转染细胞色素P450表氧化酶基因对TNF-α损伤大鼠内皮依赖性血管舒张反应的保护作用及机制研究

目的研究过度表达表氧化酶基因,增加内源性EETs的产生是否对TNF-α损伤大鼠内皮依赖性血管舒张反应具有保护作用,并初步从对血管VCAM-1表达的影响探讨其机制。方法将携带细胞色素P450表氧化酶基因的真核表达载体pCB6质粒导入大鼠体内,2周后经静脉给予TNF-α,6 h后观察去甲肾上腺素预收缩的主动脉血管环对乙酰胆碱的舒张反应,并以western blot 检测血管中VCAM-1蛋白质的表达情况。结果 TNF-α降低了主动脉环对乙酰胆碱的舒张反应, CYP2C11、CYP2J2和CYPF87V基因转染使得这种被TNF-α降低的血管舒张反应增强。TNF-α增加了血管VCAM-1表达,CYP2C11、CYP2J2和CYPF87V基因转染使得这种被TNF-α诱导的VCAM-1表达减少。结论CYP2C11、CYP2J2和CYPF87V基因能提高了血管对舒血管物质的反应性。本研究提示,通过上调体内表氧化酶基因表达水平提高内源性EETs浓度可减轻炎症介导的血管损伤,这为研究动脉粥样硬化的防治提供了新的思路。     

Le nébivolol : premier bêtabloquant vasodilatateur à activité agoniste β3-adrénergique

Several studies suggest that the β₃-adrenergic stimulation could be a new therapeutic target for the treatment of cardiovascular diseases. The vascular effects induced by β₃-adrenergic stimulation are able to decrease the left ventricular strain allowing to reduce after-load. In addition, the increased coronary blood flow due to vasorelaxation increases the myocardial oxygene delivery. The hypothesis about the beneficial role of β₃-adrenoceptors is supported by recent data about a β-blocker of third generation, nebivolol, currently used in the treatment of heart failure and hypertension. The present review presents the β₃-adrenoceptors characteristics as well as its involvement in the cardiovascular effects of nebivolol.     

内皮功能异常在X综合征患者中的发病学意义

目的 研究内皮功能异常在Ｘ综合征患者中的发病学意义。方法 测定了１５例Ｘ综合征患者胸痛发作前后血中循环内皮细胞数（ＣＥＣ）和内皮素（ＥＴ）－１含量,并采用高分辨超声技术检测其血管内皮依赖性舒张功能的变化,与２０例正常人进行对照。结果 （１）Ｘ综合征患者ＣＥＣ数及ＥＴ－１水平明显高于正常对照组（Ｐ值均〈０．０１）。ＥＴ－１含量与ＣＥＣ数变化呈显著的正相关（ｒ＝０．６７,Ｐ〈０．０１）。（２）Ｘ综合征     

阿托伐他汀对不稳定型心绞痛患者血管内皮舒张功能的影响

目的 研究不稳定型心绞痛患者应用阿托伐他汀调脂治疗后对血管内皮舒张功能的影响。方法将62例不稳定型心绞痛患者随机分成阿托伐他汀治疗组（30例）及常规治疗组（32例），比较12周治疗前后应用高频超声检测肱动脉血流介导的舒张功能及还原酶法测定血中一氧化氮浓度变化。结果阿托伐他汀治疗12周后内皮依赖性血管舒张功能明显改善，一氧化氮浓度显著增加（P〈0．01），而常规治疗组治疗前后无显著差异（P〉0．05）。结论不稳定型心绞痛患者应用阿托伐他汀降脂治疗同时可改善血管内皮舒张功能。     

Inability of HDL from type 2 diabetic patients to counteract the inhibitory effect of oxidised LDL on endothelium-dependent vasorelaxation

