Effect of calcitonin gene-related peptide-induced preconditioning on attenuated endothelium-dependent vasorelaxation induced by lysophosphatidylcholine

目的：研究降钙素基因相关肽（ＣＧＲＰ）诱导预适应对溶血磷脂酰胆碱（Ｌｙｓ）抑制内皮依赖性舒张的作用．方法：用苯福林收缩兔与大鼠离体胸主动脉环，观察Ｌｙｓ对乙酰胆碱（ＡＣｈ）所致内皮依赖性舒张的影响．结果：ＣＧＲＰ预处理兔和大鼠离体胸主动脉环显著减轻Ｌｙｓ对ＡＣｈ舒血管效应的抑制，其作用可被蛋白激酶Ｃ（ＰＫＣ）抑制剂Ｈ７所取消．结论：ＣＧＲＰ诱导预适应对所致内皮细胞损伤具有拮抗作用，此作用与激活ＰＫＣ有关．     

甲基莲心碱对氧自由基损伤血管内皮细胞的保护作用

研究了甲基莲心碱（Ｎｅｆ）对外源性氧自由基损伤兔胸主动脉内皮及培养牛胸主动脉内皮细胞的保护作用．结果发现兔胸主动脉环暴露于Ｈ２Ｏ２（０．８ｍｍｏｌＬ－１）／ＦｅＳＯ４（０．２ｍｍｏｌＬ－１）系统３０ｍｉｎ后，乙酰胆碱（ＡＣｈ），二磷酸腺苷及Ａ２３１８７诱导的内皮依赖性舒张反应显著减弱，而硝酸甘油诱导的非内皮依赖性舒张反应不受影响．Ｎｅｆ依剂量性对抗氧自由基所致ＡＣｈ诱导的内皮依赖性舒张反应减弱．培养牛胸主动脉内皮细胞暴露于黄嘌呤／黄嘌呤氧化酶系统４８ｈ后，内皮细胞的生长被抑制６２％，Ｎｅｆ（０．１２５μｍｏｌＬ－１）可使之降为４９％．结果表明Ｎｅｆ对氧自由基所致的血管内皮细胞损伤具有保护作用．     

Mediation of calcitonin gene-related peptide in protection of ischemic preconditioning in rat hindlimbs

目的：研究降钙素基因相关肽（ＣＧＲＰ）介导缺血预适应对血管内皮的保护．方法：大鼠后肢缺血２ｈ后，观察乙酰胆碱诱导血管内皮依赖性舒张反应．结果：缺血不影响去甲肾上腺素的缩血管效应，但能显著削弱乙酰胆碱的舒血管效应．缺血预适应能阻止长时间缺血对乙酰胆碱舒血管效应的抑制作用，这种保护作用可被反复应用辣椒素耗竭ＣＧＲＰ所取消．急性应用辣椒素促进ＣＧＲＰ释放或外源性应用ＣＧＲＰ均可产生预适应样的保护作用．结论：大鼠后肢缺血预适应对内皮细胞的保护与辣椒素敏感的感觉神经有关；ＣＧＲＰ能模拟缺血预适应保护血管．     

Relationship between calcitonin gene-related peptide and endothelium-dependent vasorelaxation in streptozotocin-induced diabetic rats

在糖尿病大鼠，检测血浆降钙素基因相关肽（ＣＧＲＰ）含量的变化，并探讨其与血管内皮舒张功能的关系．糖尿病大鼠血浆ＣＧＲＰ的含量显著低于对照组（０．２２±０．０８ｖｓ０．３７±０．１３μｇ·Ｌ－１，Ｐ＜０．０１），但丙二醛含量显著增加；糖尿病大鼠胸主动脉对乙酰胆碱诱导内皮依赖性舒张反应显著降低．结果提示：糖尿病大鼠血管内皮舒张功能的削弱与血浆ＣＧＲＰ含量的下降有关．     

