巯亚硝基卡托普利的抗高血压效应

目的观察巯亚硝基卡托普利（ＣａｐＮＯ）对不同类型高血压大鼠血压的影响并与卡托普利（Ｃａｐ）相比较。方法记录麻醉和清醒大鼠颈动脉血压。结果ＣａｐＮＯ对正常大鼠、急性二肾一夹高血压大鼠；自发性高血压大鼠均表现明显的剂量依赖性的降压效应，且强于同剂量Ｃａｐ。其特点表现早、快、强而持久，加速降压速率，延长降压时程、增大降压曲线面积，尤其对舒张压的降压影响更显著于对收缩压的影响，上述作用在高血压动物的表现均较正常血压动物更明显。结论ＣａｐＮＯ抗高血压作用优于Ｃａｐ，其对舒张压的作用强于对收缩压的影响。     

巯亚硝基卡托普利的抗高血压效应

AIM　To compare antihypertensive effects of S-nitrosocaptopril (CapNO) and Captopril in hypertensive models. METHODS　Measurements of cartoic arterial pressure were carried out in either anesthetized or awake rats. RESULTS　CapNO produced dosedependent antihypertensive effects in anesthetized normative, acute two-kidney one-clipped rats and awake spontancously hypertensive rats. CapNO showed a fast set-up, a prolonged time-course and a large area of depressor curve in decreasing blood pressure. The inhibition of diastolic pressure by CapNO was more prominent than Cap. CapNO preferentially inhibited the diastolic pressure, and the depressor effects of CapNO were more potent in hypertensive rats than in normative rats. CONCLUSION　CapNO preferentially inhibits diastolic pressure in various hypertensive rats and the hypotensive effects of CapNO are potent than that of Cap.     

Inhibitory effects of S-nitrosocaptopril on vasomotor tone

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Ｃａｐ作用不显著；ＣａｐＮＯ降低ＰＰｒ的作用亦呈浓度依赖性（１０ｎｍｏｌ·Ｌ－１－１０００ｎｍｏｌ·Ｌ－１，Ｐ＜００１），而Ｃａｐ只在１０００ｎｍｏｌ·Ｌ－１呈显著性变化；Ｎ单甲基左旋精氨酸和左旋精氨酸预处理均不影响ＣａｐＮＯ诱发的降ＰＰｒ作用．结论：ＣａｐＮＯ具有直接降低血管紧张性作用．     

巯亚硝基血红蛋白在小鼠体内产生一氧化氮的作用

本文用Ｂａｌｂ／ｃ小鼠观察了巯亚硝基蛋白在体内产生一氧化氮的量效关系，结果发现，ＳＮＯ－Ｈｂ在体内可剂量信赖地产生ＮＯ。     

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。     

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。     

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     

磺柳硝胺的体外舒血管作用

给予磺柳硝胺后，离体兔胸主动脉血管环标本呈剂量依赖性舒张，此作用被亚甲蓝阻断而与血管内皮存在与否无关。结果显示，磺柳硝胺释放一氧化氮发挥舒血管作用。     

巯亚硝基卡托普利对环匹阿尼酸引起的平滑肌细胞胞浆游离Ca^2＋浓度升高作用的影响

目的探讨巯亚硝基卡托普利(S-nitrosocaptopril,CapNO)对Ca 2+池操纵性Ca2+内流信号转导过程的影响.方法以Fura-2 荧光探针测定胞浆游离Ca2+ 浓度([Ca2+]I ).结果①CapNO(20～120 μmol·L -1)呈浓度依赖性抑制环匹阿尼酸(cyclopiazonic acid, CPA)引起的 [Ca2+]I升高,80 μmol·L-1 CapNO为最大效应浓度.相同浓度的captopril对CPA升高[Ca2+ ]I无明显抑制作用.②在80 μmol·L-1 CapNO抑制CPA引起[Ca2+]I升高作用的基础上(31%±11%);随后加入1 μmol·L-1硝苯地平不能降低[Ca2+ ]I,再加入20 μmol·L-1SK&F96365(最大效应浓度)可进一步降低 [Ca 2+]I(54%±18%),其中SK&F96365净抑制率为24%±10%,与SK&F96365单独作用抑制率(54%±11%)比较差异有显著性.③不同顺序给予最大效应浓度CapNO(80 μmol·L -1)和tyrphostinAG490(2 μmol·L-1)对CPA引起[Ca2+]I升高存在交叉抑制作用.结论 CapNO可通过阻断电压依赖性Ca2+通道和Ca 2+池操纵性Ca2+通道抑制CPA引起的[Ca2+]I升高,CapNO对CPA引起[ Ca2+]I升高的阻断作用存在酪氨酸激酶(Janus2亚型)敏感和非敏感两条途径.     

