Protective role of cannabinoid CB₁ receptors and vascular effects of chronic administration of FAAH inhibitor URB597 in DOCA-salt hypertensive rats

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• 作者：Marta Baranowska-Kuczko^a ; ^b ; ^{mabar@umb.edu.pl" class="auth_mail" title="E-mail the corresponding author} ; Hanna Kozłowska^a ; Monika Kloza^a ; Olga Karpińska^a ; Marek Toczek^a ; Ewa Harasim^c ; Irena Kasacka^d ; Barbara Malinowska^a
• 关键词：Ach ; acetylcholine ; AEA ; anandamide ; BP ; blood pressure ; CRCs ; concentration-response curves ; DMF ; N ; N-Dimethylformamide ; DMSO ; dimethyl sulfoxide ; DOCA ; deoxycorticosterone acetate ; FAAH ; fatty acid amide hydrolase ; H  ; +  ; E ; hematoxylin and eosin ; i.p. ; intraperitoneal ; L-NAME ; NG-nitro-l-arginine methyl ester ; MethAEA ; methanandamide ; N.D. ; not determined ; RIPA ; radioimmunoprecipitation assay ; SBP ; systolic blood pressure ; s.c. ; subcutaneous ; SHR ; spontaneously hypertensive rats ; SNP
• 刊名：Life Sciences
• 出版年：2016
• 出版时间：15 April 2016
• 年：2016
• 卷：151
• 期：Complete
• 页码：288-299
• 全文大小：1673 K

文摘

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.

Main methods

Functional studies were performed in isolated endothelium-intact aortas and small mesenteric arteries (sMAs) using organ bath technique and wire myography, respectively.

Key findings

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.

Significance

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.