自发性高血压大鼠花生四烯酸乙醇胺膜转运体活性变化及氯沙坦对其影响
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摘要
大量研究表明降钙素基因相关肽(CGRP)水平降低是原发性高血压发生发展的重要因素。CGRP的合成与释放主要受辣椒素受体(VR1)调节。花生四烯酸乙醇胺(AEA)是VR1的内源性配体,其结合点位于细胞膜内侧,必须通过AEA膜转运体(AMT)转运至细胞内才能激活VR1。现已证明转运体途径是细胞外AEA进入细胞内的主要方式。因此,血浆中AEA水平及AMT活性可能是影响机体CGRP合成与释放的重要因素,AEA转运障碍可能是导致原发性高血压患者和自发性高血压大鼠(SHR)体内CGRP水平下降的重要原因。本实验以目前公认的与人类原发性高血压最接近的SHR为动物模型,氯沙坦为干预药物,检测SHR血浆AEA、CGRP浓度及背根神经节(DRG)中CGRP mRNA表达量；测定淋巴细胞AEA摄取率,以AEA摄取率反映AMT活性；检测血浆血管紧张素Ⅱ(AngⅡ)及过氧化氢(H202)水平。检测给予不同剂量氯沙坦干预后的SHR上述指标的变化,分析上述检测结果间的相关性及内在联系,从而探讨AMT活性改变在原发性高血压发生发展中的作用及氯沙坦对AMT活性的影响及其机制。
方法：分组：18周龄雄性自发性高血压大鼠(SHR)随机分为高血压组(SHR,n=12)；氯沙坦低剂量治疗组(15mg/kg/day,n=12)：氯沙坦高剂量治疗组(30mg/kg/day,n=12)；另设一组周龄、性别相匹配的Wistar-Kyoto大鼠作为非高血压对照组(WKY,n=12)。氯沙坦低剂量治疗组以氯沙坦15mg/kg/day灌胃一次；氯沙坦高剂量治疗组以氯沙坦30mg/kg/day灌胃一次；SHR组及WKY组每天以等量蒸馏水灌胃一次,连续2周。实验过程使用尾动脉测压法监测大鼠收缩压变化。2周后,颈动脉取血,分离血浆检测AEA、CGRP、AngⅡ及H202水平,分离淋巴细胞测定淋巴细胞AEA摄取率,取DRG测定CGRP mRNA表达。
结果：
(1)实验初,各组SHR血压显著高于WKY组大鼠(P<0.01)。经连续2周氯沙坦治疗后,氯沙坦治疗组较SHR对照组血压显著下降(P<0.01),其中氯沙坦高剂量组较低剂量组降压效应更为明显。
(2)与WKY组大鼠相比SHR组大鼠血浆AEA水平显著升高(P<0.01),CGRP水平显著降低(P<0.01),DRG中α-CGRP mRNA及β-CGRP mRNA表达量显著降低(P<0.01)。氯沙坦治疗组与SHR组相比较血浆AEA水平降低,血浆CGRP水平升高,其中氯沙坦高剂量治疗组血浆AEA水平显著降低(P<0.05),CGRP水平显著升高(P<0.05)。SHR组大鼠DRG中α-CGRP mRNA及β-CGRP mRNA表达均显著低于WKY组(P<0.01)；氯沙坦治疗组大鼠DRG中α-CGRP mRNA及β-CGRP mRNA表达较SHR组大鼠升高,其中氯沙坦高剂量治疗组显著显著升高(P<0.05)。
(3)SHR组大鼠淋巴细胞AMT活性较WKY组大鼠显著降低(P<0.01)；氯沙坦治疗后治疗组大鼠淋巴细胞AMT活性升高,其中氯沙坦高剂量治疗组与SHR组相比淋巴细胞AMT活性显著升高(P<0.01)。
(4)与WKY组大鼠相比SHR组大鼠血浆AngⅡ水平及H202水平均显著升高(P<0.01)；氯沙坦治疗组大鼠血浆AngⅡ水平较SHR组升高(P<0.05),血浆H2O2水平低于SHR组,其中氯沙坦高剂量治疗组血浆H2O2水平显著降低(P<0.05)。
结论：
(1)在SHR,AMT活性降低可能是CGRP合成与释放减少的重要原因。
(2)AMT活性降低可能与AngⅡ诱导的氧化应激有关。
(3)氯沙坦可使AMT活性升高,CGRP合成释放增加,其机制可能与抑制氧化应激有关。
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.
