葛根素对自发性高血压大鼠胸主动脉结构和功能的影响(英文)

目的探讨葛根素对自发性高血压大鼠(SHR)胸主动脉结构和功能的影响及其降压机制。方法12周龄SHR适应性喂养及血压测量训练1周后,ip给予葛根素25,50和100 mg.kg-1,给药6周。以第1次给药为第1周初,分别于给药前及给药后第2,4和6周测量血压。用硝酸还原酶法检测血清一氧化氮(NO)含量,放免法测量血浆内皮素1(ET-1)含量;HE染色观察胸主动脉形态学改变。制备胸主动脉环,采用累积加药法检测各组动脉环对苯肾上腺素(PE)10-9～10-5mol.L-1及乙酰胆碱(ACh)10-7～10-3mol.L-1引起的收缩或舒张反应。结果与对照组WKY大鼠相比,SHR模型组血压升高,ET-1增多,NO减少(P<0.01);血管肌层有大量脂质及纤维组织沉积,内皮边缘粗糙不平滑。与SHR模型组相比,葛根素25,50和100 mg.kg-1组血压分别降低了6.7±1.0,5.1±0.6和(2.2±0.3)kPa,差异显著(P<0.05);葛根素100 mg.kg-1组NO含量升高了1倍(P<0.01),ET-1含量降低了(36.3±4.2)%(P<0.05);血管肌层增生及脂质、纤维组织浸润明显好转,内皮也较平滑;降低PE对胸主动脉的收缩程度(P<0.05),增大ACh对胸主动脉的舒张程度(P<0.05)。结论葛根素对SHR具有良好的降压作用。其降压机制可能与其减弱SHR血管肾上腺素受体敏感性、保护血管内皮、增加血管内皮依赖性舒血管作用及纠正血液中血管舒缩因子失衡有关。     

硫化氢对自发性高血压大鼠胸主动脉舒张反应的影响

目的 探讨内源性及外源性硫化氢(H_2S)对自发性高血压大鼠(SHR)离体胸主动脉舒张反应的影响。方法 4wb WKY大鼠24只,随机分为WKY对照组(n=8)、WKY+H_2S组(n=8)及WKY+PPG组(n=8)。同样周龄SHR大鼠24只,随机分为高血压对照组(n=8)、高血压+H_2S组(n=8)及高血压+PPG组(n=8),高血压对照组及WKY对照组大鼠每日腹腔注射生理盐水,WKY+H_2S组及高血压+H_2S组每日腹腔注射硫氢化钠(NaHS),WKY+PPG组及高血压+PPG组每日腹腔注射PPG,5 wk后处死,取胸主动脉,观察其对乙酰胆碱(ACh)、硝普钠(SNP)及NaHS的舒张反应。结果 WKY+PPG组及高血压对照组、高血压+PPG组对ACh及SNP的舒张率较WKY组降低(P<0.05),而高血压+H_2S组较高血压对照组升高(P<0.05),与WKY对照组相似;各组大鼠血管环对SNP的舒 张反应均高于ACh(P<0.05);WKY对照组及高血压对照组对不同浓度的NaHS呈现剂量依赖性舒张反应,对于同样浓度的NaHS,高血压对照组较WKY对照组的舒张率高。结论 H_2S可以独立及与一氧化氮协同发挥舒张血管效应,在自发性高血压血管舒张功能异常的形成机制中占据重要地位。     