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。     

Inhibitory effects of imidazolines on histamine liberation from human leukocytes and on tracheal smooth muscle tone.

Antigen-induced IgE-mediated release of histamine from human leukocytes, an in vitro model of allergic reactions, was blocked by imidazole and imidazole-compounds such as oxymetazoline and clonidine. The H-2-antihistamines antagonized this effect of imidazolines. Alpha- and H-1-receptor blocking agents did not antagonize the effect. The contractile effects of the imidazolines were tested on tracheal preparations from the cow and guinea-pig. Imidazole was found to be a rather potent contracting agent, while oxymetazoline only caused weak contractions. Clonidine relaxed the tracheal muscles, when used in the concentration range which were inhibitory in the leukocyte experiments. The contractions caused by imidazolines were non-competitively inhibited by clemastine, while the relaxing effects were blocked by a combination of propranolol, phentolamine and cimethidine. The results suggest that imidazolines which inhibit histamine release and relax bronchial smooth muscles may be of therapeutic importance in the treatment of human allergic disorders.     

Assessment of changes in vasomotor tone in vivo using intravascular ultrasound.

This study tested the capability of high-frequency, two-dimensional real-time intravascular ultrasound (IVUS) in the detection of dynamic changes of large vessel diameter in vivo. An IVUS-catheter (4.8 French, 20-MHz mechanical transducer) was inserted via the femoral vein, and advanced to the inferior vena cava of anesthetized rabbits (n = 7). The depth of field of the transducer allowed for visualization of the entire cross-sections of both the inferior vena cava (IVC) and the adjacent aorta. Changes in vessel diameter were induced pharmacologically using norepinephrine (NE) and glyceryltrinitrate (GTN), which were injected intravenously before and after the administration of L-NG-nitro-arginine methyl ester) L-NAME, a specific inhibitor of endothelium-derived relaxing factor (EDRF)-biosynthesis. Vasoconstriction and -dilation could be observed continuously from the two-dimensional real-time recordings of vessel cross-sections. Vessel diameters and cross-sectional areas (CA) were measured from still frames at given time intervals of drug infusion, and blood pressure and heart rate were recorded continuously. Following NE, an increase of aortic and a simultaneous decrease of venous CA were observed, while GTN elicited the opposite responses. Inhibition of EDRF was followed by an augmentation of the vascular responses. It is concluded that IVUS is capable of detecting changes in vascular dimensions in vivo. Thus in large vessels, IVUS may become a method for the direct assessment of vasomotion in vivo.     

S-nitrosocaptopril: in vitro characterization of pulmonary vascular effects in rats

