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.     

微血管张力测定技术在血管内皮去除中的应用

目的通过建立离体小动脉血管内皮去除的研究方法,提高微血管测量技术研究数据的可信度。方法选取♂自发性高血压大鼠(SHR)和正常血压大鼠(WKY),测量血压后,获取肠系膜动脉环。采取机械(血管环围绕电极尖端旋转、推注气体)和药物(L-NAME和吲哚美辛)相结合的方式去除内皮。采用压力肌动图技术检测苯肾上腺素(PE)、乙酰胆碱(ACh)、硝普钠(SNP)对肠系膜动脉直径变化的影响。结果(1)SHR血压值高于WKY大鼠(P<0.01);(2)PE浓度依赖地收缩肠系膜动脉。内皮完整和内皮去除时,与WKY相比,SHR的收缩增强(P<0.05);(3)ACh、SNP能够浓度依赖地舒张肠系膜动脉。内皮完整时,与WKY相比,SHR的舒张减弱(P<0.01);内皮去除时,与WKY相比,SHR的舒张增强(P<0.01)。结论(1)成功建立离体微小动脉血管内皮去除的研究方法。(2)高血压大鼠存在明显的血管舒缩功能障碍。     

卡托普利对大鼠血管内皮功能损伤的保护作用

目的探讨卡托普利对烟碱所致大鼠血管内皮功能损伤的影响及可能机制。方法将30只大鼠分为3组，即正常对照组、烟碱损伤组（2mg／kg，腹腔注射）、卡托普利保护组（烟碱2mg／kg，腹腔注射＋卡托普利3mg／kg，静脉注射），4周后检测各组肠系膜动脉环内皮依赖性舒张（EDR）反应及主动脉一氧化氮（NO）含量，一氧化氮合成酶（NOS）和超氧化物歧化酶（SOD）活性变化。结果烟碱损伤组肠系膜动脉环EDR明显降低，并伴随主动脉NO含量及NOS，SOD活性的下降；卡托普利保护组血管EDR得到了明显改善，并且抑制了烟碱诱导的主动脉NO含量及NOS，SOD活性的下降。结论卡托普利对烟碱所致血管内皮功能损伤有明显保护作用，该作用与其清除氧自由基、促进内皮细胞合成、释放NO有关。     

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。     

芝麻素对肾性高血压伴高血脂大鼠主动脉舒张功能的影响

目的:探讨芝麻素(Sesamin,Ses)改善肾性高血压伴高血脂大鼠(Rrenal hypertensive-hy-perlipidemia rat,RHHR)主动脉舒张功能损伤的作用机制.方法:RHHR灌服不同剂量Ses(100、33、10 mg·kg-1·d-1)8周后,测定主动脉环对乙酰胆碱(Acetylcholine,ACh)和硝普钠(Sodium nitroprusside,SNP)的舒张反应;测定一氧化氮合酶抑制剂左旋硝基精氨酸甲酯(N-ni-tro-L-arginine-methyl-ester,L-NAME)孵育后,动脉环对ACh的反应并计算一氧化氮(Nitric oxide,NO)活性.结果:与假手术组相比,RH-HR主动脉Ach和SNP诱导的舒张反应显著降低,NO活性减少,Ses治疗8周后能逆转上述作用.结论:Ses降压作用与改善RHHR主动脉内皮依赖性和非内皮依赖性舒张功能损伤有关.     

Urocortin舒张自发性高血压大鼠胸主动脉与NO和K~+通道的关系

目的探讨Urocortin(Ucn)对自发性高血压大鼠(SHR)胸主动脉舒缩功能的作用及机制。方法采用体外血管灌流,观察Ucn对SHR胸主动脉的舒张作用,以及左旋硝基精氨酸甲酯(N(ω)n itro-L-argin ine methyl ester,L-NAME)、亚甲蓝(M ethylene B lue,MB)和格列本脲(G lybenc lam ide)对其舒张作用的影响。结果Ucn(1 nmol.L-1~1μmol.L-1)可明显舒张内皮完整和去内皮SHR胸主动脉(P<0.01),此作用具有剂量依赖性;一氧化氮(NO)合成酶抑制剂L-NAME(100μmol.L-1)和鸟苷酸环化酶(GC)抑制剂MB部分抑制Ucn舒张血管的作用,而且增强去甲肾上腺素(NE)产生的收缩反应。ATP敏感钾通道(KATP)阻断剂格列本脲(10μmol.L-1)可减弱Ucn的舒血管作用。结论Ucn对SHR血管具有内皮依赖性和非内皮依赖性舒张作用,此作用部分是Ucn增加血管内皮细胞NO水平实现的,并且与NO-cGMP通路和KATP通道有关。     

