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。     

Pharmacological characteristics of Kampo medicine as a mixture of constituents and ingredients

Herbal medicine in Japan is termed as Kampo medicine, which is derived from traditional Chinese medicine. Shakuyakukanzoto (Shao-Yao-Gan-Cao-Tang) as a kind of Kampo formulations is composed of just two components; Paeoniae Radix and Glycyrrhizae Radix, which produced marked relaxation of intestinal tract. Mokuboito (Mu-Fang-Ji-Tang) inhibited cardiac ionic channel currents, and as a mixture also produced great vasodilatation. Sinomenine (a main ingredient of Mokuboito) as a single compound also caused the vasodilatation, but decreased it along with ageing. Gypsum containing in Mokuboito and Chotosan (Diao-Teng-San) caused more marked effects, as compared with those without Gypsum. On the other hand, Rokumigan (Liu-Wei-Wan), Hachimijiogan (Ba-Wei-Di-Huang-Wan) and Goshajinkigan (Niu-Che-Shen-Qi-Wan) increase in order the number of contained ingredients. The formulations with more herbs (ingredients) produced much more effective actions on rat aorta, presumably due to compensation of the decline of pharmacological sensitivity with ageing. Thus, there are some important differences between single chemical drugs and mixture drugs with many ingredients. The effects of Kampo medicine (mixture) are never just a sum of each effect induced by a lot of ingredients. For elder persons, furthermore, Kampo medicine exerts more effective actions.     

Histamine-induced vasodilatation in the human forearm vasculature

Aim

To investigate the mechanism of action of intra-arterial histamine in the human forearm vasculature.

Methods

Three studies were conducted to assess changes in forearm blood flow (FBF) using venous occlusion plethysmography in response to intra-brachial histamine. First, the dose–response was investigated by assessing FBF throughout a dose-escalating histamine infusion. Next, histamine was infused at a constant dose to assess acute tolerance. Finally, a four way, double-blind, randomized, placebo-controlled crossover study was conducted to assess FBF response to histamine in the presence of H₁- and H₂-receptor antagonists. Flare and itch were assessed in all studies.

Results

Histamine caused a dose-dependent increase in FBF, greatest with the highest dose (30 nmol min⁻¹) infused [mean (SEM) infused arm vs. control: 26.8 (5.3) vs. 2.6 ml min⁻¹ 100 ml⁻¹; P < 0.0001]. Dose-dependent flare and itch were demonstrated. Acute tolerance was not observed, with an increased FBF persisting throughout the infusion period. H₂-receptor antagonism significantly reduced FBF (mean (95% CI) difference from placebo at 30 nmol min⁻¹ histamine: −11.9 ml min⁻¹ 100 ml⁻¹ (−4.0, −19.8), P < 0.0001) and flare (mean (95% CI) difference from placebo: −403.7 cm² (−231.4, 576.0), P < 0.0001). No reduction in FBF or flare was observed in response to the H₁-receptor antagonist. Itch was unaffected by the treatments. Histamine did not stimulate vascular release of tissue plasminogen activator or von Willebrand factor.

Conclusion

Histamine causes dose-dependent vasodilatation, flare and itch in the human forearm. H₂-receptors are important in this process. Our results support further exploration of combined H₁- and H₂-receptor antagonist therapy in acute allergic syndromes.     