(1) On rat isolated pulmonary arteries, vasorelaxation by S-nitrosocaptopril (SNOcap) was compared with S-nitrosoglutathione (GSNO) and nitroprusside, and inhibition by SNOcap of contractions to angiotensin I was compared with the angiotensin converting enzyme (ACE) inhibitor, captopril. (2) SNOcap was equipotent as a vasorelaxant on main (i.d. 2-3 mm) and intralobar (i.d. 600 micro m) pulmonary arteries (pIC(50) values: 5.00 and 4.85, respectively). Vasorelaxant responses reached equilibrium rapidly (2-3 min). (3) Pulmonary vasorelaxant responses to SNOcap, like GSNO, were (i) partially inhibited by the soluble guanylate cyclase inhibitor, ODQ (1H-(1,2,4) oxadiazolo(4,3-a)-quinoxalin-1-one; 3 micro M) whereas responses to nitroprusside were abolished and (ii) potentiated by hydroxocobalamin (HCOB; NO. free radical scavenger; 100 micro M) whereas responses to nitroprusside were inhibited. (4) The relative potencies for pulmonary vasorelaxation compared with inhibition of platelet aggregation were: SNOcap 7 : 1; GSNO 25 : 1; nitroprusside >2000 : 1. (5) SNOcap, like captopril, concentration-dependently and time-dependently increased the EC(50) for angiotensin I but not angiotensin II. The dependence on incubation time was independent of the presence of tissue but differed for SNOcap and captopril. This difference reflected the slow dissociation of SNOcap and instability of captopril, and precluded a valid comparison of the potency of the two drugs. After prolonged incubation (>/=5.6 h) SNOcap was more effective than captopril. (6) Thus, in pulmonary arteries SNOcap (i) possesses NO donor properties characteristic of S-nitrosothiols but different from nitroprusside and (ii) inhibits ACE at least as effectively as captopril. These properties suggest that SNOcap could be valuable in the treatment of pulmonary hypertension.     

Antiangiogenic effects of S-nitrosocaptopril crystals as a nitric oxide donor

Angiogenesis is the formation of new capillaries from preexisting vessels by migration and proliferation of endothelial cells, which produce a cellular signaling messenger, nitric oxide (NO). The purpose of the present study was to examine the effects of exogenous NO donors on angiogenesis by using a novel crystalline NO donor, S-nitrosocaptopril. The characteristic X-ray diffraction pattern of S-nitrosocaptopril was demonstrated for the first time. On primary capillary endothelial cells pretreated with vascular endothelium growth factor (VEGF), S-nitrosocaptopril (1-500 microM), but not captopril, produced a dose-dependent inhibition of endothelial proliferation. On chick embryos of entire living eggs, gelatin sponges adsorbed with VEGF were implanted on the embryo chorioallantoic membrane to promote vascular growth activity within the sponges. Addition of S-nitrosocaptopril crystals (0.1 mg) to the gelatin sponges markedly reduced vascular density around the sponges, whereas captopril did not inhibit neovascularization. The vascular hemoglobin content surrounding each of the gelatin sponges was determined as a confirmatory test. S-nitrosocaptopril, but not captopril, significantly decreased the hemoglobin content of the embryo tissues immediately surrounding the gelatin sponges. In conclusion, S-nitrosocaptopril exerts an inhibitory effect on angiogenesis. This newly discovered function of S-nitrosocaptopril appears to be governed by distinct structural NO moiety.     

Impact of obesity and insulin resistance on vasomotor tone: nitric oxide and beyond

1. Obesity is rapidly increasing in Western populations, driving a parallel increase in hypertension, diabetes and vascular disease. Prior to the development of overt diabetes or hypertension, obese patients spend years in a state of progressive insulin resistance and metabolic disease. Mounting evidence suggests that this insulin-resistant state has deleterious effects on the control of blood flow, thus placing organ systems at a higher risk for end-organ damage and increasing cardiovascular mortality. 2. The purpose of the present review is to examine the current literature on the effects of obesity and insulin resistance on the acute control of vascular tone. Effects on nitric oxide (NO)-mediated control of vascular tone are particularly examined with regard to proximal causes and distal mechanisms of the impaired NO-mediation of vasodilation. 3. Finally, novel pathways of impaired control of perfusion are summarized from the recent literature to identify new avenues of exploring impaired vascular function in patients with metabolic disease.     

Influence of graded changes in vasomotor tone on the carotid arterial mechanics in live spontaneously hypertensive rats.