方法：分组：18周龄雄性自发性高血压大鼠(SHR)随机分为高血压组(SHR,n=12)；氯沙坦低剂量治疗组(15mg/kg/day,n=12)：氯沙坦高剂量治疗组(30mg/kg/day,n=12)；另设一组周龄、性别相匹配的Wistar-Kyoto大鼠作为非高血压对照组(WKY,n=12)。氯沙坦低剂量治疗组以氯沙坦15mg/kg/day灌胃一次；氯沙坦高剂量治疗组以氯沙坦30mg/kg/day灌胃一次；SHR组及WKY组每天以等量蒸馏水灌胃一次,连续2周。实验过程使用尾动脉测压法监测大鼠收缩压变化。2周后,颈动脉取血,分离血浆检测AEA、CGRP、AngⅡ及H202水平,分离淋巴细胞测定淋巴细胞AEA摄取率,取DRG测定CGRP mRNA表达。
结果：
(1)实验初,各组SHR血压显著高于WKY组大鼠(P<0.01)。经连续2周氯沙坦治疗后,氯沙坦治疗组较SHR对照组血压显著下降(P<0.01),其中氯沙坦高剂量组较低剂量组降压效应更为明显。
(2)与WKY组大鼠相比SHR组大鼠血浆AEA水平显著升高(P<0.01),CGRP水平显著降低(P<0.01),DRG中α-CGRP mRNA及β-CGRP mRNA表达量显著降低(P<0.01)。氯沙坦治疗组与SHR组相比较血浆AEA水平降低,血浆CGRP水平升高,其中氯沙坦高剂量治疗组血浆AEA水平显著降低(P<0.05),CGRP水平显著升高(P<0.05)。SHR组大鼠DRG中α-CGRP mRNA及β-CGRP mRNA表达均显著低于WKY组(P<0.01)；氯沙坦治疗组大鼠DRG中α-CGRP mRNA及β-CGRP mRNA表达较SHR组大鼠升高,其中氯沙坦高剂量治疗组显著显著升高(P<0.05)。
(3)SHR组大鼠淋巴细胞AMT活性较WKY组大鼠显著降低(P<0.01)；氯沙坦治疗后治疗组大鼠淋巴细胞AMT活性升高,其中氯沙坦高剂量治疗组与SHR组相比淋巴细胞AMT活性显著升高(P<0.01)。
(4)与WKY组大鼠相比SHR组大鼠血浆AngⅡ水平及H202水平均显著升高(P<0.01)；氯沙坦治疗组大鼠血浆AngⅡ水平较SHR组升高(P<0.05),血浆H2O2水平低于SHR组,其中氯沙坦高剂量治疗组血浆H2O2水平显著降低(P<0.05)。
结论：
(1)在SHR,AMT活性降低可能是CGRP合成与释放减少的重要原因。
(2)AMT活性降低可能与AngⅡ诱导的氧化应激有关。
(3)氯沙坦可使AMT活性升高,CGRP合成释放增加,其机制可能与抑制氧化应激有关。
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.
引文
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[30]Ford WR, Honan SA White R et al. Evidence of a novel site mediating anandamide-induced negativen inotropic and coronary vasodilatator responses in rat isolated hearts. Bri J Pharmacol,2002,135:1191-1198.
[31]Wagner JA, Abesser M, Karcher J, et al. Coronary vasodilator effects of endogenous cannabinoids in vasop resin-preconstructed unpaced rat isolated hearts. J Cardiovasc Pharmacol,2005,46 (3):348-355.
[32]Bonz A, LaserM, Kullmer S, et al. Cannabinoids acting on CB1 receptors decrease contractile performance in human atrial muscle. J Cardiovasc Pharmacol,2003,41 (4):57-64.
[33]Sterin-Borda L, Del Zar CF, Borda E. Differential CB1 and CB2 cannabinoid receptor-inotropic response of rat isolated atria:endogenous signal transduction pathways. Biochem Pharmacol,2005,69:1705-1713.