超声评价无大血管并发症的2型糖尿病患者血管内皮舒张功能及其影响因素分析

目的 超声评价无大血管并发症的2型糖尿病患者血管内皮舒张功能并分析其影响因素.方法 选择无大血管并发症的2型糖尿病患者50例(糖尿病组),以34名年龄、性别相匹配健康志愿者作对照(健康对照组).超声检测、计算肱动脉血流介导的内皮依赖性血管舒张功能(FMD)和硝酸甘油介导的内皮非依赖性血管舒张功能(NMD),同时检测血糖(FBG)、糖化血红蛋白(HbA1c)、总胆固醇(TC)、三酰甘油(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、载脂蛋白A1(ApoA1)、载脂蛋白B(ApoB)、脂蛋白α(Lpα)、血清铁蛋白(SF)和氧化低密度脂蛋白(ox-LDL)水平.采用多元线性回归分析分析FMD、NMD与实验室检测指标之间的关系.结果 (1)糖尿病组FBG、HbA1c、TC、TG、LDL-C、ApoB、Lpα、SF和ox-LDL水平分别为(8.58±1.90)mmol/L、(8.66±2.60)%、(5.43±0.79)mmol/L、(1.96±0.94)mmol/L、(3.22±0.73)mmol/L、(0.87±0.23)g/L、(215.69±81.9 )mg/L、(279.19±92.68)ng/ml、(24.95±7.2)μg/dl,均明显高于健康对照组的(5.31±0.42)mmol/L、(5.16±0.41)% 、(4.64±0.54)mmol/L、(1.45±0.62)mmol/L、(2.32±0.55)mmol/L、(0.69±0.16)g/L、(178.26±20.2 )mg/L、(151.21±84.37)ng/ml、(10.62±8.46)μg/dl,且差异均有统计学意义(t值分别为2.653、2.986、2.252、2.224、2.321、2.096、2.786、2.965、2.996,P均＜0.05).糖尿病组HDL-C水平为(1.02±0.23)mmol/L,明显低于健康对照组的(1.27±0.25)mmol/L,差异也有统计学意义(t=2.320,P均＜0.05).(2)糖尿病组FMD、NMD分别为(7.10±2.23)%、(20.22±4.68)%,均高于健康对照组的(4.11±1.13)% 、(13.02±4.25)%,且差异有统计学意义(t=2.217、2.121,P均＜0.05).(3)多元线性回归分析提示,FMD和TC、ApoB、SF和ox-LDL水平显著相关(r=0.681,P＜0.05),而NMD只与TC和ApoB水平显著相关(r=0.642,P＜0.05).结论 2型糖尿病早期患者血管内皮舒张功能降低,TC、ApoB、SF和ox-LDL水平可能与糖尿病患者血管内皮舒张功能障碍有关.     

Vasodilation Responses to Non-Selective α-Adrenergic Blockage of Coronary Bypass Grafts in Diabetic and Non-Diabetic Patients: In Vitro Study

Background: Adrenergic tonus is increased in atherosclerotic coronary arteries. In this study, we aimed to demonstrate in vitro effects of phentolamine, a reversible nonselective alpha (α) adrenergic blocker, on coronary artery bypass grafts (CABG) and compare its effects in diabetic and nondiabetic patients.Methods: A total number of 30 patients (15 diabetic and 15 nondiabetic) who were assigned to elective CABG surgery were enrolled into the study. For both groups of patients, 16 internal mammarian artery (IMA) samples, 16 saphenous vein (SV) samples and 16 radial artery (RA) samples were collected and studied in the tissue bath system. The vasodilatation responses to increasing doses of phentolamine were recorded.Results: When grafts were compared in terms of amount of vasodilatation to phentolamine, IMA had the most prominent vasodilatation followed by RA and SV respectively. Although the vasodilatation responses in nondiabetic patients were numerically higher than diabetic patients, there was no statistically difference between the groups.Conclusion: Phentolamine, a nonselective α adrenergic blocker, is proven to have equal vasodilatory effects in diabetic and nondiabetic CABG grafts and can safely be used both intravenously and topically in the perioperative period.     

Complex vasoactivity of liraglutide. Contribution of three gasotransmitters

BackgroundIncretine hormone glucagon-like peptide-1 (GLP-1) causes dose-dependent relaxation of the thoracic aorta of rats and other arteries via nitric oxide (NO), cAMP and ATP-sensitive potassium channels, however, through a mechanism not thoroughly described. Hereby we aimed to determine the mediators involved in the vasoactive effect of liraglutide.MethodsIsolated rat aortic rings and segments of the femoral artery were mounted in a wire myograph to study the vasoactive effect of liraglutide. Vessels were preincubated either with inhibitors of gasotransmitter-, prostaglandin- or reactive oxygen species-formation, or with inhibitors of protein kinases, potassium channels or the Na⁺/Ca²⁺-exchanger.ResultsAccording to our findings, liraglutide activates endothelial cells and vascular smooth muscle cells leading to the production of NO, carbon monoxide, hydrogen sulphide, superoxide anion, and hydrogen peroxide. Increased production of such relaxing factors promotes the activation of protein kinase– A and –G, resulting in the activation of potassium channels (ATP-sensitive-, voltage-gated-, large-conductance-calcium activated), which profoundly contributes to the activation of the Na⁺/Ca²⁺-exchanger, thereby leading to calcium efflux and smooth muscle relaxation and vasorelaxation.ConclusionsWe reveal the contribution of all gasotransmitters in the vasorelaxation induced by liraglutide. We provide ex vivo evidence that liraglutide is capable of causing vasodilatation in the central and peripherial vessels, thereby supporting the clinical observation that it lowers blood pressure.     