SHR高血压进程中不同类型血管内皮功能损伤及药物修复研究

目的探讨SHR大鼠在高血压发展进程中,不同血管内皮功能损伤程度及抗高血压药物对其的修复。方法以SHR为模型,7～24wk(wk:周龄)给予卡托普利(3.375g.kg-1.d-1),停药观察至32wk。6、18、24和32wk时分别进行病理学切片检查胸主动脉、肠系膜上动脉和心尖小动脉形态结构,及胸主动脉和肠系膜上动脉乙酰胆碱(ACh)浓度依赖性血管舒张功能检测(n=6)。结果SHR在18wk时胸主动脉、肠系膜上动脉和小动脉均出现结构病变,并随时间逐渐加重,三级动脉中胸主动脉病变较之严重,表现为内皮细胞脱落和中膜增厚;随年龄增大SHR胸主动脉和肠系膜上动脉ACh依赖性舒张度均下降,但胸主动脉舒张度降低幅度大于肠系膜上动脉(P=0.10,18wk;P<0.01,24、32wk);卡托普利能抑制18wkSHR胸主动脉舒张度的降低(P<0.05vsSHR),但对肠系膜上动脉没有该作用。结论伴随SHR高血压的发病进程,体内各级动脉内皮细胞均发生损伤,内皮依赖性舒张功能降低,大动脉内皮功能损伤出现早,程度也往往高于中、小动脉,抗高血压药物可抑制大动脉内皮功能障碍,但对中、小动脉内皮功能损伤无作用。     

缬沙坦对自发性高血压大鼠血管结构和舒缩功能的影响

目的观察缬沙坦对自发性高血压大鼠(SHR)的血压、血管功能和结构的影响.方法30只12 wk龄雄性SHR,随机分成3组,每组10只缬沙坦大剂量组(30 mg*kg-1*d-1);缬沙坦小剂量组(10 mg*kg-1*d-1); SHR模型对照组,另设同龄雄性正常血压WKY大鼠作为正常对照组(n=10).用无创法测定尾动脉收缩压及心率,至给药 4 wk 处死.测定胸主动脉、肠系膜动脉分支第三级血管壁(中膜)/腔面积比,并采用平衡记录仪记录离体的动脉环对血管活性药物去甲肾上腺素(NE)和硝普钠反应的敏感性.结果与模型组相比,大、小剂量缬沙坦均能降低SHR血压,肠系膜动脉壁肥厚明显改善(P＜0.01);大剂量明显减少主动脉腔壁比(P＜0.01),小剂量缬沙坦也可减少腔壁比,但无统计学意义;大、小剂量均能使胸主动脉及肠系膜动脉对硝普钠的舒张敏感性增加 (P<0.05),对NE收缩的敏感性降低(P<0.05).结论缬沙坦能改善SHR的非内皮依赖性血管舒张功能,使SHR血管对循环〗活性物质的异常反应改善,并抑制SHR的血管壁变厚.     

高浓度葡萄糖抑制兔胸主动脉内皮依赖的血管舒张(英文)

目的:研究高浓度葡萄糖是否能抑制兔胸主动脉内皮依赖的血管舒张以及可能的机制。方法:利用器官组织浴动脉环法测定血管张力,观察去除内皮、NO合酶抑制剂L-NMMA,不同浓度的葡萄糖对乙酰胆碱(ACh)产生的内皮依赖的和硝普钠(SNP)产生的非内皮依赖的血管舒张功能的影响以及维生素C和膜渗透性抗氧化剂MnTMPyP对高浓度葡萄糖作用的影响。结果:ACh和SNP均产生浓度依赖的血管舒张效应,高浓度葡萄糖明显抑制ACh产生的血管舒张,而对SNP的作用无明显影响,维生素C和MnTMPyP不能逆转高浓度葡萄糖对ACh产生的血管舒张的抑制作用。结论:高浓度葡萄糖抑制内皮依赖的血管舒张,这种作用不是通过增加氧自由基的产生介导的。     