[34]Underdown NJ, Hiley CR, Ford WR. Anandamide reduces infarct size in rat isolated hearts subjected to ischaemia reperfusion by a novel cannabinoid mechanism. Br J Pharmacol,2005,146:809-816
[35]Krylatov AV, Uzhachenko RV, Maslov LN, et al. Anandamide and R-(+)-methanandamide prevent development of ischemic and reperfusion arrhythmia in rats by stimulation of CB2-receptors. Eksp Klin Farmakol,2002, 65:6-9.
[36]Batkai S, Pacher P, Osei-Hyiaman D, et al. Endoeannabinoids acting at CB1 receptors regulate cardiovascular function in hypertension. Circulation,2004, 110(14):1996-2002.
[37]Akerman S, Kaube H, Goadsby PJ. Anandamide acts as a vasodilator of dural blood vessels in vivo by activating TRPV1 receptors. Br J Pharmacol.2004; 142:1354-1360.
[38]Wang Y, Kaminski NE, Wang DH. Endocannabinoid regulates blood pressure via activation of the transient receptor potential vanilloid type 1 in Wistar rats fed a high-salt diet.J Pharmacol Exp Ther,2007,321 (2):763-769.
[39]Li J, Kaminski NE, Wang DH. Anandamide-induced depressor effect in spontaneously hypertensive rats:role of the vanilloid receptor. Hypertension, 2003,41 (Pt 2):757-762.
[40]Wang Y, Kaminski NE, Wang DH. VR1-mediated depressor effects during high-salt intake:role of anandamide. Hypertension,2005,46 (4):986-991.
[41]Steffens S, Veillard NR, Amaud C, et al. Low dose oral cannabinoid therapy reduces progression of athewseleresis in mice. Nature,2005,434:782-786.
[42]Rajesh M,Mukhopadllyay P, Hask6 G, et al. CB2 cannabinoid receptor agunists attenuate TNF·alpha-induced human vB-scular smooth muscle cell proliferation and migration. Br J Pharmacol,2008,153(2):347-357.
[43]Wagner JA, Hu K, Bauer'sachs J, et al. Endogenous eannabinoids mediate hypertcnsion after experimental myocardial infarction. J Am co Ⅱ Cardiol,2001, 38:2048-2054.
[44]Batkai S. Rajesh M, Mukhopadhyay P, et al. Decreased age-related cardiac dysfunction, myocardial nitrative stress, inflammatory gene expression, and apeptosis in mice lacking fatty acid amide hydrolaso. Am J Physiol Heart Cire Physiol。2007,293:H909-H918.
[45]Dol-Gleizes F. Paumelle R. Visontin V, et al. Rimonabant. a selective cannabinoid CB1 receptor antagonist.inhibits atheresclerosis in LDL receptor-deficient mice. Arteriescler Thromb Vase. Biol.2009.29:12-18.
[46]Motobe T, Hashiguchi T, Uchimura T, et al.Endogenous cannabinoids are candidates for lipid mediators of bone cement implantation syndrome. Shock 2004;21:8-12.
[47]Mukhopadhyay P, Batkai S, Rajesh M, et al. Pharmacological inhibition of CB1 cannabinoid receptor protects against doxorubicin-induced cardiotoxicity. J Am Coll Cardiol 2007;50:528-536.
[48]Batkai S, Mukhopadhyay P, Harvey-White J, et al. Endocannabinoidsacting at CB1 receptors mediate the cardiac contractile dysfunction in vivo in cirrhotic rats. Am J Physiol 2007;293:H1689-1695.
[49]Batkai S, Rajesh M, Mukhopadhyay P, et al. Decreased age-related cardiac dysfunction, myocardial nitrative stress, inflammatory gene expression, and apoptosis in mice lacking fatty acid amide hydrolase. Am J Physiol 2007;293:H909-918.
[50]Pacher P, Batkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy.Pharmacol Rev 2006;58:389-462.
[51]Wagner JA, Hu K, Karcher J, et al. CB1 cannabinoid receptor antagonism promotes remodeling and cannabinoid treatment prevents endothelial dysfunction and hypotension in rats with myocardial infarction. Br J Pharmacol 2003;138:1251-1258.
[52]Athanasiou A, Clarke AB, Turner AE, et al. Cannabinoid receptor agonists are mitochondrial inhibitors:a unified hypothesis of how cannabinoids modulate mitochondrial function and induce cell death. Biochem Biophys Res Commun 2007;364:131-137.
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