卡托普利对尼古丁所致大鼠血管内皮功能损伤的保护作用

目的:探讨卡托普利对尼古丁损伤大鼠肠系膜动脉内皮依赖性舒张功能的保护作用及其机制。方法:将30只大鼠分为3组,即正常对照组、尼古丁损伤组(2mg·kg-1)、卡托普利组(尼古丁2mg·kg-1+卡托普利3mg·kg-1),4周后检测各组肠系膜动脉环血管舒张率及血清一氧化氮(NO)含量,一氧化氮合成酶(NOS)、超氧化物歧化酶(SOD)活性。结果:尼古丁使肠系膜动脉环血管舒张率明显降低,并伴随血清NO含量及NOS、SOD活性的明显下降(P<0.01或P<0.05);而卡托普利可升高血管舒张率,并且抑制了尼古丁诱导的NO含量及NOS、SOD活性的下降(P<0.01)。结论:卡托普利对尼古丁所致的血管内皮功能损伤具有明显保护作用,该作用可能与其抗氧化、促进内皮细胞合成、释放NO有关。     

卡托普利抗同型半胱氨酸和溶血性磷脂酰胆碱损伤大鼠血管内皮功能

目的　研究卡托普利能否保护同型半胱氨酸(Hcy)和溶血性磷脂酰胆碱 (LPC)在体外直接损伤的大鼠离体胸主动脉内皮功能。方法　用Hcy或LPC孵育大鼠离体胸主动脉环 3 0min诱导血管内皮损伤 ,观察卡托普利对Hcy和LPC损伤血管内皮依赖性舒张反应的影响。结果　Hcy( 0 .3～ 3mmol·L-1)或LPC( 1～1 0 μmol·L-1)呈浓度依赖性地损伤乙酰胆碱诱导的内皮依赖性血管舒张反应 ,但不影响硝普钠诱导的内皮非依赖性血管舒张。卡托普利( 3～3 0 μmol·L-1)预孵育血管环 1 5min,再与Hcy( 1mmol·L-1)共同孵育 3 0min,浓度依赖性改善Hcy对血管内皮依赖性舒张反应的损害。 3 0 μmol·L-1卡托普利也可完全逆转LPC( 3 μmol·L-1)对内皮依赖性血管舒张反应的损害。结论　卡托普利对Hcy和LPC所引起的血管内皮依赖性舒张反应的损害都具有明显的保护作用     

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。     

卡托普利对蛋氨酸所致血管内皮功能损伤的保护作用与对氧磷酶1的关系

目的探讨卡托普利对高蛋氨酸饮食所致大鼠血管内皮功能损伤的保护作用及其机制。方法将蛋氨酸通过灌胃的方法,1次.d-1,连续4周,诱导大鼠血管功能损伤,治疗组同时给予卡托普利、依那普利、N-乙酰半胱氨酸灌胃。4周后处死动物,检测血清一氧化氮(nitric oxide,NO)、丙二醛(malondialdehyde,MDA)含量、对氧磷酶(paraoxonase 1,PON1)、超氧化物歧化酶(superoxide dismutase enzyme,SOD)、血管紧张素转换酶(an-giotensin-converting enzyme,ACE)活性。取胸主动脉检测由乙酰胆碱(acetylcysteine,Ach)诱导的血管内皮依赖性舒张反应。结果高蛋氨酸损伤组大鼠血管内皮依赖性舒张反应显著减弱,血清中MDA浓度升高,PON1活性、血浆NO浓度与SOD活性降低;卡托普利、N-乙酰半胱氨酸和依那普利能显著改善血管内皮依赖性舒张反应、降低MDA浓度、提高血清中的PON1活性、SOD活性和NO浓度。结论卡托普利能够改善高蛋氨酸引起的血管内皮功能的损伤,该作用可能与保护PON1活性及其抗氧化作用、促进内皮细胞释放NO有关。     

