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。     

前胡丙素对高血压大鼠血管肥厚、细胞内钙、胶原及NO的影响

目的　研究前胡丙素对自发性高血压大鼠SHR及肾型高血压大鼠RHR的血管肥厚、细胞内钙、胶原、NO及血管收缩的反应性影响。方法用显微测微仪测定血管中膜层厚度,细胞大小,用Fura-2/AM为荧光指示剂,测定单细胞内［Ca²⁺］i,以测定羟脯氨酸含量反映胶原含量,用Griess法测定NO含量,以血管环观察收缩反应。结果　前胡丙素抑制血管中膜层增厚,维持细胞内［Ca²⁺］i稳态。减少胶原形成,增加SMCs释放NO。抑制血管环高反应状态。结论　前胡丙素抑制高血压血管肥厚,降低胶原含量及血管异常反应。     

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     

The alpha-adrenoceptor antagonist, zolertine, inhibits alpha1D- and alpha1A-adrenoceptor-mediated vasoconstriction in vitro

1. The antagonist effect of zolertine (4-phenyl-1-[2-(5-tetrazolyl)ethyl]piperazine trihydrochloride), on vascular contraction elicited by noradrenaline in aorta, carotid (alpha1D-adrenoceptors), mesenteric (alpha1A/D-adrenoceptors) and caudal arteries (alpha1A-adrenoceptors) from Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats and rabbit aorta (alpha1B-adrenoceptors), was investigated in endothelium-denuded arterial rings. 2. The selective alpha1D-adrenoceptor agonist, noradrenaline, elicited concentration-dependent contractions in all arterial rings from both species. Noradrenaline selectivity was: carotid = aorta > mesenteric = rabbit aorta > caudal arteries. 3. The contractile responses induced by noradrenaline were competitively antagonized by zolertine in rat carotid and aorta arteries, yielding pA2 values of WKY, 7.48 +/- 0.18; SHR, 7.43 +/- 0.13 and WKY, 7.57 +/- 0.24; SHR, 7.40 +/- 0.08, respectively. Zolertine was a non-competitive antagonist in some blood vessels as Schild plot slopes were lower than unity. The pKb estimates for zolertine were WKY, 6.98 +/- 0.16; SHR, 6.81 +/- 0.18 in the mesenteric artery, WKY, 5.73 +/- 0.11; SHR, 5.87 +/- 0.25 in the caudal artery and 6.65 +/- 0.09 in rabbit aorta. 4. Competition binding experiments using the alpha1-adrenoceptor antagonist [3H]prazosin showed a zolertine pKi of 6.81 +/- 0.02 in rat liver (alpha1B-adrenoceptors) and 6.35 +/- 0.04 in rabbit liver (alpha1A-adrenoceptors) membranes. 5. Zolertine showed higher affinity for alpha1D-adrenoceptors compared to alpha1A-adrenoceptors, while it had an intermediate affinity for alpha1B-adrenoceptors. The ability of the alpha1-adrenoceptor antagonist zolertine to block alpha1D-adrenoceptor-mediated constriction in different vessels of WKY and SHR rats may explain its antihypertensive efficacy despite its low order of potency.     

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。     

培哚普利,普萘洛尔与双氢氯噻嗪对自发性高血压大鼠心血管结？…

AIM: To investigate the effects of perindopril, propranolol, and dihydrochlorothiazide on artery wall thickening, left ventricular hypertrophy, and cardiac fibrosis in spontaneously hypertensive rats (SHR). METHODS: After measurement of systolic blood pressure (SBP), 16-wk-old Male SHR were randomly divided into 3 groups (each n = 10), given perindopril (Per, 5 mg.kg-1.d-1), propranolol (Pro, 40 mg.kg-1.d-1), dihydrochlorothiazide (DCT, 100 mg.kg-1.d-1) respectively by gavage for 12 wk. Sex-, age-, and number-matched untreated SHR and normotensive Wistar Kyoto rats (WKY) served as controls. When the treatment finished, body weights (BW) and SBP were measured before decapitation of the rats. The heart was excised rapidly, the left ventricle was weighed and then subjected to collagen content analysis. Vascular wall and lumen ratio from aorta, renal arteries and branch III vessels of mesenteric arteries were determined morphometrically. RESULTS: Treated rats in 3 groups showed a lower SBP and the ratio of left ventricle weight to body weight (LVW/BW) compared with WKY. Artery wall thickening was similarly inhibited in the treated groups. Per and Pro inhibited cardiac fibrosis, but collagen concentration increased in DCT treated SHR [collagen volume fraction (CVF): 19 +/- 4 vs SHR 14 +/- 4, P < 0.05; perivascular collagen fraction(PVCF): 84 +/- 7 vs SHR 79 +/- 5, P < 0.05]. CONCLUSION: Per and Pro inhibited, but DCT promoted, cardiac fibrosis.     

