Manrique-Maldonado Guadalupe, González-Hernández Abimael, Altamirano-Espinoza Alain H, Marichal-Cancino Bruno A, Ruiz-Salinas Inna, Villalón Carlos M
Departamento de Farmacobiología, Cinvestav-Coapa, Tlalpan, México D.F., México.
Basic Clin Pharmacol Toxicol. 2014 Feb;114(2):174-80. doi: 10.1111/bcpt.12122. Epub 2013 Sep 25.
Calcitonin gene-related peptide (CGRP) released from perivascular sensory nerves plays a role in the regulation of vascular tone. Indeed, electrical stimulation of the perivascular sensory out-flow in pithed rats produces vasodepressor responses, which are mainly mediated by CGRP release. This study investigated the potential role of dopamine D1 -like and D2 -like receptors in the inhibition of these vasodepressor responses. For this purpose, male Wistar pithed rats (pre-treated i.v. with 25 mg/kg gallamine and 2 mg/kg min. hexamethonium) received i.v. continuous infusions of methoxamine (20 μg/kg min.) followed by physiological saline (0.02 ml/min.), the D1 -like receptor agonist SKF-38393 (0.1-1 μg/kg min.) or the D2 -like receptor agonist quinpirole (0.03-10 μg/kg min.). Under these conditions, electrical stimulation (0.56-5.6 Hz; 50 V and 2 ms) of the thoracic spinal cord (T9 -T12 ) resulted in frequency-dependent vasodepressor responses which were (i) unchanged during the infusions of saline or SKF-38393 and (ii) inhibited during the infusions of quinpirole (except at 0.03 μg/kg min.). Moreover, the inhibition induced by 0.1 μg/kg min. quinpirole (which failed to inhibit the vasodepressor responses elicited by i.v. bolus injections of exogenous α-CGRP; 0.1-1 μg/kg) was (i) unaltered after i.v. treatment with 1 ml/kg of either saline or 5% ascorbic acid and (ii) abolished after 300 μg/kg (i.v.) of the D2 -like receptor antagonists haloperidol or raclopride. These doses of antagonists (enough to completely block D2 -like receptors) essentially failed to modify per se the electrically induced vasodepressor responses. In conclusion, our results suggest that quinpirole-induced inhibition of the vasodepressor sensory CGRPergic out-flow is mainly mediated by pre-junctional D2 -like receptors.
从血管周围感觉神经释放的降钙素基因相关肽（CGRP）在血管张力调节中发挥作用。实际上，对脊髓麻醉大鼠的血管周围感觉传出神经进行电刺激会产生血管减压反应，这主要由CGRP释放介导。本研究调查了多巴胺D1样和D2样受体在抑制这些血管减压反应中的潜在作用。为此，雄性Wistar脊髓麻醉大鼠（静脉注射25mg/kg加拉明和2mg/kg六甲铵预处理）静脉持续输注甲氧明（20μg/kg·min），随后输注生理盐水（0.02ml/min）、D1样受体激动剂SKF-38393（0.1 - 1μg/kg·min）或D2样受体激动剂喹吡罗（0.03 - 10μg/kg·min）。在这些条件下，对胸段脊髓（T9 - T12）进行电刺激（0.56 - 5.6Hz；50V和2ms）会导致频率依赖性血管减压反应，该反应在输注生理盐水或SKF-38393期间（i）无变化，而在输注喹吡罗期间（ii）受到抑制（0.03μg/kg·min除外）。此外，0.1μg/kg·min喹吡罗诱导的抑制作用（未能抑制静脉推注外源性α - CGRP；0.1 - 1μg/kg引起的血管减压反应）在静脉注射1ml/kg生理盐水或5%抗坏血酸后（i）未改变，而在300μg/kg（静脉注射）D2样受体拮抗剂氟哌啶醇或雷氯必利后（ii）被消除。这些拮抗剂剂量（足以完全阻断D2样受体）本身基本未能改变电诱导的血管减压反应。总之，我们的结果表明，喹吡罗诱导的对血管减压感觉CGRP能传出神经的抑制主要由突触前D2样受体介导。