氟伐他汀对自发性高血压大鼠阻力血管 功能的影响

AIM: To evaluate the effects of fluvastatin, a hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor, on the alterations of structure and function of resistant vessels in spontaneously hypertensive rats (SHR). METHODS: Eight-week-old male SHR were given fluvastatin 20 mg.kg-1.d-1 by gavage. Rats were decapitated at 16 wk. Wall-to-lumen area ratios (W/L) of thoracic aorta and mesenteric arteries (3rd grade branch) were assessed by morphometric assay. The effects of fluvastatin on vascular reactivity to sodium nitroprusside (SNP) and norepinephrine (NE), were studied with rings of thoracic aorta and mesenteric arteries isolated from rats. RESULTS: After 8 wk of treatment, histological examination showed that the wall-to-lumen area ratio was lower in SHRflu than that in SHR (0.44 +/- 0.09 vs 0.79 +/- 0.09, P < 0.05). EC50 of vasodilation response was much lower in SHRflu than that in SHR [(4.9 vs 190) pmol.L-1, P < 0.05], while EC50 of mesenteric artery rings from SHRflu was somewhat lower than that of SHR [(0.02 vs 0.04) nmol.L-1, P > 0.05]. In both aortic and mesenteric artery rings, EC50 of vasoconstriction in response to NE from SHRflu was higher than that of SHR [thoracic aorta: (0.20 vs 0.02) nmol.L-1, P < 0.05; mesentric arteries: (1.46 vs 0.72) nmol.L-1, P < 0.05]. CONCLUSION: Short-term treatment with fluvastatin ameliorated the vasomotoricity of resistant vessels, enhanced the sensitivity to vasodilator and depressed the sensitivity to vasoconstrictor; fluvastatin also attenuated the resistant vascular hypertrophy during the development of hypertension in SHR.     

Effects of the flavonoid quercetin and its methylated metabolite isorhamnetin in isolated arteries from spontaneously hypertensive rats

Chronic oral quercetin exerts antihypertensive effects in spontaneously hypertensive rats (SHR). In the present study, the vasodilator effects of the flavonoid quercetin and its main metabolite isorhamnetin were analysed in isolated thoracic aorta, iliac artery and on the isolated perfused mesenteric resistance vascular bed from SHR and normotensive Wistar Kyoto rats (WKY). In noradrenaline-precontracted vessels from SHR there was an inverse correlation between the relaxant potency (pIC50) of quercetin (4.76 +/- 0.02, 5.08 +/- 0.12, 5.30 +/- 0.18, in aorta, iliac arteries and mesentery, respectively) and isorhamnetin (4.90 +/- 0.11, 5.38 +/- 0.15 and 5.80 +/- 0.10, respectively) and the diameter of the vessel studied. Both flavonoids were more potent in endothelium-denuded aortae and iliac arteries from SHR than from normotensive WKY rats. In addition, in aortae from SHR both flavonoids restored the endothelial-dependent vasodilation. Isorhamnetin, but not quercetin, also reduced the endothelium-dependent contractile responses induced by acetylcholine. These direct vasodilator effects, together with the improvement of endothelial function, are good candidates to explain the blood pressure reduction and vascular protective effects of quercetin in animal models of hypertension and possibly in human cardiovascular diseases.     

Pathological role of a constitutively active population of alpha(1D)-adrenoceptors in arteries of spontaneously hypertensive rats.

1. The role of a constitutively active population of alpha(1D)-adrenoceptors was analysed in arteries obtained from spontaneously hypertensive rats (SHR) and controls (WKY) divided into three groups: young prehypertensive, adult hypertensive, and adult animals chronically treated with captopril (50 mg kg(-1) per day orally) in order to prevent the hypertensive state. 2. In adult SHR, a significant increase in BMY 7378 potency (not in prazosin potency) was observed in aorta, mesenteric artery, and the first and second branches of the small mesenteric arteries with respect to WKY rats. This difference was not observed in iliac and tail arteries, which suggests an increased functional role of alpha(1D)-adrenoceptors only in some vessels of SHR. 3. The increase in the resting tone (IRT) observed in absence of agonist, inhibited by BMY 7378, that represents the constitutively active population of alpha(1D)-adrenoceptors, was also significantly greater in aorta and mesenteric artery from adult SHR. 4. In young and captopril treated adult animals, no differences between strains with respect to BMY 7378 potency, or IRT were observed. 5. The increase in the functional role of alpha(1D)-adrenoceptors and their constitutive activity observed in hypertension is prevented by captopril treatment. The pathological consequence of this change is the slower rate of recovery of the basal tone after removal of an adrenergic stimulus, observed in vessels from hypertensive animals that had shown an increase in the functionality of constitutively active alpha(1D)-adrenoceptors. This change was not observed in prehypertensive or captopril treated animals.     