降钙素基因相关肽介导大鼠后肢缺血预适应的保护作用

目的：研究降钙素基因相关肽（ＣＧＲＰ）介导缺血预适应对血管内皮的保护。方法：大鼠后肢缺血２ｈ后，观察乙酰胆碱诱导血管内皮依赖性舒张反应。结果：缺血不影去甲蛹 腺素的缩血管效应，但能显著削弱乙酰胆碱的舒血管效应。缺血预适应能阻止长时间缺血对惭酰胆碱舒血管效应的抑制作用，这种保护作用可被反复应用辣椒素耗竭ＣＧＲＰ所取消。急性应用辣椒素促进ＣＧＲＰ释放或外源性应用ＣＧＲＰ均可产生预适应样的保护作用。结论     

卡托普利对糖基化终产物损伤大鼠血管内皮功能的保护作用

目的研究卡托普利对外源性制备的糖基化终末产物损伤大鼠离体胸主动脉环内皮依赖性舒张功能的影响及其机制。方法按文献方法制备糖基化终末产物,采用外源性糖基化终末产物（AGE-BSA）孵育大鼠离体胸主动脉环90 min诱导血管内皮功能的损伤,并观察卡托普利、超氧化物歧化酶和L-精氨酸对糖基化终末产物所致的血管内皮依赖性舒张反应损伤的影响。结果外源性糖基化终末产物孵育大鼠离体胸主动脉环90 min,明显抑制乙酰胆碱诱导的内皮依赖性血管舒张反应（endothelium-dependent relaxation,EDR）。但对硝普钠诱导的内皮非依赖性血管舒张反应没有影响。卡托普利（3、10和30μmol.L^-1）与AGE-BSA共同孵育血管环90 min,浓度依赖性地改善AGE-BSA对血管内皮依赖性舒张反应的损害。依那普利拉、氧自由基清除剂超氧化物歧化酶（superoxidedismutase,SOD,200 U.mL^-1）也可改善AGE-BSA对内皮依赖性血管舒张反应的损害,而L-精氨酸（L-argi-nine,L-Arg,3 mmol.L^-1）却没有明显的保护作用。结论卡托普利对AGE-BSA所引起的血管内皮依赖性舒张反应的损害具有明显的保护作用,该作用可能与其抗氧化作用有关,同时可能是部分巯基依赖性的。     

氨基胍对糖基化蛋白损伤大鼠血管内皮功能的影响

目的　探讨糖基化终末产物形成抑制药氨基胍对外源性制备的糖基化终末产物损伤大鼠离体胸主动脉环内皮依赖性舒张功能的影响及其机制。方法　采用外源性制备的糖基化牛血清白蛋白孵育大鼠离体胸主动脉环 60min诱导血管内皮损伤 ,观察氨基胍对糖基化牛血清白蛋白所致的血管内皮依赖性舒张反应损伤是否具有保护作用。结果　外源性糖基化牛血清白蛋白明显抑制乙酰胆碱诱导的内皮依赖性血管舒张反应 ,但并不影响硝普钠诱导的内皮非依赖性血管舒张反应。用氨基胍 (50～ 50 0 μmol·L- 1 )预孵育血管环 1 5min ,再与糖基化牛血清白蛋白共同孵育 60min ,呈浓度依赖性降低糖基化终末产物对血管内皮依赖性舒张反应的抑制。此外 ,氧自由基清除剂超氧化物歧化酶 (superox idedismutase,SOD ;2× 1 0 5U·L- 1 )也能完全取消糖基化终末产物的抑制作用 ,并与 50 0 μmol·L- 1 氨基胍的保护作用相似。氨基胍 (50 0 μmol·L- 1 )亦能完全逆转SOD抑制剂二乙基二硫氨甲酸酯 (diethyldithiocarbamate,DETC ;1 0 μmol·L- 1 )诱导产生内源性氧自由基所致的血管内皮依赖性反应的损害。结论　氨基胍能取消糖基化终末产物所致大鼠离体胸主动脉环内皮依赖性舒张反应的抑制 ,氨基胍的这种保护作用可能与其抗氧化作用有关     

