharmacology and Toxicology, Michigan State University, MI, USA.
Department of Pharmacology and Toxicology, Michigan State University, MI, USA.
Pharmacol Res. 2019 Feb;140:43-49. doi: 10.1016/j.phrs.2018.08.024. Epub 2018 Sep 3.
Perivascular adipose tissue (PVAT) modulates vascular tone and altered PVAT function is observed in vascular diseases such as hypertension and atherosclerosis. We discovered that the PVAT surrounding rat thoracic aorta (RA) and the superior mesenteric artery (SMA) contain significant amounts of 5-hydroxytryptamine (5-HT). We hypothesized that the 5-HT contained within the PVAT is functional and vasoactive. Isolated tissue baths were used for isometric contractility studies and high performance liquid chromatography was used to quantitatively measure amines in the PVAT and release studies. The 5-HT releaser fenfluramine (10 nM-100 μM) was tested for its ability to contract arteries with and without PVAT. Contraction was reported as a percentage of the initial contraction to 10 μM phenylephrine. The RA with PVAT contracted to fenfluramine to a greater maximum (98 ± 10%) than RA without PVAT (24 ± 4%), while no difference in contraction of SMA to maximum fenfluramine with (78 ± 2%) and without (75 ± 6%) PVAT was observed. Contradicting our hypothesis, the maximum contraction of RA with PVAT to fenfluramine was diminished by the alpha-1 adrenoreceptor antagonist prazosin (100 nM; vehicle: 71 ± 4%, prazosin: 24 ± 2%) and the norepinephrine transporter (NET) inhibitor nisoxetine (1 μM; vehicle: 71 ± 4%, nisoxetine: 25 ± 4%) but not the 5-HT receptor antagonist ketanserin (10 nM) or serotonin specific reuptake inhibitor fluoxetine (10 μM). To test if fenfluramine caused release of 5-HT or NE from PVAT, PVAT from RA was incubated with vehicle or fenfluramine (10 μM-10 mM), and amines released into the incubating buffer were quantified. A pronounced concentration-dependent NE-release (more than 5-HT) was observed. Collectively, this research illustrates the pharmacology of fenfluramine to primarily stimulate NE release (better than 5-HT) in a NET-dependent manner, leading to vasoconstriction. This adds additional support to PVAT as being an important reservoir of amines.
血管周围脂肪组织 (PVAT) 调节血管张力，在高血压和动脉粥样硬化等血管疾病中观察到 PVAT 功能改变。我们发现，大鼠胸主动脉 (RA) 和肠系膜上动脉 (SMA) 周围的 PVAT 含有大量 5-羟色胺 (5-HT)。我们假设 PVAT 内的 5-HT 是有功能和血管活性的。使用等长收缩研究的离体组织浴和高效液相色谱法定量测量 PVAT 中的胺和释放研究。5-HT 释放剂芬氟拉明 (10 nM-100 μM) 用于测试其收缩有和无 PVAT 的动脉的能力。收缩以相对于 10 μM 苯肾上腺素的初始收缩的百分比报告。含有 PVAT 的 RA 对芬氟拉明的收缩达到更大的最大值 (98 ± 10%)，而不含 PVAT 的 RA 收缩达到 24 ± 4%，而 SMA 对最大芬氟拉明的收缩没有差异，无论是否存在 PVAT (78 ± 2% 和 75 ± 6%)。与我们的假设相反，含有 PVAT 的 RA 对芬氟拉明的最大收缩被 α-1 肾上腺素能受体拮抗剂哌唑嗪 (100 nM；载体：71 ± 4%，哌唑嗪：24 ± 2%) 和去甲肾上腺素转运蛋白 (NET) 抑制剂奈西汀 (1 μM；载体：71 ± 4%，奈西汀：25 ± 4%) 减弱，但 5-HT 受体拮抗剂酮色林 (10 nM) 或 5-羟色胺特异性再摄取抑制剂氟西汀 (10 μM) 没有减弱。为了测试芬氟拉明是否引起 PVAT 释放 5-HT 或 NE，将 RA 的 PVAT 与载体或芬氟拉明 (10 μM-10 mM) 孵育，并定量测量释放到孵育缓冲液中的胺。观察到明显的浓度依赖性 NE 释放 (超过 5-HT)。总的来说，这项研究说明了芬氟拉明的药理学，主要是以 NET 依赖性方式刺激 NE 释放 (优于 5-HT)，导致血管收缩。这为 PVAT 作为胺的重要储存库提供了更多支持。