The protective effect of captopril on nicotine-induced endothelial dysfunction in rat

This study was designed to examine the in vivo and in vitro effects of captopril, an angiotensin-converting enzyme inhibitor, on nicotine-induced endothelial dysfunction in rats. Endothelial dysfunction was induced by exposing isolated rat mesenteric arteries to nicotine (0.01, 0.1, or 1 mM) for 24 hr using an organ culture system, or by treating rats with nicotine (2 mg/kg/day, intraperitoneally) for 4 weeks. The protective effects of captopril were tested by exposing isolated mesenteric arteries to captopril (0.01, 0.03, or 0.1 mM) + nicotine (0.1 mM) for 24 hr, or by treating rats with captopril (3 mg/kg/day, intravenously) + nicotine (2 mg/kg/day, intraperitoneally) for 4 weeks. Exposure of the isolated mesenteric arteries to nicotine induced a significant concentration -dependent inhibition of endothelium-dependent relaxation. Co-culture of segments of mesenteric artery with captopril (0.03 or 0.1 mM) attenuated the nicotine-induced impairment of vasorelaxation in a dose-dependent manner. Administration of nicotine to rats for 4 weeks significantly impaired endothelium-dependent relaxation compared with control rats. This impairment was accompanied by a reduction in nitrite/nitrate, nitric oxide (NO) synthase (NOS), and superoxide dismutase (SOD) activities in the serum and aorta. Chronic captopril treatment not only improved the impairment of endothelium-dependent relaxation, but also prevented the reduction of nitrite/nitrate contents and of NOS and SOD activities in the serum and aorta. However, there were no significant differences in serum angiotensin-converting enzyme activity among the three groups. These results indicate that captopril can be used to attenuate nicotine-induced endothelial dysfunction, an effect that may be related not only to antioxidation, but also to enhancing NO production by preventing the decrease in NOS.     

Role of nitric oxide and carbon monoxide in N(omega)-Nitro-L-arginine methyl ester-resistant acetylcholine-induced relaxation in chicken carotid artery

Vascular contractility and endothelium-dependent vasodilatation were studied in mesenteric, aorta and coronary vasculature from male and female LDL receptor deficient (LDLR(-/-)) and wild type C57BL/6 mice fed either a high-fat Western Diet (WD) or regular animal chow (RD). Endothelium-dependent vasodilatation was also studied in small mesenteric arteries and aorta from C57BL/6 mice following a 20 h exposure in vitro to 30 mM glucose. Compared with RD-fed animals, WD-fed LDLR-/- animals had increased body weights, elevated triglycerides and total cholesterol, but not glucose. Control C57BL6 animals had elevated body weight without increased cholesterol, triglyceride or glucose levels. The contractile sensitivity to cirazoline (pD(2)) of small mesenteric arteries was the same for RD-fed LDLR-/- and RD-fed C57BL6 mice, but was reduced in WD-fed male LDLR-/- and WD-fed female C57BL/6 mice. Maximum mesenteric contractile values for cirazoline (Emax) were unchanged; however, the Emax for phenylephrine in the aorta from WD-fed male C57BL/6 (but not LDLR-/- or female C57BL/6) mice was reduced. The Emax for acetylcholine-mediated endothelium-dependent vasodilatation in micro- and macro vessels (small mesenteric artery, coronary artery and aorta) from WD-fed LDLR-/- and C57BL/6 mice was unaltered, in contrast to the reduction in Emax for glucose-exposed tissues. Furthermore, the component of acetylcholine-mediated vasodilatation resistant to the combination of inhibitors of nitric oxide synthase, cyclooxygenase and guanylyl cyclase (nitro L-arginine methyl ester - 100 microM; indomethacin 10 microM and 1H-[1,2,4]-oxadiazolo[4,3,-a]quinoxalin-1-one, ODQ - 10 microM, respectively) was generally greater in WD-fed mice. Thus, vasculature from WD-fed mice with short-term dyslipidaemia do not exhibit reduced endothelium-dependent vasodilatation, but the WD is associated with changes in the overall endothelial-dependent relaxation and contractile responses thus suggesting an impact of diet rather than dyslipidaemia on cellular signalling pathways in vascular tissue. In contrast, acute hyperglycaemia resulted in endothelial dysfunction in both small mesenteric arteries and thoracic aorta.     