尼可地尔及RP49356在高浓度胰岛素维持状态下的血管舒张作用

本研究旨在高胰岛素浓度状态，比较两处没结构的ＡＴＰ敏感钾通道开放剂尼可地尔及ＲＰ４９３５６对离体兔胸主动脉环的舒血管作用。结果显示，Ｎｉｃ、ＲＰ舒张苯肾上腺素诱导的血管收缩无内皮依赖性，格列苯脲能完全阻断ＲＰ的作用，，但仅部分抑制Ｎｉｃ的作用的。亚甲蓝仅对Ｎｉｃ的作用有部分抑制作用，Ｉｎｓ可加强ＲＰ的舒血管作用而对Ｎｉｃ的影响不明显，结果提示，ＲＰ在高胰岛素浓度状态下的血管舒张机制存在差异。     

黄芩苷对离体大鼠胸主动脉的舒张作用及机制

研究黄芩苷对大鼠离体胸主动脉环的舒张作用并探讨其可能的机制。记录去甲肾上腺素(NE)和KCl预收缩的大鼠离体主动脉环张力变化,观察黄芩苷的舒血管作用及不同工具药对其影响。实验发现黄芩苷对NE和KCl引起的去内皮和内皮完整大鼠胸主动脉环的收缩均有舒张作用;L-硝基精氨酸甲酯、亚甲蓝不能抑制黄芩苷对大鼠胸主动脉环的舒张作用,吲哚美辛能显著抑制;钾离子通道阻断剂4-氨基吡啶、四乙基胺、BaCl2不能抑制黄芩苷对胸主动脉环的舒张作用,格列苯脲能抑制黄芩苷的舒张作用;无钙环境下,黄芩苷预处理对NE收缩有明显抑制作用。因此,黄芩苷具有浓度依赖性血管舒张作用,此作用具有内皮依赖性和非内皮依赖性特点,内皮依赖性收缩可能与前列环素途径有关,非内皮依赖机制可能与KATP通道及钙离子通道有关。     

四乙酰葛根素对离体大鼠胸主动脉环作用初步研究

目的观察四乙酰葛根素（Tp）对离体大鼠胸主动脉环的作用以及作用机制。方法采用大鼠离体胸主动脉环灌流装置,观测四乙酰葛根素对重酒石酸去甲肾上腺素（NA）和氯化钾（Kcl）预收缩主动脉环张力的影响。结果四乙酰葛根素对去甲肾上腺素预收缩主动脉环有明显的舒张作用,与空白对照相比,具有显著性差异（P〈0．01）;由KCl引起主动脉环预收缩,Tp与空白对照相比,具有统计学差异（P〈0．01）,对内皮完整血管环的舒张作用明显强于去内皮血管环（P〈0．01）;Tp对NA在无钙液及正常钙液所致离体血管环收缩的舒张作用不明显（P〉O．05）。结论四乙酰葛根素的舒血管作用与受体依赖性钙通道和电压依赖性钙通道均有关,并且其舒血管作用可能与内皮有一定关系。     

链佐星所致糖尿病大鼠主动脉内皮依据舒张反应损伤的特征

AIM: To study whether impaired endothelium-dependent relaxation (EDR) in early diabetic mellitus in response to different receptor-mediated and nonreceptor-mediated vasodilators ran parallel and its possible mechanism. METHODS: Isometric tension recording in aortic rings from streptozotocin (Str)-induced diabetic and age-matched nondiabetic rats. RESULTS: EDR induced by receptor agonist acetylcholine (ACh), histamine (His) or bradykinin (BK) were all significantly reduced in diabetic rings compared with control rings, whereas nonreceptor agonist calcimycin-induced EDR was well reserved in diabetic rings [IC50 control: (0.13 +/- 0.07) mumol.L-1 diabetic: (0.14 +/- 0.06) mumol.L-1, P > 0.05, n = 7]. Cyclopiazonic acid (CPA) which also is a nonreceptor mediated endothelium-dependent vasorelaxant and cells' capacitative Ca2+ entry stimulant, failed to trigger EDR in diabetic rings. Pretreatment with N omega-nitro-L-arginine methylester (L-NAME, 0.3 mmol.L-1) not only abolished all of the EDR elicited by above mentioned vasodilators in either of diabetic or control rings, but also leveled responses triggered by each of the agonists between diabetic and control rings. Upon the maximal EDR induced by ACh (1 mol.L-1) or CPA (3 mumol.L-1) in phenylephrine (1 mumol.L-1) precontracted rings, calcimycin (1 mumol.L-1) further relaxed diabetic rings, but contracted control preparations. When endothelium was denuded, relaxation evoked by sodium nitroprusside and contractions triggered by CPA or His were all identical between diabetic and control rings. CONCLUSION: Receptor agonists but not nonreceptor agonists-induced EDR are commonly impaired in 4-wk Str-induced diabetic rat aorta, and this defective effect is attributable to the low formation of EDRF/NO which is related to impaired capacitative Ca2+ entry pathway in endothelium.     