盐酸关附甲素对大鼠血管舒缩功能的影响及其机制

目的研究盐酸关附甲素(guanfu base-A,GFA)对大鼠离体胸主动脉舒缩功能的影响,并探讨其可能机制。方法将SD大鼠胸主动脉分离并制成血管环,分成内皮完整组和去内皮组,采用离体血管环实验,观察GFA对基础状态,氯化钾(KCl)预收缩及苯肾上腺素(phenylephrine,PE)预收缩的血管舒张功能的影响,并结合不同抑制剂及无钙液处理,探讨其舒张血管的可能机制。结果累积浓度的GFA(10-8～10-4mol·L-1)对基础状态或KCl预收缩的有无内皮的血管环的张力均无明显影响(P>0.05);对PE(10-6mol·L-1)预收缩内皮完整的血管有浓度依赖性舒张作用,而与PE预收缩的去内皮组相比,从10-7mol·L-1开始差异有显著性(P<0.01)。一氧化氮合酶抑制剂L-NAME、鸟苷酸环化酶抑制剂亚甲蓝及环氧合酶抑制剂吲哚美辛孵育后,均能明显抑制GFA的扩血管作用(P<0.01);经无钙液及GFA处理后,胸主动脉对PE的反应性降低(P<0.01)。结论 GFA对大鼠胸主动脉的舒张作用主要通过两种途径:内皮依赖性舒张作用的机制主要与NO-GC-cGMP途径及激活环氧合酶有关;非内皮依赖性舒张机制主要与抑制内钙释放有关,与门控钙通道引起的外钙内流无关。     

高浓度葡萄糖抑制兔胸主动脉内依赖的血管舒张

目的：研究高浓度葡萄糖是否能抑制兔胸主动脉内皮依赖的血管舒张以及可能的机制。方法：利用器官组织浴动脉环法测定血管张力,观察去除内皮、NO合酶抑制剂L－NMMA,不同浓度的葡萄糖对乙酰胆碱（ACh)产生的内皮依赖的和硝普钠（SNP）产生的非内皮依赖的血管舒张功能的影响以及维生素C和膜渗透性抗氧化剂MnTMPyP对高浓度葡萄糖作用的影响。结果：ACh和SNP均产生浓度依赖的血管舒张效应,高浓度葡萄糖明显抑制ACh产生的血和舒张,而对SNP的作用无明显影响,维生素C和MnTMPyP不能逆转高浓度葡萄糖对ACh产生的血管舒张的抑制作用。结论：高浓度葡萄糖抑制内皮依赖的血管舒张,这种作用不是通过增加氧自由基的产生介导的。     

NADPH氧化酶对自发性高血压大鼠体内氧化应激的影响

目的考察NADPH氧化酶对自发性高血压大鼠体内氧化应激的影响。方法22wk龄自发性高血压大鼠(SHR)和正常血压WKY大鼠,采用尾套法测定血压,Greiss反应测定血清一氧化氮分泌量,ABTS和FRAP法进行血清总抗氧化能力测定,血管环舒缩测定来评价超氧阴离子清除剂超氧化物歧化酶(SOD)和NADPH氧化酶抑制剂夹竹桃麻素(Apo)对大鼠腹主动脉内皮依赖性舒张反应;采用RT-PCR考察内皮型一氧化氮合酶(eNOS)、NADPH氧化酶亚基p22phox以及NADPH氧化酶亚基gp91phox类似物nox4mRNA表达。结果与WKY大鼠相比,SHR血压升高,而血清总抗氧化水平及NO分泌量均降低。PCR显示SHR胸主动脉中eNOS及p22phoxmRNA表达与WKY大鼠相比差异无显著性,而nox4表达则升高。SHR腹主动脉内皮依赖性舒张反应与WKY相比降低,SOD或Apo均能明显逆转该变化。结论结果提示SHR体内氧化应激状态与NADPH氧化酶gp91phox类似物nox4mRNA过表达有关;NADPH氧化酶依赖性的氧化应激参与了SHR内皮功能障碍的发生发展;药理调节NADPH氧化酶功能或应用抗氧化治疗可明显改善SHR内皮依赖性舒张反应。     