钩藤生物碱抑制高血压大鼠主动脉胶原沉积及对基质金属蛋白酶的影响

目的探讨钩藤碱、异钩藤碱和钩藤总生物碱抑制SHR(自发性高血压大鼠(spontaneous hypertension rats,SHR)胸主动脉胶原沉积的实验效应及相关机制。方法 40只SHR随机分为5组:模型组、卡托普利组、异钩藤碱组、钩藤碱组和钩藤总生物碱组;Wistar大鼠8只作为正常对照组。卡托普利组给药量为每天17.5 mg.kg-1,异钩藤碱组、钩藤碱组和钩藤总生物碱组的给药量分别为每天5、5、50 mg.kg-1,模型组和正常组给予等容量生理盐水。灌胃给药8周。取胸主动脉,通过Masson染色法、免疫组织化学染色法、原位杂交法并结合图像分析技术,观察钩藤碱、异钩藤碱和钩藤总生物碱对SHR胸主动脉胶原、ColⅠ、ColⅢ、MMP-9、MMP-2、TIMP-2表达的影响。结果钩藤碱、异钩藤碱和钩藤总生物碱能够降低SHR胸主动脉胶原含量,下调ColⅠ、ColⅢ的蛋白和mRNA表达水平,上调MMP-9和MMP-2蛋白表达水平,上调MMP-9 mRNA表达水平,下调TIMP-2蛋白和mRNA表达水平。结论钩藤碱、异钩藤碱和钩藤总生物碱具有抑制SHR胸主动脉胶原重塑的效应,部分机制与上调MMP-9和MMP-2、下调TIMP-2的表达有关。     

Studies on the effects of viprostol in isolated small blood vessels and thoracic aorta of the rat.

1. The effects of viprostol, prostaglandin E2 (PGE2) and nitroglycerin were studied in basilar artery, small mesenteric artery and the vein parallel to it as well as thoracic aorta of the rat. 2. In KCl-contracted basilar artery, viprostol produced a concentration-related biphasic response, contraction at concentrations less than 3 X 10(-6) M and relaxation at concentrations greater than 3 X 10(-6) M. PGE2 produced a concentration-related contraction while nitroglycerin produced a concentration-related relaxation. 3. In KCl-contracted small mesenteric artery, viprostol produced a biphasic response which was similar to that in the basilar artery. PGE2 produced a contraction and nitroglycerin produced relaxation in a concentration-dependent manner. 4. In KCl-contracted small mesenteric vein, in contrast to basilar and mesenteric artery, viprostol produced only a concentration-related relaxation in the range of 1 X 10(-6) to 1 X 10(-4) M. PGE2 produced a contraction and nitroglycerin produced a concentration-related relaxation. 5. In KCl-contracted thoracic aorta, PGE2 produced a biphasic response, relaxation at concentrations less than 3 X 10(-7) M and a concentration-related contraction at concentrations greater than 3 X 10(-7) M. Viprostol only produced a concentration-related contraction at concentrations greater than 1 X 10(-6) M, which was significantly less in magnitude than the contraction produced by PGE2. Nitroglycerin produced a concentration-related relaxation as seen in the small vessels. 6. In conclusion, the present data demonstrate that viprostol is a vasorelaxant agent which effectively dilates KCl-contracted basilar, small mesenteric artery and vein, but not the thoracic aorta of rat.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differences in acetylcholine- and bradykinin-induced vasorelaxation of the mesenteric vascular bed in spontaneously hypertensive rats of different ages

