2ME抑制高血压和Up4A诱导胃平滑肌收缩的机制
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摘要
第一部分雌激素代谢产物2-甲氧雌二醇治疗DOCA-盐大鼠高血压
目的：使用低雌激素受体亲和性的雌激素代谢产物治疗高血压,具有降低女性化等副作用的优势。2-甲氧雌二醇(2MEthoxyestradiol,2ME))最早发现于妊娠妇女的尿液中,是雌二醇在细胞色素P450及儿茶酚-O-甲基转移酶等作用下,先羟基化再甲基化形成的一种主要代谢产物。我们先前的研究表明,2ME可以通过内皮依赖机制抑制血管平滑肌增殖和血管收缩。本研究的目的是探讨2ME是否可以治疗大鼠高血压。
方法：利用单侧肾摘除和注射醋酸脱氧皮质酮,辅以高盐饮食的方法获得高血压大鼠模型—DOCA-盐大鼠。利用tail cuff方法实时监测2ME对DOCA-盐大鼠收缩压变化的影响(在血压升高前注射或在血压升高过程中注射)。使用Power Lab系统测量DOCA-盐大鼠的平均动脉压,并检测2ME对其急性降血压的作用。利用儿茶酚-O-甲基转移酶抑制剂恩他卡朋处理DOCA-盐大鼠,实时监测DOCA-盐大鼠收缩压变化并检测其平均动脉压。
结果：我们的结果显示,用DOCA处理大鼠,可使其收缩压在3-10周明显上升。而用DOCA和2ME(100-300μg/kg)共同处理大鼠,可阻止大鼠血压上升。2ME处理十周后利用Power Lab Data Acquisition System测得的假手术对照组大鼠平均动脉压为84±16mmHg,DOCA-盐大鼠的平均动脉压为150±9mmHg。使用低剂量或高剂量2ME处理的大鼠,其血压接近假手术对照组。同时使用恩他卡朋抑制内源性2ME生成,并不能明显影响各组大鼠的血压。
结论：2ME处理可以阻止DOCA-盐大鼠血压升高,显示了2ME在高血压治疗方面的潜在能力。
第二部分Up4A引起大鼠胃平滑肌收缩的机理
目的：细胞外核苷ATP和UTP可以诱导胃平滑肌收缩,最近发现尿苷腺苷四磷酸盐(Up4A),是一种可以诱导血管平滑肌收缩的内皮衍生的收缩因子,但它对胃平滑肌是否具有收缩能力尚未可知。我们假设Up4A通过不同机制在胃纵行平滑肌(LM)和胃环行平滑肌(CM)中引发收缩反应。为此检测P2X和P2Y受体拮抗剂,P2X受体激活剂,Rho激酶抑制剂以及环氧合酶抑制齐(IP5I,Suramin, α,β-Me-ATP,Y-27632和吲哚美辛)对Up4A在LM和CM中引发的收缩反应的影响。
方法：获取大鼠全胃,分离LM和CM,使用organ bath系统测量平滑肌收缩。利用50mM KCl作为收缩基准,使用Up4A产生收缩,再分别使用钙离子通道拮抗剂尼莫地平,IP5I, Suramin,α,β-Me-ATP,Y-27632和吲哚美辛孵育,检测这些药物对Up4A在LM和CM中的收缩是否具有不同的影响。
合成P2X和P2Y引物,使用RT-PCR检测P2X受体和P2Y受体在大鼠胃平滑肌中的表达状况。
结果：Up4A可以在LM和CM中引起与ATP和UTP类似的收缩；Up4A对LM和CM的收缩需钙离子通道参与,使用尼莫地平孵育,不能使Up4A诱发LM和CM收缩,IP5I和α,β-Me-ATP对LM和CM中由Up4A引起的收缩并无影响,α,β-Me-ATP本身也不能引起大鼠胃平滑肌收缩；但Y-27632,Suramin和吲哚美辛则能在CM中显著抑制由Up4A引起的收缩,而LM中无此现象。RT-PCR结果显示,P2X1,2,4,5,7以及P2Y1,2,4,6在大鼠胃平滑肌中均有表达。
结论：Up4A通过细胞外Ca2+可以引发大鼠胃LM和CM的收缩。Up4A在CM中引发的收缩是由suramin敏感的P2Y受体和Rho激酶途径激活介导的。
Part-Ⅰ Estrogen Metabolite2Methoxyestradiol Prevents Hypertension in Deoxycorticosterone Acetate-salt Rats
Purpose:Our early work showed that the estrogen metabolite2Methoxyestradiol (2ME) inhibits proliferation of vascular smooth muscle cells (SMCs) and vascular contractility through an endothelium-dependent mechanism. The aim of this study was to examine whether2ME prevents the development of hypertension in rats.
