Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
Pharmacol Rep. 2019 Jun;71(3):522-527. doi: 10.1016/j.pharep.2019.02.010. Epub 2019 Feb 19.
There is a definite association between antipsychotic drugs and arterial hypertension. However, endothelium functions are scarcely considered. This investigation was carried out to study the mechanisms involved in clozapine endothelium-dependent vascular reactivity.
The experimental animals were male Wistar rats with a mean age of 70-90 days (250-300 g). The endothelium-dependent vascular reactivity was studied by measuring the isometric force and then constructing clozapine concentration-response curves. The force registrations were obtained in the aorta rings with and without the endothelium precontracted with phenylephrine (PE10M) treatment; this followed incubation for 30 min in "organ chambers" with different inhibitors: l- NAME (nitric oxide/cGMP); indomethacin (PGI2/cAMP); tetraethylammonium (TEA), and specific hyperpolarization blockers (paxillin, apamin, glibenclamide). The data were presented as the mean ± standard error of the mean (SEM) and were compared by one-way ANOVA or two-way ANOVA followed by the Bonferroni post-test.
The primary outcomes were: 1) Clozapine-induced endothelium-dependent relaxation was not inhibited by indomethacin, l-NAME, ODQ, and methylene blue (MB); 2) The combination of l-NAME + indomethacin partially prevented the relaxation; 3) Clozapine did not induce relaxation in vessels contracted with KCl; 4) TEA did not block the clozapine-induced relaxation in vessels precontracted with PE (10 M); 5) The potassium channel blockers paxillin and apamin did not prevent relaxation but glibenclamide did.
Concerning the mechanisms involved in clozapine endothelium-dependent vascular reactivity, the present study suggests that there is synergistic participation that probably occurs through a crosstalk mechanism of the cAMP, cGMPpathways and hyperpolarization.
抗精神病药物与动脉高血压之间存在明确的关联。然而，很少考虑到内皮细胞功能。这项研究旨在研究氯氮平对内皮依赖性血管反应性的作用机制。
实验动物为雄性 Wistar 大鼠，平均年龄为 70-90 天（250-300g）。通过测量等长力，然后构建氯氮平浓度-反应曲线来研究内皮依赖性血管反应性。在预先用苯肾上腺素（PE10M）收缩的主动脉环中进行力记录；这是在不同抑制剂的“器官室”中孵育 30 分钟后进行的：l-NAME（一氧化氮/cGMP）；吲哚美辛（PGI2/cAMP）；四乙铵（TEA）和特定的超极化阻断剂（paxillin、apamin、格列本脲）。数据以平均值±标准误差（SEM）表示，并通过单向方差分析或双向方差分析，然后进行 Bonferroni 事后检验进行比较。
主要结果是：1）吲哚美辛、l-NAME、ODQ 和亚甲蓝（MB）不能抑制氯氮平诱导的内皮依赖性松弛；2）l-NAME+吲哚美辛联合部分预防了松弛；3）氯氮平不能诱导 KCl 收缩的血管松弛；4）TEA 不能阻断 PE（10M）预收缩血管中氯氮平诱导的松弛；5）钾通道阻断剂 paxillin 和 apamin 不能预防松弛，但格列本脲可以。
就氯氮平内皮依赖性血管反应性的作用机制而言，本研究表明存在协同作用，可能通过 cAMP、cGMP 途径和超极化的串扰机制发生。