The present study examined whether alterations of endothelium-dependent vasorelaxation in spontaneously hypertensive rats (SHR) in response to the endothelium-dependent vasodilators acetylcholine and bradykinin ran parallel. We tried to find out the age at which endothelium-dependent vasorelaxation in response to each agonist became impaired and compared three different groups of SHR aged 7, 21 and 51 weeks. To be able to separate hypertension-induced alterations from age-dependent changes age-matched normotensive Wistar rats were included. Endothelium-dependent vasorelaxation was studied in the mesenteric vascular bed precontracted with noradrenaline, a typical resistance vessel, which showed relaxation to both acetylcholine and bradykinin, and the precontracted thoracic aorta, which only responded to acetylcholine.There were major differences in the agonist-dependent vasorelaxation between bradykinin and acetylcholine in SHR as a function of age. A surprising finding was that acetylcholine-induced relaxation was preserved, even slightly improved not only in young SHR (7 weeks) with developing hypertension but also in adult SHR (21 weeks) with established hypertension, which can be interpreted as a compensatory mechanism. As expected, in old SHR (51 weeks) acetylcholine induced vasorelaxation was impaired as a consequence of the detrimental effects of long-term hypertension on endothelium. The parallel changes observed with acetylcholine in the mesenteric vascular bed and thoracic aorta provided mutual confirmation.In clear contrast to acetylcholine bradykinin-induced vasorelaxation was already impaired in young SHR with developing hypertension suggesting that bradykinin-induced vasorelaxation is either much more sensitive to detrimental effects of (even slightly) increased blood pressure or, more likely, that there is a basic deficiency in the action of bradykinin in SHR. Thus, our study allows to conclude that impairment of acetylcholine-induced endothelium-dependent vasorelaxation in the mesenteric vascular bed of SHR is a secondary phenomenon developing as a consequence of long-term hypertension while the impaired bradykinin-induced vasorelaxation seems to be a primary phenomenon that could be closely related to the development of hypertension.     

Changes in α1-adrenergic vascular reactivity in monocrotaline-treated rats

In rats, injection of monocrotaline (MCT) causes pulmonary hypertension that leads to right ventricular failure. The aim of the present study was to characterize the responses of various vessels (the pulmonary artery, the thoracic aorta and small mesenteric arteries) to noradrenaline (NA; 10(-10)-10(-5) M) and carbachol (10 microM) in MCT-treated rats. For this purpose 6-week-old male Wistar rats ( n=13) were treated with 60 mg/kg MCT i.p. After 4-6 weeks the rats were killed and the heart, lungs and vessels removed and compared with those from age-matched saline-treated control rats ( n=47). First, the alpha(1)-adrenoceptor subtype(s) involved in the vascular NA-responses were characterized in normal rats using the alpha(1)-adrenoceptor subtype-selective antagonists 5-methylurapidil (5-MU; competitive alpha(1A)-adrenoceptor antagonist; 10(-8)-10(-6) M), BMY 7378 (competitive alpha(1D)-adrenoceptor antagonist; 10(-7)-10(-6) M) and chloroethylclonidine (CEC; irreversible alpha(1B)-adrenoceptor antagonist; 30 microM). In the pulmonary artery the pA(2) for BMY 7378 was 7.93, while that for 5-MU could not be calculated. CEC suppressed the NA-induced contraction significantly. In the thoracic aorta, the pA(2) for BMY 7378 was 8.06, while 5-MU was less effective (pA(2) 7.31). CEC again suppressed the NA-induced contraction significantly. In mesenteric arteries, CEC was ineffective whereas 5-MU induced a significant, rightwards shift of the concentration/response curve for NA (pA(2) 8.05). BMY 7378 had a lower pA(2) (6.6). MCT-treated rats developed an increased right ventricular pressure, obliteration of pulmonary vessels and inflammatory lung infiltration. In the pulmonary artery, but not in the thoracic aorta or mesenteric artery of MCT-treated rats NA-induced contraction was attenuated. In addition, carbachol-induced relaxation was reduced in the pulmonary and mesenteric arteries.In conclusion, NA-induced contraction is mediated predominantly by alpha(1A)-adrenoceptors in small mesenteric arteries, by alpha(1D)-adrenoceptors in the thoracic aorta (with a contribution from alpha(1A)- and alpha(1B)-adrenoceptors) and by alpha(1D)- and alpha(1B)-adrenoceptors in pulmonary arteries. MCT leads to reduced NA-responsiveness exclusively in the pulmonary artery that does not, however, account for the development of pulmonary hypertension, and to a more generalized endothelial dysfunction which may contribute to the pathogenesis of pulmonary hypertension in this model.