Methods:A hypertensive model was established in uninephrectomized rats using deoxycorticosterone acetate (DOCA)-salt. Blood pressure in response to2ME (treatment up to10weeks or single bolus) was monitored.
Results:Our results showed that systolic blood pressure, as measured by tail-cuff plethysmography, was significantly increased in conscious rats treated with DOCA-salt for3-10weeks. Co-treatment with2ME (100-300μg/kg), but not dimethyl sulfoxide (DMSO), completely prevented the increase in blood pressure of DOCA-salt rats. After10-week treatment, the mean arterial blood pressure (MABP) of anesthetized rats measured using Power Lab Data Acquisition System was:84±16mmHg in normotensive control rats and150±9mmHg in DOCA-salt rats, which was similar to that of DMSO-treated rats. Treatment with2ME at low or high doses reduced MABP of DOCA-salt rats close to that of control normotensive rats. In addition, MABP of hypertensive DOCA-salt rats was significantly reduced inresponse to a single injection of2ME. Delayed administration of2ME reduced the further increase of blood pressure in DOCA-salt rats. However, inhibition of2ME production by entacapone did not significantly affect blood pressure in either control or DOCA-salt rats.
Conclusions:2ME treatment prevents the development of hypertension in DOCA-salt rats, implicating a therapeutic potential of2ME in hypertension treatment.
Part-II The Mechanism of Uridine Adenosine Tetraphosphate Induces Contraction of Circular and Longitudinal Gastric Smooth Muscle
Purpose:Extracellular nucleotides uridine-50-triphosphate (UTP) andadenosine triphosphate (ATP) induce contraction of gastricsmooth muscle (SM). The dinucleotide uridine adenosine tetraphosphate(Up4A), an endothelium-derived contraction factor, induces vascular SM contraction. Its effect on gastric SM contractions, however, is unknown. We addressed the hypothesis that Up4A induces gastric SM contraction via a mechanism that may differ between circular and longitudinal muscle(CM and LM, respectively).
Methods:CM and LM were isolated from rat gastric fundus for the measurement of isometric tension.Up4A induced transient contractile responses in both CM and LM, which were similar to those induced by ATP and UTP.
Results:Up4A failed to induce contraction of either LM or CM in the absence of extracellular Ca2+or in the presence of nimodipine,an inhibitor of voltage-gated Ca2+channels. P2X1,2,4,5and7and P2Y1,2,4and6receptor expression was detected in gastric SM by reverse transcription-polymerase chain reaction.IP5I (a P2X receptor antagonist) anda,p-methylene-ATP(a P2X receptor agonist) had no effect on Up4A-induced contractions of either LM or CM, and α,β-methylene-ATP alone failed to induce a contractile response in either tissue. Suramin(a P2Y receptor antagonist), on the other hand, significantly inhibited Up4A-induced contraction of CM, but not LM.Up4A-induced contraction of CM, but not LM, was also inhibited by pretreatment with Y-27632, an inhibitor of Rho-associated kinase.
ConcIusions:We conclude that Up4A induces extracellular Ca2+-dependent contractions of rat gastric LM and CM, and Up4A-induced contraction of CM is mediated by suramin-sensitive P2Y receptors and subsequent activation of the Rho associated kinase pathway.
