Departamento de Farmacología y Terapéutica, Universidad Autónoma de Madrid, Madrid, Spain; Instituto-Fundación Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain.
Departamento de Farmacología y Terapéutica, Universidad Autónoma de Madrid, Madrid, Spain.
Neuropharmacology. 2021 Sep 1;195:108632. doi: 10.1016/j.neuropharm.2021.108632. Epub 2021 Jun 4.
Cardiovascular side effects of varenicline and a case report of a hypertensive crisis in a varenicline-prescribed patient with pheochromocytoma have been reported. The goal of the present study was to determine whether such side effects might derive, in part, from increased exocytosis of secretory vesicles and subsequent catecholamine release triggered by varenicline in human chromaffin cells of the adrenal gland. In this study, we performed electrophysiological plasma membrane capacitance and carbon fiber amperometry experiments to evaluate the effect of varenicline on exocytosis and catecholamine release, respectively, at concentrations reached during varenicline therapy (100 nM). Experiments were conducted in the absence or presence of nicotine, at plasma concentrations achieved right after smoking (250 nM) or steady-state concentrations (110 nM), in chromaffin cells of the adrenal gland obtained from human organ donors. Cells were stimulated with short pulses (10 ms) of acetylcholine (ACh; 300 μM) applied at 0.2 Hz, in order to closer mimic the physiological situation at the splanchnic nerve-chromaffin cell synapse. In addition, rat chromaffin cells were used to compare the effects obtained in cells from a more readily available species. Varenicline increased the exocytosis of secretory vesicles in human and rat chromaffin cells in the presence of nicotine, effects that were not due to an increase of plasma membrane capacitance or currents triggered by the nicotinic agonists alone. These results should be considered in nicotine addiction therapies when varenicline is used.
已报道了伐伦克林的心血管副作用，以及在接受伐伦克林治疗的嗜铬细胞瘤患者中发生高血压危象的病例报告。本研究的目的是确定这些副作用是否部分源于伐伦克林在人肾上腺嗜铬细胞中引发的分泌囊泡的胞吐作用增加和随后的儿茶酚胺释放。在这项研究中，我们进行了电生理质膜电容和碳纤维安培计实验，以分别评估伐伦克林在 100 nM 治疗浓度下对胞吐作用和儿茶酚胺释放的影响。实验在无尼古丁或存在尼古丁、尼古丁在吸烟后即刻达到的血浆浓度（250 nM）或稳态浓度（110 nM）的情况下进行，在从人器官捐献者获得的肾上腺嗜铬细胞中进行。细胞用乙酰胆碱（ACh；300 μM）的短脉冲（10 ms）刺激，以 0.2 Hz 的频率施加，以更接近模拟内脏神经-嗜铬细胞突触的生理情况。此外，还使用大鼠嗜铬细胞来比较在更易于获得的物种的细胞中获得的效果。在尼古丁存在的情况下，伐伦克林增加了人源和大鼠源嗜铬细胞中分泌囊泡的胞吐作用，这些作用不是由于单独的烟碱激动剂引起的质膜电容或电流的增加所致。在使用伐伦克林进行尼古丁成瘾治疗时，应考虑这些结果。