单纯肾性和复合型肾性高血压大鼠主动脉功能的对比研究

目的探讨肾性高血压和肾性高血压伴高血脂大鼠主动脉功能的异同。方法实验分为假手术组、复合型肾性高血压伴高血脂(renal hypertensive-hyperlipidemia rat,RHHR)组和单纯肾性高血压(2K1C)组。采用离体血管灌流法测主动脉环对苯肾上腺素(PE)、乙酰胆碱(ACh)和硝普钠(SNP)的反应;一氧化氮合酶(NOS)抑制剂左旋硝基精氨酸甲酯(L-NAME)孵育后,动脉环对ACh的反应。结果两模型组对PE的收缩反应高于假手术组;两模型组对ACh引起的舒张反应低于假手术组,RHHR低于2K1C;两模型组有由NO引起舒张能力的降低;SNP在3组中均诱导完全舒张反应,但RHHR对SNP敏感性低于假手术和2K1C组。结论RHHR血管舒张功能损伤较2K1C严重,其原因可能与高脂血症降低血管平滑肌对NO利用能力有关。     

H_2O_2氧化损伤血管内皮模型的构建及超氧化物歧化酶对损伤的逆转作用

目的构建离体血管H2O2氧化损伤模型,并初步探讨其损伤机制,实验超氧化物歧化酶(superoxide dismutase,SOD)对该损伤的修复作用。方法采用大鼠离体胸主动脉环,构建H2O2氧化损伤血管模型,通过乙酰胆碱(acetylcho-line,ACh)引起的舒张评价该模型的内皮功能;通过硝普钠(nitroprusside sodium,SNP)引起的舒张及苯肾上腺素(phenylephrine,PE)引起的收缩评价该模型的平滑肌功能。同时,用120U·ml-1的SOD作用于该模型30min,评价SOD对模型损伤的修复作用。结果H2O2氧化损伤的血管,对SNP引起的舒张及PE引起的收缩无影响,而对ACh引起的内皮依赖性舒张程度降低,120U·ml-1 SOD作用后,能明显改善该模型的氧化损伤状态。结论H2O2 1mmol·L-110min能够氧化损伤大鼠胸主动脉内皮,120U·ml-1的SOD可以较好地修复H2O2造成的内皮损伤。     

左旋氨氯地平对自发性高血压大鼠胸主动脉重构及内皮功能的影响

目的 观察左旋氨氯地平(降压药)对自发性高血压大鼠胸主动脉结构及内皮依赖性舒张功能的影响.方法 20只自发性高血压大鼠,分为左旋氨氯地平治疗组和高血压对照组;同周龄WKY大鼠作为正常对照.治疗组,给予左旋氨氯地平(2 mg·kg-1·d-1),12周后,观察胸主动脉对乙酰胆碱和硝普钠的舒张反应,比较各组主动脉中膜厚度及中膜截面积,检测血清一氧化氮、内皮素的水平.结果 同高血压对照组相比,治疗组的胸主动脉对乙酰胆碱的最大舒张反应明显增强,(48.39±14.86)%vs(34.71±9.23)%,P=0.03;胸主动脉中膜厚度及截面积明显减小(P<0.05),血清一氧化氮浓度明显增加(P<0.05).结论 左旋氨氯地平能够改善自发性高血压大鼠血管内皮依赖性舒张功能,抑制血管重构,机制可能与增加一氧化氮的合成和释放有关.     

Nitric oxide in mesenteric vascular reactivity: a comparison between rats with normotension and hypertension