目的：使用低雌激素受体亲和性的雌激素代谢产物治疗高血压,具有降低女性化等副作用的优势。2-甲氧雌二醇(2MEthoxyestradiol,2ME))最早发现于妊娠妇女的尿液中,是雌二醇在细胞色素P450及儿茶酚-O-甲基转移酶等作用下,先羟基化再甲基化形成的一种主要代谢产物。我们先前的研究表明,2ME可以通过内皮依赖机制抑制血管平滑肌增殖和血管收缩。本研究的目的是探讨2ME是否可以治疗大鼠高血压。
方法：利用单侧肾摘除和注射醋酸脱氧皮质酮,辅以高盐饮食的方法获得高血压大鼠模型—DOCA-盐大鼠。利用tail cuff方法实时监测2ME对DOCA-盐大鼠收缩压变化的影响(在血压升高前注射或在血压升高过程中注射)。使用Power Lab系统测量DOCA-盐大鼠的平均动脉压,并检测2ME对其急性降血压的作用。利用儿茶酚-O-甲基转移酶抑制剂恩他卡朋处理DOCA-盐大鼠,实时监测DOCA-盐大鼠收缩压变化并检测其平均动脉压。
结果：我们的结果显示,用DOCA处理大鼠,可使其收缩压在3-10周明显上升。而用DOCA和2ME(100-300μg/kg)共同处理大鼠,可阻止大鼠血压上升。2ME处理十周后利用Power Lab Data Acquisition System测得的假手术对照组大鼠平均动脉压为84±16mmHg,DOCA-盐大鼠的平均动脉压为150±9mmHg。使用低剂量或高剂量2ME处理的大鼠,其血压接近假手术对照组。同时使用恩他卡朋抑制内源性2ME生成,并不能明显影响各组大鼠的血压。
结论：2ME处理可以阻止DOCA-盐大鼠血压升高,显示了2ME在高血压治疗方面的潜在能力。
第二部分Up4A引起大鼠胃平滑肌收缩的机理
目的：细胞外核苷ATP和UTP可以诱导胃平滑肌收缩,最近发现尿苷腺苷四磷酸盐(Up4A),是一种可以诱导血管平滑肌收缩的内皮衍生的收缩因子,但它对胃平滑肌是否具有收缩能力尚未可知。我们假设Up4A通过不同机制在胃纵行平滑肌(LM)和胃环行平滑肌(CM)中引发收缩反应。为此检测P2X和P2Y受体拮抗剂,P2X受体激活剂,Rho激酶抑制剂以及环氧合酶抑制齐(IP5I,Suramin, α,β-Me-ATP,Y-27632和吲哚美辛)对Up4A在LM和CM中引发的收缩反应的影响。
方法：获取大鼠全胃,分离LM和CM,使用organ bath系统测量平滑肌收缩。利用50mM KCl作为收缩基准,使用Up4A产生收缩,再分别使用钙离子通道拮抗剂尼莫地平,IP5I, Suramin,α,β-Me-ATP,Y-27632和吲哚美辛孵育,检测这些药物对Up4A在LM和CM中的收缩是否具有不同的影响。
合成P2X和P2Y引物,使用RT-PCR检测P2X受体和P2Y受体在大鼠胃平滑肌中的表达状况。
结果：Up4A可以在LM和CM中引起与ATP和UTP类似的收缩；Up4A对LM和CM的收缩需钙离子通道参与,使用尼莫地平孵育,不能使Up4A诱发LM和CM收缩,IP5I和α,β-Me-ATP对LM和CM中由Up4A引起的收缩并无影响,α,β-Me-ATP本身也不能引起大鼠胃平滑肌收缩；但Y-27632,Suramin和吲哚美辛则能在CM中显著抑制由Up4A引起的收缩,而LM中无此现象。RT-PCR结果显示,P2X1,2,4,5,7以及P2Y1,2,4,6在大鼠胃平滑肌中均有表达。
结论：Up4A通过细胞外Ca2+可以引发大鼠胃LM和CM的收缩。Up4A在CM中引发的收缩是由suramin敏感的P2Y受体和Rho激酶途径激活介导的。
Part-Ⅰ Estrogen Metabolite2Methoxyestradiol Prevents Hypertension in Deoxycorticosterone Acetate-salt Rats
Purpose:Our early work showed that the estrogen metabolite2Methoxyestradiol (2ME) inhibits proliferation of vascular smooth muscle cells (SMCs) and vascular contractility through an endothelium-dependent mechanism. The aim of this study was to examine whether2ME prevents the development of hypertension in rats.