Aims/hypothesis In healthy normolipidaemic and normoglycaemic control subjects, HDL are able to reverse the inhibition of vasodilation that is induced by oxidised LDL. In type 2 diabetic patients, HDL are glycated and more triglyceride-rich than in control subjects. These alterations are likely to modify the capacity of HDL to reverse the inhibition of vasodilation induced by oxidised LDL.Subjects and methods Using rabbit aorta rings, we compared the ability of HDL from 16 type 2 diabetic patients and 13 control subjects to suppress the inhibition of vasodilation that is induced by oxidised LDL.Results Oxidised LDL inhibited endothelium-dependent vasodilation (maximal relaxation [Emax]=58.2±14.6 vs 99.3±5.2% for incubation without any lipoprotein, p<0.0001). HDL from control subjects significantly reduced the inhibitory effect of oxidised LDL on vasodilatation (Emax=77.6±12.9 vs 59.5±7.7%, p<0.001), whereas HDL from type 2 diabetic patients had no effect (Emax=52.4±20.4 vs 57.2±18.7%, NS). HDL triglyceride content was significantly higher in type 2 diabetic patients than in control subjects (5.3±2.2 vs 3.1±1.4%, p<0.01) and was highly inversely correlated to Emax for oxidised LDL+HDL in type 2 diabetic patients (r=−0.71, p<0.005).Conclusions/interpretation In type 2 diabetes mellitus, the ability of HDL to counteract the inhibition of endothelium-dependent vasorelaxation induced by oxidised LDL is impaired and is inversely correlated with HDL triglyceride content. These findings suggest that HDL are less atheroprotective in type 2 diabetic patients than in control subjects.     

Assessment of noninvasive tests of cutaneous vascular control in the forearm using a laser Doppler meter and a Finapres blood pressure monitor

The control of human forearm cutaneous vascular resistance was examined using a combination of laser Doppler perfusion measurement and continuous Finapres blood pressure measurement. Tests which provoke changes in blood flow via different control mechanisms (local and neural) were applied in a group of ten healthy subjects. The purpose was to select from them a suitable (i.e. statistically significant) group to apply in cases where a disease process is suspected of interfering with the control of the skin circulation. Deep inspiration, immersion of the feet in water at 15°C (both eliciting sympathetic vasoconstrictor nerve activity) and arm dependency (eliciting the local veni-arteriolar response) produced statistically significant, symmetrical increases in cutaneous vascular resistance in both arms (p < 0.05, Wilcoxon's test for paired differences). Similarly, post-ischaemic reactive hyperaemia (mediated by local vasodilator mechanisms) and indirect heating of the body (eliciting increased sympathetic vasodilator nerve activity) resulted in significant decreases in cutaneous vascular resistance (p < 0.01). When deep inspiration was repeated from a vasodilated baseline after indirect heating, the increases in cutaneous vascular resistance were smaller than those obtained before heating. Isometric handgrip exercise failed to produce a significant change in contralateral cutaneous vascular resistance (p > 0.05). There were no differences between right and left arms for any test (p > 0.05). The successful tests were subjected to power analysis in order to predict likely patient sample sizes required to demonstrate altered responsiveness at sites of microcirculatory disturbance compared with normal skin.     

cAMP and cGMP do not mediate the vasorelaxation induced by iodinated radiographic contrast media in isolated swine renal arteries

Purpose: Vasodilatation is a frequent side effect of radiographic contrast media, partially due to a direct effect on vascular smooth muscles. Our purpose was therefore to examine any possible implication of the cyclic adenosine monophospate (cAMP) and cyclic guanosine monophosphate (cGMP) pathways in contrast media induced vasorelaxation.Material and Methods: Isolated segments of swine renal arteries were precontracted with 10 μM phenylephrine and relaxed with iomeprol before and after blockade of the cAMP and cGMP pathways.Results: 80 mM and 160 mM of iomeprol significantly relaxed about 52% and 68% of the precontracted arterial rings, respectively. 10 μm of IBMX, a phosphodiesterase inhibitor, did not increase the relaxant effect of 80 mM iomeprol but increased the relaxations induced by 400 nM forskolin by about 1.9 times (which stimulates the production of cAMP), and by 1 μm sodium nitroprusside (which stimulates the production of cGMP). 1 μm of H89 (an inhibitor of the cAMP-dependent protein kinase), was able to reduce the relaxation induced by 4 μM forskolin by about 2.5 times but had no significant effect on the relaxation induced by 160 mM iomeprol. 10 μM of ODQ (an inhibitor of the soluble guanylate cyclase), could reduce the relaxation induced by 10 μM of SNP but not the one induced by 160 mM iomeprol. Moreover, the absence of endothelial cells did not alter the relaxation induced by iomeprol.Conclusion: The activation of the cAMP and cGMP pathways are not involved in the in vitro relaxation induced by iomeprol in swine renal arteries.     