1. Nitric oxide (NO) plays an important role in various physiological functions. The continuous formation of endogenous NO from endothelial cells maintains a vasodilator tone and regulates blood flow and pressure. However, the role of NO in hypertension remains controversial. 2. In the present study, we used an in situ mesenteric perfusion system. The primary objectives of the study were to examine whether or not mesenteric vasoreactivity is changed by alterations in perfusion pressure and to assess the role of NO in changes of vascular reactivity in hypertension. 3. Spontaneously hypertensive rats (SHR; 12-15 weeks of age) and age-matched normotensive Wistar-Kyoto (WKY) rats were used as the experimental and control groups, respectively. Endothelium-dependent and -independent vasodilation was detected by acetylcholine (ACh) or NO donors (sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP)). Dose-dependent reactivity to these agents (10(-6) to 10(-4) mol/L) was detected by bolus intra-arterial injections of 10 microL of the test agents at 5 min intervals. Dose-dependent responses to vasoconstrictor drugs, such as noradrenaline (NA) and phenylephrine (PE; 10(-6) to 10(-4) mol/L) were also observed. The NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 10 mg/kg) was given to examine the contribution of NO to the vasoreactivity of the mesenteric bed. 4. Acetylcholine, SNP and SNAP produced dose-dependent vasodilation in both WKY rats and SHR. The magnitude of the vasodilation was significantly greater in SHR than in WKY rats. It was also greater at high than low flow rates in SHR. The increase in mesenteric perfusion pressure following L-NAME was significantly higher in SHR than in WKY rats. However, there were no differences in responses to L-NAME between low and high flow rates in SHR. Endothelium-independent vasoconstriction (NA and PE) was dose dependent in both SHR and WKY rats. The magnitude of the endothelium-independent vasoconstriction was greater in SHR than in WKY rats. 5. The results suggest that endothelium-dependent or -independent mesenteric vasoconstriction and vasodilation is enhanced in SHR compared with WKY rats, supporting the concept of enhancement of NO function in the hypertensive state. Flow-induced shear stress is also a key factor in the regulation of peripheral resistance depending on NO formation in hypertension.     

Modulation of vascular reactivity in normal, hypertensive and diabetic rat aortae by a non-antioxidant flavonoid.

In this study, we report the effects of a non-antioxidant flavonoid flavone on vascular reactivity in Wistar-Kyoto (WKY) rat isolated aortae. Whether flavone directly modulates vascular reactivity in spontaneously hypertensive rat (SHR) and streptozotocin-induced diabetic-WKY rat isolated aortae was also determined. Thoracic aortic rings were mounted in organ chambers and exposed to various drug treatments in the presence of flavone (10 microM) or its vehicle (DMSO), which served as control. Pretreatment with flavone enhanced relaxant effects to endothelium-dependent vasodilator acetylcholine (ACh) and attenuated contractile effects to alpha(1)-receptor agonist phenylephrine (PE) in WKY aortae compared to those observed in control aortic rings. Flavone had no effect on relaxations to ACh in WKY aortae incubated with either L-NAME or methylene blue, but enhanced relaxations to ACh in WKY aortae incubated with indomethacin or partially depolarized with KCl. Relaxations to ACh are totally abolished in both control or flavone pretreated endothelium-denuded WKY aortae. Flavone attenuated the inhibition by beta-NADH of ACh-induced relaxation in WKY aortae, but it had no significant effect on the transient contractions induced by beta-NADH nor the pyrogallol-induced abolishment of ACh-induced relaxation in WKY aortae. Flavone enhanced endothelium-independent relaxation to sodium nitroprusside (SNP) in both endothelium-intact and -denuded WKY aortae. Flavone enhanced relaxation to ACh and SNP as well as attenuated contractile effects to PE in SHR and diabetic aortae, a finding similar to that observed in normal WKY aortae. From these results, we conclude that flavone modulates vascular reactivity in normal as well as hypertensive and diabetic aortae. These effects of flavone results probably through enhanced bioactivity of nitric oxide released from the endothelium.     