高糖损伤兔主动脉内皮依赖性舒张反应(英文)

目的:研究高糖对兔胸主动脉内皮依赖性舒张反应(EDR)的影响及L-精氨酸、超氧化物歧化酶(SOD)和高糖撤除的作用。方法:以主动脉环EDR为检测指标。结果:高糖可使乙酰胆碱(ACh)诱导的EDR明显受损,高糖撤除24h后不能恢复ACh的舒血管作用,而甘露醇(19.5mmol·L~(-1))不影响血管环EDR。L-精氨酸1mmol·L~(-1)或SOD 150U·L~(-1)可取消高糖对EDR的损伤作用,高糖不影响硝普钠的舒血管作用。结论:高糖可损伤血管EDR,短时间高糖撤除不能逆转,其机制可能与自由基产生及L-精氨酸代谢改变有关。     

钾通道阻滞剂及毒毛花甙G对依血管内皮舒张作用的影响

四乙铵(TEA),Ba~(2+),格列本脲(可阻滞ATP敏感K~+通道)及毒毛花甙G均显著抑制Ach诱发的兔主动脉环依内皮舒血管效应.cromakalim的舒血管作用是不依赖内皮的,且为上述药物所抑制,本实验结果提示离体兔主动脉环上ACh诱发的依内皮舒张中,可能有ATP敏感的K~+通道及Na~-—K~+泵参与.     

Effects of ascorbic acid on impaired vascular reactivity in aortas isolated from age-matched hypertensive and diabetic rats

Impaired vascular reactivity is a hallmark of several cardiovascular diseases that include hypertension and diabetes. This study compared the changes in vascular reactivity in age-matched experimental hypertension and diabetes, and, subsequently, tested whether these changes could be affected directly by ascorbic acid (10 microM). Endothelium-derived nitric oxide (NO) modulation of ascorbic acid effects was also investigated. All the experiments were performed in the presence of a cyclooxygenase inhibitor, indomethacin (10 microM). Results showed that the endothelium-dependent and -independent relaxations induced by acetylcholine (ACh) and sodium nitroprusside (SNP), respectively, were blunted to a similar extent in isolated aortic rings from age-matched spontaneously hypertensive (SHR) (R(max): ACh = 72.83+/-1.86%, SNP = 96.6+/-1.90%) and diabetic (Rmax: ACh = 64.09+/-5.14%, SNP = 95.84+/-1.41%) rats compared with aortic rings of normal rats (Rmax: ACh = 89%, SNP = 104.0+/-1.0%). The alpha1-receptor-mediated contractions induced by phenylephrine (PE) were augmented in diabetic (Cmax = 148.8+/-9.0%) rat aortic rings compared to both normal (Cmax = 127+/-6.9%) and SHR (Cmax = 118+/-4.5%) aortic rings. Ascorbic acid pretreatment was without any significant effects on the vascular responses to ACh, SNP and PE in aortic rings from normal rats. Ascorbic acid significantly improved ACh-induced relaxations in SHR (Rmax = 89.09+/-2.82%) aortic rings to a level similar to that observed in normal aortic rings, but this enhancement in ACh-induced relaxations was only partial in diabetic aortic rings. Ascorbic acid lacked any effects on SNP-induced relaxations in both SHR and diabetic aortic rings. Ascorbic acid markedly attenuated contractions induced by PE in aortic rings from both SHR (Cmax = 92.9+/-6.68%) and diabetic (Cmax = 116.9+/-9.4%) rats. Additionally, following inhibition of nitric oxide synthesis with l-NAME, ascorbic acid attenuated PE-induced contractions in all aortic ring types studied. These results suggest that (1) vascular hyper-responsiveness to alpha(1)-receptor agonists in diabetic arteries is independent of endothelial nitric oxide dysfunction; (2) ascorbic acid directly modulates contractile responses of hypertensive and diabetic rat aortas, likely through mechanisms in part independent of preservation of endothelium-derived nitric oxide.     

