| A large number of studies have shown that the decreased level of calcitonin gene-related peptide (CGRP) is thought as one of the main factors involved in the occurrence and development of hypertension. It has been shown that the synthesis and release of CGRP is regulated by vanilloid receptor subtype 1(VR1). Anandamide (AEA) is an endogenous ligand of VR1. Recent studies demonstrated that VR1 is located in superficies interna of membrane, so its specific ligands (such as AEA) need to across membrane before binding to it. The AEA uptake is mediated by the so-called AEA transporter (AMT) which is across the membrane and is the major channel for AEA uptake. Therefore, the plasma level of AEA and the activity of AEA transporter are the two key factors which determine the efficiency of AEA uptake, and in turn to regulate the synthesis and release of CGRP via VR1. We speculate that the decrease in plasma levels of CGRP in essential hypertension patients and SHR is likely due to the reduced activity of AEA transporter. In this experiment, spontaneously hypertensive rats (SHR) were selected as animal model and losartan as intervention drugs. The AEA, CGRP levels in plasma and CGRP mRNA expression in dorsal root ganglia (DRG) were measured. We measured the AngⅡ, H2O2 levels in plasma and AEA transporter activity to determine whether oxidative stress plays a role in the AMT dysfunction.Methods:18 weeks male spontaneous hypertensive rats (SHR), were randomly assigned into three groups:SHR group(SHR, n=12), low-dose losartan treated group (15mg/kg/day, n=12) and high-dose losartan treated group (30mg/kg/day, n= 12). Another 12 Wistar-Kyoto rats (WKY)were served as normal control group(WKY, n=12). The low-dose losartan treated group and high-dose losartan treated group was received 15mg/kg losartan and 30mg/kg losartan dissolved in distilled water daily through gastric tube for 2 weeks respectively, and the SHR and WKY groups received distilled water alone. Systolic blood pressure (SBP) was monitored by the tail-cuff method. At the end point of the 2-week intervention, the animals were sacrificed and blood samples were collected from carotid artery. AEA concentrations and CGRP, AngⅡ, H2O2 levels in plasma were measured. The AEA uptake rate in lymphocytes and the expression of CGRP mRNA in DRG were also measured.Results:(1) At the beginning of experiment, SBP of the SHR was significantly higher than WKY(P<0.01). Treatment losartan for 2 weeks could reduce SBP significantly with dose-dependently.(2) Compared with the WKY group, the plasma AEA level was significantly increased(P<0.01), whereas the CGRP levels was significantly decreased in SHR(P< 0.01), accompanied by reduced expression ofα-CGRP mRNA andβ-CGRP mRNA in DRG(P< 0.01). The AEA level was significantly decreased(P<0.05),while the CGRP levels was increased(P<0.05)and the expression ofα-CGRP mRNA andβ-CGRP mRNA in DRG were higher(P<0.05)in the high-dose losartan treatment groups compared with the SHR group.(3) The activity of AEA transporter in lymphocytes of the SHR was significantly decreased compared with the WKY(P<0.01). The activity of AEA transporter in lymphocytes from high-dose losartan treatment groups SHR was significantly increased compared with the SHR group(P <0.01).(4) The AngⅡand H2O2 levels in plasma of the SHR was significantly higher compared with the WKY(P< 0.01). The AngⅡlevel was elevated(P< 0.05)in the losartan treatment groups compared with the SHR group. The H2O2 level was decreased in the high-dose losartan treated SHR compared with the SHR (P< 0.05).Conclusions:(1) The decrease in plasma levels of CGRP in SHR is likely due to the reduced activity of AMT.(2) The reduced activity of AMT may be related to oxidative stress induced by AngⅡ.(3) Losartan can increase AMT activity and then increases the synthesis and release of CGRP. The mechanism may be related to inhibiting oxidative stress. |
PDF Full Text Request