Vasorelaxant effects of benzodiazepines, non-benzodiazepine sedative-hypnotics, and tandospirone on isolated rat arteries

• Published in: European journal of pharmacology 2021-02, Vol.892, p.173744-173744, Article 173744
• Main Authors: Kagota, Satomi, Morikawa, Kana, Ishida, Hirotake, Chimoto, Junko, Maruyama-Fumoto, Kana, Yamada, Shizuo, Shinozuka, Kazumasa
• Format: Article
• Language: English
• Subjects: Animals; Aorta, Thoracic - drug effects; Aorta, Thoracic - physiopathology; Benzodiazepine; Benzodiazepines - toxicity; Blood pressure; Dose-Response Relationship, Drug; Hypnotics and Sedatives - toxicity; Hypotension, Orthostatic - chemically induced; Hypotension, Orthostatic - physiopathology; In Vitro Techniques; Isoindoles - toxicity; Male; Mesenteric Arteries - drug effects; Mesenteric Arteries - physiopathology; Nitric oxide; Non-benzodiazepine sedative-hypnotics; Piperazines - toxicity; Pyrimidines - toxicity; Rats; Rats, Wistar; Tandospirone; Vasodilation - drug effects; Vasorelaxation
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2020.173744

Benzodiazepines (BDZs) and non-BDZ sedative-hypnotics are effective for the management of chronic insomnia; however, they are associated with adverse effects such as headache, dizziness, and palpitations. Furthermore, long-term use of these medications is associated with decreased blood pressure (BP) or depressed baroreflex function. Therefore, here, we assessed whether BDZs and non-BDZs cause vasorelaxation directly. Vasorelaxation in response to 22 BDZs, 2 non-BDZs, and tandospirone was determined by myograph methods using isolated Wistar rat thoracic aortas. All the drugs relaxed phenylephrine-contracted rat aortas in a concentration-dependent manner. Zolpidem and tandospirone caused over 80% relaxation at a concentration of 10 μM; diazepam, estazolam, etizolam, and tofisopam caused 60–70% relaxation; whereas 18 other BDZs (alprazolam, bromazepam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, ethyl loflazepate, flunitrazepam, flurazepam, lorazepam, lormetazepam, midazolam, nimetazepam, nitrazepam, oxazepam, temazepam, and triazolam) and zaleplon caused less than 50% relaxation. The relaxation was partially but significantly inhibited to the same extent by a nitric oxide (NO) synthase antagonist and after endothelium removal. Binding assay of gamma-aminobutyric acid type A receptors was performed using [3H]flunitrazepam. No correlation was observed between vasorelaxation at a concentration of 10 μM and the binding affinities for 23 drugs. The study demonstrated that zaleplon, zolpidem, tandospirone, and many BDZs cause vasorelaxation to different extents via endothelial NO-dependent and endothelium-independent pathways. In conclusion, the direct vasodilatory effects of these drugs may be involved in the mechanisms underlying their adverse effects. Additionally, the decreased BP observed in persons who take BDZs or non-BDZs may be partly due to direct vasodilation. [Display omitted] •The use of sedative-hypnotics is often associated with palpitations and dizziness.•Long-time users of BDZs are at a high risk of developing orthostatic hypotension.•There are variations in the responses to BDZs, non-BDZs, and tandospirone.•Vasorelaxation was induced via endothelial-dependent and -independent pathways.•The side effects and orthostatic hypotension may have resulted from vasorelaxation.