Direct effects of quercetin on impaired reactivity of spontaneously hypertensive rat aortae: comparative study with ascorbic acid

1. There is a growing interest in the anti-oxidant characteristics and use of flavonoids in the management of cardiovascular diseases. The cardiovascular mechanism of action of these plant derivatives remains controversial. This study compared the effects of the flavonoid quercetin with those of the anti-oxidant vitamin ascorbic acid (vitamin C) on the reactivity of aortic rings from spontaneously hypertensive rats (SHR). 2. The phenylephrine (PE)-induced contractile and the endothelium-dependent and independent relaxant responses of aortic rings from 21 to 22 week old SHR and age-matched normotensive Wistar (WKY) rats were observed in the presence of quercetin or ascorbic acid. All the experiments were performed in the presence of the cyclooxygenase inhibitor, indomethacin (10 micromol/L). 3. The endothelium-dependent and independent relaxations to acetylcholine (ACh) and sodium nitroprusside (SNP), respectively, were significantly lesser in the SHR compared to the WKY tissues whereas the contractile responses to PE were similar in both tissues. Pretreatment of WKY rings with quercetin or ascorbic acid had no effect on the responses to ACh or PE. In the SHR tissues, however, quercetin or ascorbic acid significantly improved the relaxation responses to ACh and reduced the contractions to PE with greater potency for quercetin. Both compounds lacked any effects on the responses to SNP in either aortic ring types. N(omega)-nitro-L-arginine methyl ester (l-NAME, 10 micromol/L) significantly attenuated the vasodepressor effects of quercetin and ascorbic acid, raising the responses to PE to a level similar to that observed in the control SHR tissues. In l-NAME pretreated aortic rings, quercetin and ascorbic acid inhibited the contractile responses to PE with the same magnitude in WKY and SHR tissues. 4. The present results suggest that acute exposure to quercetin improves endothelium-dependent relaxation and reduces the contractile responses of hypertensive aortae with a greater potency than ascorbic acid. This suggests a better vascular protection with this flavonoid than ascorbic acid in the SHR model of hypertension and possibly in human cardiovascular diseases.     

Apocynin reduces blood pressure and restores the proper function of vascular endothelium in SHR

This study has evaluated how the vascular endothelium of hypertensive rats chronically treated with apocynin affects acetylcholine (ACh), sodium nitroprusside (SNP), and phenylephrine (PE) action on the nitric oxide (NO) signal transduction pathway in endothelial (EC) and vascular smooth muscle cells. Treatment with apocynin significantly reduced the mean arterial pressure in spontaneously hypertensive rats (SHR). In addition, apocynin improved the impaired ACh hypotensive effect on SHR. Although systemic oxidative stress was high in SHR, SHR treated with apocynin and normotensive rats presented similar systemic oxidative stress levels. Endothelium significantly blunted PE contractions in intact aortas of treated SHR. The ACh effect was impaired in resistance arteries and aortas of SHR, but this same effect was improved in treated SHR. The SNP potency was higher in intact resistance arteries of treated SHR than in intact resistance arteries of untreated SHR. NO and calcium concentrations increased, whereas reactive oxygen species levels decreased in EC of treated SHR. Aortas of untreated and treated SHR did not differ in terms of sGC alpha or beta units expression. Aorta of treated SHR expressed higher eNOS levels as compared to aorta of untreated SHR. The study groups did not differ with respect to NOX1, NOXO1, or NOX4 expression. However, treatment with apocynin normalized overexpression of NOX2 and its subunit p47phox in aortas of SHR. Based on all the results presented in this study, we suggest apocynin increases NO biovailability by different mechanisms, restoring the proper function of vascular endothelium in SHR.     

Endothelial function in mesenteric resistance arteries from the genetically hypertensive rat