Methods:A hypertensive model was established in uninephrectomized rats using deoxycorticosterone acetate (DOCA)-salt. Blood pressure in response to2ME (treatment up to10weeks or single bolus) was monitored.
Results:Our results showed that systolic blood pressure, as measured by tail-cuff plethysmography, was significantly increased in conscious rats treated with DOCA-salt for3-10weeks. Co-treatment with2ME (100-300μg/kg), but not dimethyl sulfoxide (DMSO), completely prevented the increase in blood pressure of DOCA-salt rats. After10-week treatment, the mean arterial blood pressure (MABP) of anesthetized rats measured using Power Lab Data Acquisition System was:84±16mmHg in normotensive control rats and150±9mmHg in DOCA-salt rats, which was similar to that of DMSO-treated rats. Treatment with2ME at low or high doses reduced MABP of DOCA-salt rats close to that of control normotensive rats. In addition, MABP of hypertensive DOCA-salt rats was significantly reduced inresponse to a single injection of2ME. Delayed administration of2ME reduced the further increase of blood pressure in DOCA-salt rats. However, inhibition of2ME production by entacapone did not significantly affect blood pressure in either control or DOCA-salt rats.
Conclusions:2ME treatment prevents the development of hypertension in DOCA-salt rats, implicating a therapeutic potential of2ME in hypertension treatment.
Part-II The Mechanism of Uridine Adenosine Tetraphosphate Induces Contraction of Circular and Longitudinal Gastric Smooth Muscle
Purpose:Extracellular nucleotides uridine-50-triphosphate (UTP) andadenosine triphosphate (ATP) induce contraction of gastricsmooth muscle (SM). The dinucleotide uridine adenosine tetraphosphate(Up4A), an endothelium-derived contraction factor, induces vascular SM contraction. Its effect on gastric SM contractions, however, is unknown. We addressed the hypothesis that Up4A induces gastric SM contraction via a mechanism that may differ between circular and longitudinal muscle(CM and LM, respectively).
Methods:CM and LM were isolated from rat gastric fundus for the measurement of isometric tension.Up4A induced transient contractile responses in both CM and LM, which were similar to those induced by ATP and UTP.
Results:Up4A failed to induce contraction of either LM or CM in the absence of extracellular Ca2+or in the presence of nimodipine,an inhibitor of voltage-gated Ca2+channels. P2X1,2,4,5and7and P2Y1,2,4and6receptor expression was detected in gastric SM by reverse transcription-polymerase chain reaction.IP5I (a P2X receptor antagonist) anda,p-methylene-ATP(a P2X receptor agonist) had no effect on Up4A-induced contractions of either LM or CM, and α,β-methylene-ATP alone failed to induce a contractile response in either tissue. Suramin(a P2Y receptor antagonist), on the other hand, significantly inhibited Up4A-induced contraction of CM, but not LM.Up4A-induced contraction of CM, but not LM, was also inhibited by pretreatment with Y-27632, an inhibitor of Rho-associated kinase.
ConcIusions:We conclude that Up4A induces extracellular Ca2+-dependent contractions of rat gastric LM and CM, and Up4A-induced contraction of CM is mediated by suramin-sensitive P2Y receptors and subsequent activation of the Rho associated kinase pathway.
引文
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