Mediation of calcitonin gene-related peptide in protection of ischemic preconditioning in rat hindlimbs.

AIM: To study modulation of calcitonin gene-related peptide (CGRP) in the protective effect of ischemic preconditioning on endothelial cells. METHODS: Rat hindlmbs were subjected to ischemia for 2 h, and endothelium-dependent vasorelaxation to acetylcholine (ACh) was examined in rat hindlimbs. RESULTS: Two hours of ischemia elicited no effect on vasoconstrictor responses to norepinephrine, but markedly impaired vasodilator responses to ACh. Ischemic preconditioning induced by 5-min aortic occlusion and 10-min blood reperfusion prevented the impairment of vasorelaxation to ACh due to long-term ischemia. The protection of ischemic preconditioning was abolished by repeated pretreatments with capsaicin to deplete CGRP. Acute application of capsaicin to evoke CGRP release or CGRP caused an ischemic preconditioning-like protection. CONCLUSION: Capsaicin-sensitive sensory nerves are involved in the protective effect of ischemic preconditioning on endothelial cells in the rat hindlimbs, and CGRP can mimic the protective effect of ischemic preconditioning in blood vessels.     

Absence of effect of calcium antagonists on endothelium-dependent relaxation in rabbit aorta.

The effect of chronic feeding of New Zealand White rabbits with nicardipine (60 mg kg-1 daily for 5 weeks) on the endothelium-dependent relaxation (EDR) to acetylcholine (ACh) was examined in vitro. The effect of acute exposure to nicardipine and diltiazem (10 mumol l-1) in the tissue bath was also examined. A bioassay system for endothelium-dependent relaxation factor (EDRF) in which a rabbit aortic ring with endothelium removed was used as recipient and a segment of rabbit aorta with endothelium as donor (producing EDRF in response to ACh) was developed. This system enabled the effect of nicardipine on the synthesis/release and on the relaxation to EDRF to be studied separately. The maximum relaxations to ACh in control and nicardipine-fed animals were 43.6 +/- 5.5 and 53.8 +/- 6.7% (mean +/- s.e. mean) of the contractile response to noradrenaline (NA, 1 mumol l-1) (n = 6, P greater than 0.05). Similarly the EDR to ACh was not significantly altered by acute exposure (30 min) to nicardipine or diltiazem. The maximum relaxations without and with nicardipine were 32.4 +/- 4.2% and 28.0 +/- 3.1% of the contraction to NA (1 mumol l-1) (n = 11, P greater than 0.05). The corresponding data for diltiazem were 42.1 +/- 5.7 and 36.4 +/- 7.3% respectively (n = 11, P greater than 0.05). Both calcium antagonists inhibited the contraction induced by potassium (100 mmol l-1). Nicardipine and diltiazem in concentrations of 100 mumol l-1 reduced the potassium-induced contraction to 33.0 +/- 9.0% and 53.8 +/- 6.7% of control respectively (n = 6, P less than 0.05). In the bioassay experiments the infusion of nicardipine on (a) the recipient tissue only and (b) the donor and the recipient tissue had no significant effect on the relaxant response observed in the recipient tissue when superfused with Krebs-bicarbonate buffer containing ACh via the donor tissue (n = 6, P greater than 0.05). These results indicate that nicardipine and diltiazem had no significant effect on synthesis/release and the relaxant response to EDRF in the rabbit aorta. Thus the translocation of Ca2+ accompanying the EDR to ACh in the rabbit aorta is likely to utilize Ca2+ channels not blocked by these calcium antagonists.     

