Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, ul. Mickiewicza 2A, 15-222 Białystok, Poland; Department of Clinical Pharmacy, Medical University of Białystok, ul. Mickiewicza 2A, 15-222 Białystok, Poland.
Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, ul. Mickiewicza 2A, 15-222 Białystok, Poland.
Life Sci. 2016 Apr 15;151:288-299. doi: 10.1016/j.lfs.2016.03.014. Epub 2016 Mar 9.
This study examined whether the fall in blood pressure (BP) induced by the chronic inhibition of fatty acid amide hydrolase (FAAH) by URB597 in deoxycorticosterone acetate (DOCA-salt) hypertensive rats correlates with endocannabinoid-mediated vascular changes.
Functional studies were performed in isolated endothelium-intact aortas and small mesenteric arteries (sMAs) using organ bath technique and wire myography, respectively.
In the DOCA-salt rats, methanandamide-stimulated relaxation was enhanced in sMAs or diminished in aortas. Its vasorelaxant effect in sMAs was sensitive to the antagonist of the Transient Receptor Potential Vanilloid type 1 (TRPV1), capsazepine, in normo- and hypertensive animals and to the antagonist of the cannabinoid CB1 receptors, AM6545, only in DOCA-salt rats. Cannabinoid CB1 receptors were up-regulated merely in DOCA-salt sMAs. URB597 decreased elevated BP in DOCA-salt rats, medial hypertrophy in DOCA-salt aortas. In sMAs it reduced FAAH expression and restored the augmented phenylephrine-induced contraction in the DOCA-salt rats to the level obtained in normotensive controls. In normotensive rats it diminished endothelium-dependent relaxation and increased phenylephrine-induced contraction.
The study showed the protective role of cannabinoid CB1 receptors in DOCA-salt sMAs. Reduction in BP after chronic administration of the FAAH inhibitor URB597 in DOCA-salt hypertensive rats only partially correlates with structural and functional changes in conductance and resistance vessels, respectively. Caution should be taken in studying cannabinoids and FAAH inhibitors as potential therapeutics, because of their vessel- and model-specific activities, and side effects connected with off-target response and activation of alternative pathways of anandamide metabolism.
本研究旨在探讨慢性抑制脂肪酸酰胺水解酶（FAAH）是否与内源性大麻素介导的血管变化有关。
采用器官浴技术和电生理记录仪，分别在分离的完整内皮主动脉和小肠系膜动脉（sMAs）中进行功能研究。
在 DOCA-盐大鼠中，甲酰胺刺激松弛在 sMAs 中增强，在主动脉中减弱。其在 sMAs 中的血管舒张作用对 Transient Receptor Potential Vanilloid type 1（TRPV1）拮抗剂辣椒素敏感，在正常和高血压动物中以及对大麻素 CB1 受体拮抗剂 AM6545 敏感，仅在 DOCA-盐大鼠中敏感。大麻素 CB1 受体仅在 DOCA-盐 sMAs 中上调。URB597 降低 DOCA-盐大鼠的血压，降低 DOCA-盐主动脉的中膜肥厚。在 sMAs 中，它降低 FAAH 表达，并将 DOCA-盐大鼠中增强的苯肾上腺素诱导收缩恢复至正常血压对照的水平。在正常血压大鼠中，它降低内皮依赖性松弛并增加苯肾上腺素诱导的收缩。
该研究表明大麻素 CB1 受体在 DOCA-盐 sMAs 中具有保护作用。慢性给予 FAAH 抑制剂 URB597 后，DOCA-盐高血压大鼠的血压降低与传导和阻力血管的结构和功能变化仅部分相关。在研究大麻素和 FAAH 抑制剂作为潜在治疗方法时，应谨慎行事，因为它们具有血管和模型特异性作用，以及与脱靶反应和内源性大麻素代谢替代途径激活相关的副作用。