1. Endothelial function in mesenteric resistance arteries (MRA) from male 12-week-old New Zealand genetically hypertensive (GH) rats and their normotensive control strain (N) was compared in vessels mounted on a wire myograph and by the production of intracellular cGMP. In parallel experiments, MRA from the spontaneously hypertensive (SHR) rat strain, in which there is an endothelial defect, and from GH rats, in which an endothelial defect was induced by chronic nitric oxide synthase (NOS) inhibition with Nomega-nitro-L-arginine methyl ester (L-NAME), were studied. 2. Contractile responses to potassium (124 mmol/L) depolarization and to NA (10(-8) to 10(-4) mol/L) were similar in GH and N rats; however, in SHR, enhanced contractile responses were found (P < 0.05). The endothelium-dependent relaxation induced by acetylcholine (ACh; 10(-9) to 10(-4) mol/L) and endothelium- independent relaxation induced by sodium nitroprusside (SNP; 10(-9) to 10(-4) mol/L) were identical in preparations from GH and N. A significantly attenuated (P < 0.01) vasodilator response to ACh was observed in preparations from SHR. 3. Levels of intracellular cGMP were similar in untreated small mesenteric arterial trees from GH, N and SHR rats. Acetylcholine (10-5 mol/L) significantly (P < 0.001) increased the cGMP content in both GH and N rats. A non-significant increase occurred in cGMP content in preparations from SHR. 4. In GH rats given L-NAME (10 mg/kg per day for up to 5 weeks), an attenuated (P < 0.01) endothelium-dependent relaxation to ACh and an enhanced (P < 0.01) endothelium- independent relaxation to SNP were observed. Lower basal cGMP levels were found in preparations from L-NAME-treated GH rats and ACh (10-5 mol/L) failed to significantly elevate the cGMP content in these preparations. 5. These experiments failed to show evidence of reduced endothelial function in GH rats, although an endothelial defect in SHR rats and after NOS inhibition in GH rats could be demonstrated.     

Secondary hyperalgesia in the rat first degree burn model is independent of spinal cyclooxygenase and nitric oxide synthase

The present study investigated the mechanisms of vasodilatation of the human pancreatic polypeptide [cPP(1-7), NPY(19-23),Ala(31),Aib(32),Gln(34)]hPP (hPP) in mesenteric small arteries from Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). The arteries were isolated and mounted in microvascular myographs for isometric tension recording. In vasopressin-contracted preparations with endothelium from WKY rats, hPP evoked concentration-dependent relaxations with maximal responses of 50+/-2% (n=5). hPP relaxation was reduced by endothelial cell removal and abolished in the presence of a nitric oxide (NO) synthase inhibitor, N(G)-nitro-L-arginine-methylester (L-NAME). hPP relaxation was blunted in segments with endothelium, and absent in segments without endothelium from SHR. The combined neuropeptide Y(1)- and Y(4)-receptor antagonist, GR23118 (Ile-Glu-Pro-Dpr-Tyr-Arg-Leu-Arg-Tyr-CONH(2)), and the neuropeptide Y(1) receptor antagonist, BIBP3226 ((R) -N2-(diphenylacetyl)-N-[(4-hydroxyphenyl)-methyl]-arginineamide), inhibited hPP-induced vasodilatation. Calcitonin gene-related peptide (CGRP) relaxation was reduced in arteries from SHR compared to WKY. The CGRP receptor antagonist, CGRP (8-37), antagonized vasodilatation induced by CGRP and rightward shifted concentration-response curves for hPP in arteries from WKY rats. There were no differences in nerves immunoreactive for CGRP in arteries from SHR compared to WKY rats. In contrast to neuropeptide Y which evokes contraction by activation of neuropeptide Y(1) and Y(2) receptors, the present results suggest hPP evokes relaxation of mesenteric small arteries by activation of prejunctional neuropeptide Y(1)-like receptors localized in CGRP-containing nerves followed by release of CGRP and of endothelium-derived NO. hPP relaxation is blunted in arteries from SHR probably as a consequence of endothelial cell dysfunction leading to reduced efficacy of CGRP.     

Contractions induced by potassium-free solution and potassium relaxation in vascular smooth muscle of hypertensive and normotensive rats.