内源性阿片肽介导大鼠后肢缺血预适应的保护作用

研究了内源性阿片肽介导大鼠后肢缺血预适应的保护作用. 后肢缺血2 h，乙酰胆碱（ACh）诱导的血管内皮依赖性舒张性反应明显下降. 缺血预适应（缺血5 min，再灌5 min，重复3 次）能显著减弱长时间缺血对ACh舒血管效应的抑制作用，这种保护作用可被纳洛酮（3 mg·kg^-1）取消. 预先给予吗啡（300 μg·kg^-1）也能产生与缺血预适应相同的血管内皮保护作用. 然而，预先用辣椒素（50 mg·kg^-1）耗竭降钙素基因相关肽后，吗啡的保护作用被取消. 结果提示，内源性阿片肽介导大鼠后肢缺血预适应的血管保护作用，其机理可能涉及内源性降钙素基因相关肽.     

巯亚硝酸卡托普利的降低血管紧张性作用

目的：观察巯亚硝酰卡托普利（ＣａｐＮＯ）和卡托普利（Ｃａｐ）对血管紧张性的影响。方法：记录家兔胸主动脉环张力和大鼠肾动脉灌流压（ＰＰｒ）。结果：ＣａｐＮＯ对苯福林预收缩的内皮完整与去内皮主动脉环，均呈浓度依赖性（３０ｎｍｏｌ·Ｌ＾－１－１０μｍｏｌ·Ｌ＾－１，Ｐ〈０．０１）的舒张作用，而相同浓度的依赖性（１０ｎｍｏｌ·Ｌ＾－１－１０００ｎｍｏｌ·Ｌ＾－１呈显著性变化；Ｎ－单甲基左旋精氨酸和左旋精氨     

Divergent effects of vitamin C on relaxations of rabbit aortic rings to acetylcholine and NO-donors

1. Vitamin C may influence NO-dependent relaxation independently of effects on oxidant stress. 2. We investigated effects of vitamin C (0.1 -- 10 mmol l(-1)) on relaxation of pre-constricted rabbit aortic rings to acetylcholine (ACh), authentic NO and the NO-donors glyceryl trinitrate (GTN), nitroprusside (NP) and S-nitroso-N-acetyl-penicillamine (SNAP). DETCA (2 -- 6 mmol l(-1)), a cell permeable inhibitor of endogenous Cu-Zn superoxide dismutase (SOD) was used to increase intracellular superoxide anion (O(2)(-)). 3. Vitamin C reduced the response to ACh (71 +/- 7% inhibition of maximum relaxation at 10 mmol l(-1)) and inhibited relaxation to authentic NO. Vitamin C inhibited relaxation to GTN but potentiated relaxations to NP and SNAP, causing a parallel shift to a lower concentration range of the log dose-response curve by approximately one log unit at the highest dose. 4. Vitamin C increased the concentration of NO in bath solution (plus EDTA, 1.0 mmol l(-1)) following the addition of SNAP from 53 +/- 14 to 771 +/- 101 nmol l(-1) over the range 0.1-3.0 mmol l(-1). 5. DETCA inhibited relaxation to ACh (71 +/- 9% inhibition of maximum relaxation). This inhibition was abolished by a cell permeable SOD mimetic, but not by vitamin C. DETCA inhibited relaxation to SNAP but not that to NP nor to GTN. 6. Vitamin C inhibits endothelium-dependent relaxations of rabbit aortic rings to ACh and authentic NO and does not reverse impaired relaxation resulting from increased intracellular oxidant stress. Vitamin C potentiates relaxation to the NO-donors NP and SNAP by a mechanism that could involve release of NO from nitrosothiols.     

降钙素基因相关肽介导缓激肽预处理对离体大鼠心脏的保护作用

目的：研究降钙素基因相关肽（ＣＧＲＰ）在缓激肽预处理保护离体大鼠心脏中的调节作用。方法：Ｌａｎｇｅｎｄｏｒｆｆ法灌流心脏观测心功能与肌酸激酶（ＣＫ）释放。结果：缓激肽显著改善再灌时心功能（ＣＫ）释放。缓激肽作用可被缓激肽受体拮抗剂Ｈｏｅ１４０（１μｍｏｌ．Ｌ＾－１）或ＣＧＲＰ受体拮抗剂ＣＧＲＰ８－３７（０．１μｍｏｌ．Ｌ＾－１）所取消预先用辣椒素处理也能取水缓蚀激肽的作用。结论：缓激肽诱导预处理的