Iloprost

Zusammenfassung Iloprost ist ein länger wirkendes Prostazyklinanalogon mit starken vasodilatierenden Eigenschaften. Wird Iloprost per inhalationem angewandt, kommt es bereits kurze Zeit später zu einem deutlichen Abfall des pulmonalvaskulären Widerstands und damit zu einer Senkung des pulmonalarteriellen Drucks; die Wirkdauer wird dabei mit 60–120 min angegeben. Durch die selektiv pulmonale Anwendung können systemische Nebenwirkungen, wie ein systemischer Blutdruckabfall, weitestgehend vermieden werden. Die Verneblung von Iloprost kann entweder mit einem Ultraschallvernebler oder mit einem O₂-Fluss-betriebenen Vernebler durchgeführt werden. Beide Verneblertypen können problemlos in die üblichen Intensivrespiratoren integriert werden. Das Problem der Inhalation von Iloprost im Kreisteil eines Anästhesierespirators wurde durch eine spezielle Konstruktion gelöst.     

The cerebrovascular dilatation effects of olprinone, a phosphodiesterase III inhibitor, in comparison with acetazolamide--a pilot study

To examine the effects of olprinone, a phosphodiesterase III inhibitor, on cerebral blood flow (CBF), we compared the effects of olprinone on CBF to that of acetazolamide. Using technetium-99m-ethyl cysteinate dimer (^99mTc-ECD) brain SPECT, we measured regional CBF (rCBF) at 33 sites, including 16 right and left pairs of non-infarct cerebral cortexes, in seven stroke patients (66.0±3.2 years) in a resting state and 15 min after the administration of acetazolamide. Within 1 week, rCBF at each site was measured 15 min after the initiation of olprinone infusion. Resting rCBF showed a significant negative correlation with the change in rCBF (ΔCBF) during olprinone infusion (r=−0.43, P=0.013), but no significant correlation was seen following acetazolamide administration. The difference in rCBF between the right and left cortex increased more following acetazolamide administration (14.1±10.9 ml/(min 100 g)) than during olprinone infusion (5.4±4.8 ml/(min 100 g), P=0.013). The rCBF at four regions of interest (ROI) with low-resting CBF (<49 ml/(min 100 g)) further decreased following the administration of acetazolamide. The vasodilatory effects of olprinone are dependent on resting CBF instead of on the intracerebral steal phenomenon that occurs with acetazolamide.     

Unique gradual and sustained vasodilator response to substance P in the rabbit knee joint

The effects of substance P on blood flow, plasma extravasation, and knee joint sizes in the rabbit were investigated. Topical bolus application of substance P (1 nmol) onto the exposed rabbit knee joint capsule increased its blood flow from 15 min onwards and reached a peak of 46% at 90 min compared to saline administration. However, administration by the same route and the same dose of the NK(1) receptor agonist [Sar(9), Met (O(2))(11)]substance P produced no change on the knee joint blood flow compared to the saline control. The NK(1) receptor antagonist N(2)-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-L-prolyl]-N-m ethyl-N-phenylmethyl-3-(2-naphthyl)-L-alaninamide (FK888) and the NK(2) receptor antagonist (S)-N-methyl-N-[4-acetylamino-4-phenylpiperidino)-2-(3, 4-dichlorophenyl)-butyl] benzamide (SR48968), at 2x1 nmol and 2x10 nmol, had no effect on the substance P-induced response, which however was reduced by pyrilamine, cimetidine, and flurbiprofen (all at 2x10 nmol). N(G)-nitro-L-arginine methyl ester (L-NAME) and N(G)-nitro-D-arginine methyl ester (D-NAME), both at 2x100 nmol, did not significantly affect the substance P-induced response. Unilateral intra-articular administration of substance P (1 nmol) into synovial cavities of the rabbit knee joint increased basal blood flow of the ipsilateral joint at 4 h post-injection, and bilateral increase of basal blood flow was observed at 24 h. Plasma extravasation was significantly higher in the substance P-injected knee compared to the contralateral saline-injected knee at 4 h after intra-articular administrations, but not at 24 h. Knee joint sizes were not affected at both time points. The present study is the first to demonstrate that substance P possesses a gradual and persistent vasorelaxant action in the rabbit knee joint. This novel action of substance P is not mediated by NK(1) or NK(2) receptors, but involves histamine and prostaglandins. The degree of plasma extravasation elicited by substance P in the rabbit knee joint is small and short-lived, and with no concurrent oedema of the joint. These results suggest that substance P can evoke acute inflammatory responses in the rabbit knee joint, but on its own, it is unlikely to cause chronic joint inflammation in this species.