1. The contribution of vasomotor tone to the increased stiffness of carotid arteries in living spontaneously hypertensive rats (SHR) is largely unknown. Whether a reduced vascular tone is associated with an increase or a decrease in arterial stiffness in vivo remains to be determined. The goal of the present investigation was to show that a decrease in vascular tone is associated with a decrease in arterial stiffness, independent of the structural composition of the arterial wall. 2. New high resolution echo-tracking techniques were used to evaluate pulsatile changes of carotid blood pressure and diameter following transient and graded changes of vasomotor tone produced by the dihydropyridine derivative, isradipine. Treatment for 8 weeks was given to groups of SHR rats either with a low (0.6 kg day-1) or a high (2.6 mg kg-1 day-1) dose. Another SHR group received an acute dose of 2.6 mg kg-1 day-1. Results were compared to those of placebo-treated Wystar-Kyoto (WKY) and SHR rats. Whatever the dosage, acute or chronic calcium blockade caused a decrease in blood pressure which was maximal 1 h after administration and disappeared after the 16th h. Carotid arterial thickness and the composition of the arterial wall was determined from histomorphometry. 3. In placebo-treated SHR, the inverse relationship relating blood pressure to carotid arterial distensibility was significantly shifted toward higher values of blood pressure compared to the curve of normotensive placebo-treated WKY rats. The curve of SHR receiving chronically a non antihypertensive (0.6 mg kg-1 day-1) isradipine dose prolonged that of placebo-treated SHR toward lower values of blood pressure, so that carotid distensibility was significantly higher than in WKY for the same diameter and blood pressure level (145 mmHg). With administration of a chronic antihypertensive dose (2.6 mg kg-1 day-1) causing a significant decrease in arterial function. Acute antihypertensive calcium blockade with a single isradipine dose (2.6 mg kg-1 day-1) caused a similar shift in the pressure-distensibility curve toward the WKY curve although the histomorphometric composition of the arterial wall differed significantly from that of chronically treated animals.(ABSTRACT TRUNCATED AT 400 WORDS)     

Calcitonin gene-related peptide (CGRP) is a potent non-endothelium-dependent inhibitor of coronary vasomotor tone.

1 Ring segments of bovine left circumflex coronary artery were pre-contracted with 5-hydroxytryptamine or phenylephrine and then exposed to increasing concentrations of calcitonin gene-related peptide (CGRP) and other drugs. 2 CGRP administration resulted in dose-dependent inhibition of induced tone. Maximal relaxation to CGRP was 89 +/- 5% and the concentration required to achieve 50% maximal relaxation (EC50) was 2.11 +/- 1.35 X 10(-9)M. 3 CGRP-induced relaxation was not affected by removal of endothelial cells nor was it significantly altered by incubation of coronary vessels with atropine, propranolol, phentolamine (all 10(-6)M) or indomethacin (10(-5)M). 4 From these data we conclude that CGRP is a potent inhibitor of coronary artery vasomotor tone which appears to act directly on vascular smooth muscle rather than through the release of a secondary mediator. These data support the possibility that CGRP may play a role in non-adrenergic, non-cholinergic regulation of coronary artery tone.     

Effect of imipramine on the vasomotor tone, blood supply and activity of the heart

In tests conducted on anesthetized cats it was shown that imipramine used in doses of 1 and 3 mg/kg causes hypertension, increases the vascular tone in the kidneys and limbs. In doses of 5 and 10 mg/kg the drug provokes a short-lived (1--3 minutes) hypertension with a subsequent prolonged drop of the arterial pressure. The tonicity of the kidney and limb arteries changes in the same way as the arterial pressure, but the vascular tone in the heart only falls. In these doses imipramine blocks the adrenergic transmission of the excitation from the sympathetic nerve to the effector, e. g. produces a sympatholytic effect. Imipramine in a dose of 1 mg/kg intensifies the coronary circulation and then the oxygen absorption by the heart increases to a still greater degree. This is attended by the development of tachycardia, a greater cardiac output and an intensified contractility of the myocardium. In doses of 5 and 10 mg/kg imipramine protractedly reduces the cardiac ejection, coronary blood flow and significantly lowers the contractile function of the heart muscle.