二-(4-氯苯甲酰异羟肟酸)二正丁基合锡(DBDCT)对大鼠离体胸主动脉环的舒张作用及机制

目的观察抗肿瘤化合物二-(4-氯苯甲酰异羟肟酸)二正丁基合锡(DBDCT)对去甲肾上腺素和氯化钾预收缩健康成年大鼠胸主动脉环的舒张作用,并探讨其作用机制。方法应用离体血管环技术观察DBDCT对大鼠胸主动脉环张力的作用,然后使用一氧化氮合酶(eNOS)抑制剂L-NAME、环氧合酶抑制剂吲哚美辛(Indo)和不同的钾通道阻滞剂预孵后观察DBDCT对血管环张力改变的影响,并观察DBDCT对NE诱发的内钙释放和CaCl2引起的外钙内流的影响。结果 DBDCT对去甲肾上腺素(NE,10-6mol·L-1)或氯化钾(KCl,60 mmol·L-1)预收缩的内皮完整和去内皮大鼠离体胸主动脉环均产生明显的舒张作用,与溶剂组相比差异有统计学意义(P<0.01);但DBDCT对内皮完整与去内皮胸主动脉环作用差异无统计学意义。预先用L-NAME、Indo、KV通道阻断剂四氨基吡啶(4-AP)、KATP通道阻断剂格列苯脲(Gli)孵浴后,DBDCT对NE和KCl预收缩的血管张力的改变与无阻断药时比较,均差异无统计学意义(P>0.05);预先用KCa通道阻断剂四乙胺(TEA)、Kir通道阻断剂氯化钡(BaCl2)孵浴后,DBDCT的舒张血管作用减弱,与无阻断药比较差异有统计学意义(P<0.05);且DBDCT对NE诱发的内钙释放和外钙内流引起的收缩均有明显的抑制作用。结论 DBDCT可明显降低由NE和KCl诱发的血管环张力的升高,且其作用与内皮生成的NO和PGI2均无关,而可能是直接作用于血管平滑肌,激活KCa和Kir通道,抑制钙内流和肌浆网钙释放。     

依托咪酯削弱去甲肾上腺素对自发性高血压大鼠离体胸主动脉收缩作用的实验研究

目的:观察不同浓度的依托咪酯对自发性高血压大鼠(SHR)和正常血压大鼠(NTR)离体血管收缩功能的影响。方法:取雄性NTR和SHR各18只,二者均分为依托咪酯干预组(再分为低、中、高浓度组,即5×10-6、3×10-5、5×10-5mol·L-1,n=6)、生理盐水对照组(n=6)和溶剂对照组(20%力保肪宁脂肪乳剂,n=6);分离各组大鼠胸主动脉的血管环并以不同试药溶液预孵后,加入不同浓度的去甲肾上腺素(NE)收缩血管环,将其悬挂于血管张力测量装置后连续记录血管张力的变化(g)以观察血管收缩幅度。结果:与NTR各组比较,SHR各组血管由NE引起的收缩幅度明显增强(P<0.05或P<0.01);与对照组比较,NTR组中中、高浓度的依托咪酯可减弱血管收缩幅度(P<0.05或P<0.01),SHR组中3种浓度的依托咪酯均可减弱血管收缩幅度(P<0.05或P<0.01),并呈浓度依赖性;在同种NE浓度下,高浓度的依托咪酯对SHR组的血管收缩幅度的作用显著大于NTR组(P<0.05或P<0.01)。结论:SHR胸主动脉对NE的反应性与NTR比较显著增强,依托咪酯可削弱NE对血管的收缩作用且对SHR作用更明显。     

The α‐adrenoceptor antagonist,zolertine, inhibits α1D‐ and α1A‐adrenoceptor‐mediated vasoconstriction in vitro

1 The antagonist effect of zolertine (4‐phenyl‐1‐[2‐(5‐tetrazolyl)ethyl]piperazine trihydrochloride), on vascular contraction elicited by noradrenaline in aorta, carotid (α1D‐adrenoceptors), mesenteric (α1A/D‐adrenoceptors) and caudal arteries (α1A‐adrenoceptors) from Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats and rabbit aorta (α1B‐adrenoceptors), was investigated in endothelium‐denuded arterial rings.
2 The selective α1D‐adrenoceptor agonist, noradrenaline, elicited concentration‐dependent contractions in all arterial rings from both species. Noradrenaline selectivity was: carotid=aorta>>.Gt;mesenteric=rabbit aorta>caudal arteries.
3 The contractile responses induced by noradrenaline were competitively antagonized by zolertine in rat carotid and aorta arteries, yielding pA2 values of WKY, 7.48±0.18; SHR, 7.43±0.13 and WKY, 7.57±0.24; SHR, 7.40±0.08, respectively. Zolertine was a non‐competitive antagonist in some blood vessels as Schild plot slopes were lower than unity. The pKb estimates for zolertine were WKY, 6.98±0.16; SHR, 6.81±0.18 in the mesenteric artery, WKY, 5.73±0.11; SHR, 5.87±0.25 in the caudal artery and 6.65±0.09 in rabbit aorta.
4 Competition binding experiments using the α1‐adrenoceptor antagonist [³H]prazosin showed a zolertine pKi of 6.81±0.02 in rat liver (α1B‐adrenoceptors) and 6.35±0.04 in rabbit liver (α1A‐adrenoceptors) membranes.
5 Zolertine showed higher affinity for α1D‐adrenoceptors compared to α1A‐adrenoceptors, while it had an intermediate affinity for α1B‐adrenoceptors. The ability of the α1‐adrenoceptor antagonist zolertine to block α1D‐adrenoceptor‐mediated constriction in different vessels of WKY and SHR rats may explain its antihypertensive efficacy despite its low order of potency.