1. Vascular contractions induced by K(+)-free solution and relaxation responses following the return of K+ to the organ bath were studied in mesenteric arterial rings from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) with particular focus on the role of vascular adrenergic nerve-endings and endothelium. 2. In endothelium-denuded rings the omission of K+ from the incubation medium resulted in gradual contractions, the rate of which was slower in SHR than WKY. Nifedipine (1 microM) inhibited the contractions more effectively in SHR than WKY. 3. Adrenergic denervation in vitro with 6-hydroxydopamine reduced the contractions induced by the K(+)-free medium in endothelium-denuded rings. The remaining contractions after denervation were markedly greater in SHR than WKY. 4. The presence of intact vascular endothelium attenuated the K(+)-free contractions in both strains, the attenuation being smaller in SHR than WKY. NG-nitro-L-arginine methyl ester (L-NAME, 0.1 mM) and methylene blue (10 microM), but not indomethacin (10 microM), abolished the attenuating effect of endothelium on the K(+)-free contractions. L-Arginine (1 mM) reversed the effect of L-NAME in WKY but not in SHR. 5. The re-addition of K+ after full K(+)-free contractions dose-dependently relaxed the rings. The rate of this K(+)-induced relaxation was significantly slower in SHR than WKY at all K+ concentrations (0.1-5.9 mM) studied, whether the endothelium or functioning adrenergic nerve-endings were present or not. Ouabain (1 mM) totally inhibited the K+ relaxation in SHR but only partially in WKY.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of celiprolol therapy on arterial dilatation in experimental hypertension.

1. It has recently been suggested that therapy with beta-adrenoceptor blockers reduces peripheral arterial resistance via enhanced vascular dilatation. Therefore, we studied the effects of celiprolol, which is a specific beta 1-antagonist that has a weak beta 2-agonist action, on arterial tone in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. 2. Two doses of celiprolol (5 and 50 mg kg-1 day-1) were administered to the SHR, while the WKY rats received only the higher dose of the drug. During the 12-week treatment period the higher dose attenuated the increase in blood pressure by approximately 20 mmHg in SHR, whereas the lower dose was without significant antihypertensive effect. Celiprolol therapy did not affect blood pressure in the normotensive WKY rats. 3. Responses of mesenteric arterial rings in vitro were examined at the end of the study. Interestingly, endothelium-mediated relaxations of noradrenaline (NA)-precontracted rings to acetylcholine (ACh) in the absence and presence of the cyclo-oxygenase inhibitor, diclofenac, were equally enhanced in both celiprolol-treated SHR groups. The nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) practically abolished the relaxations to ACh in all SHR irrespective of whether they had received celiprolol, whereas in WKY rats L-NAME only attenuated the responses to ACh. However, no differences were found between the SHR groups in relaxations to ACh when hyperpolarization of smooth muscle was prevented by precontractions induced by 50 mM KCl. Vasorelaxation of NA-precontracted rings to the exogenous nitric oxide donor, nitroprusside, was also moderately augmented in both celiprolol-treated SHR groups, while the relaxation to beta-adrenoceptor agonist, isoprenaline, remained equally impaired in all SHR whether or not they had received celiprolol. No differences were observed between the two WKY groups in the responses to ACh, nitroprusside or isoprenaline. 4. Contractile sensitivity of mesenteric arterial rings to the receptor-mediated agonists, NA and 5-hydroxytryptamine, was comparable in all study groups. 5. In conclusion, SHR treatment with either the low or the higher dose of celiprolol was accompanied by enhancement of both endothelium-dependent and endothelium-independent nitric oxide-mediated arterial relaxation, possibly via a hyperpolarization mechanism. Interestingly, this effect appeared to be independent of the reduction in blood pressure.     

肌内皮缝隙连接在失血性休克大鼠内皮依赖和非内皮依赖的血管舒/缩功能调节中的作用

目的 研究肌内皮缝隙连接(myo-endothelial gap junction,MEGJ)通道在失血性休克大鼠肠系膜上动脉血管(SMA)的内皮依赖和非内皮依赖的血管收缩/舒张功能调节中的作用.方法 利用在体血管管径测定技术,观察MEGJ的阻断剂18α-甘草次酸(18α-GA)对非内皮依赖的血管收缩剂去甲肾上腺素(N...