Effect of nitroprusside on wave reflections in patients with heart failure

The relationship between wave reflections and ventricular-vascular coupling has been the subject of considerable speculation. Since we have previously shown that low-dose nitroprusside infusion improved ventricular-vascular coupling (as evidenced by increases in cardiac output and in aortic and pulmonary arterial total external power) in patients with severe left ventricular failure and secondary pulmonary hypertension, we chose to examine the changes in their aortic and pulmonary arterial wave reflections in this study. Wave reflection indexes examined included [1] calculated backward and forward pressure waves and the ratio of their magnitudes (reflection factor), [2] the reflection coefficient spectrum obtained by taking the ratios of the corresponding Fourier harmonics of the backward and forward waves, [3] two terminal reflection coefficients calculated as Γ _t =(R-Z _c )/R+Z _c ) where Z is characteristic impedance and R is either total resistance or vascular resistance, and [4] the difference between the maximum and minimum impedance moduli for frequencies of 4 to 15 Hz. In the systemic vasculature, nitroprusside produced large reductions in the elevated vascular resistances and decreased aortic reflections as indexed by the reflection factor and by both terminal reflection coefficients. In contrast, however, no significant changes were found in the pulmonary artery wave reflection indexes despite large reductions in the pulmonary resistances. Supported in part by Grant #P-50-HL17655 from the National Institutes of Health Ischemic Heart Disease Specialized Center on Research. Dr. Brin is a recipient of a Public Health Service Clinical Investigator Award (HL-01028) from the National Heart, Lung, and Blood Institute. Dr. Yin was a recipient of a Frank T. McClure Fellowship from the Johns Hopkins University Applied Physics Laboratory.     

Myogenic tone and neurogenic vasoconstriction in microcirculatory bed of rat cerebral cortex

The reaction of rat parietal cortical vessels to stimulation of the sympathetic ganglion was studied by intravital microscopy. stimulation induced constriction of cerebral arterioles. Clamping of one or both carotid arteries led to myogenic vasodilatation in the majority of cases. Constrictive response of brain arterioles to ganglion stimulation under conditions carotid occlusion did not differ from that under conditions of baseline cerebral blood supply.     

Graded effects of oxygen and respiratory inhibitors on cell metabolism and spontaneous contractions in smooth muscle of the rat portal vein

The basis for the hypoxic relaxation of spontaneous activity in the rat portal vein was investigated by comparing responses to oxygen and the respiratory chain inhibitors amobarbital and cyanide. With the inhibitors, 0₂ consumption (J_O2) is uniformly decreased throughout the cell mass, and thus O₂ gradients in the tissue are avoided. Hence the effects are not to be attributed to all-or-none inhibition in anoxic regions, a possibility that might complicate the interpretation of responses to hypoxia. With stepwise reduction in P_Q2 (96 to o % O₂ in N₂ + 4 % CO₂) or increasing concentration of inhibitor (0–5 mmol), J_O2, decreased with a concomitant reduction in mean contractile activity (p?) and increase in lactate production (J L_A). The calculated ATP production (J ATP) was linearly related to p? for p? > 10% of the control value in 96% O₂, with the same slope for hypoxia and both inhibitors. In this range the reduced J_ATP with can largely be attributed to decreased metabolic demand of contraction, as evident from a comparison with the responses to hypoxia of portal veins relaxed in nominally Ca²⁺-free medium. With reduced P_O2 or increased amobarbital concentration the tissue content of phosphocreatine decreased, whereas ATP remained constant for p? gt; 10% of control. Similar responses to hypoxia and respiratory inhibition demonstrate graded effects on metabolism and contractility in the vascular smooth muscle cells, correlating with reported vasodilatory effects of these interventions in vivo.     

Prejunctional β2-adrenoreceptor blockade reduces nerve stimulation evoked release of endogenous noradrenaline in skeletal muscle in situ

Prejunctional β-adrenoceptor-mediated modulation of endogenous noradrenaline (NA) overflow elicited by sympathetic nerve stimulation was studied in blood-perfused canine gracilis muscle in situ. An attempt was made to subclassify these β-adrenoceptors by comparing the effects of β₁-selective (metoprolol) and non-selective (propranolol) β-adrenoceptor blockade. Animals were pre-treated with desipramine and phenoxybenzamine in order to counteract possible influences of neuronal uptake and stimulation-evoked changes in vascular resistance on the diffusion of NA into the blood stream. Metoprolol did not decrease stimulation-evoked NA overflow, as compared with control experiments (?10 and ?8 %, respectively). However, propranolol reduced stimulation-evoked NA overflow by 30% in metoprolol pre-treated animals (P < 0.05 vs. control experiments). Both antagonists elevated basal perfusion pressure, suggesting that vascular post-junctional β₁-as well as β₂-adrenoceptors are present. Propranolol increased stimulation-evoked vasoconstriction in metoprolol pre-treated animals, indicating that neuronally released NA may activate postjunctional β₂-adrenoceptors under these experimental conditions. In conclusion, our findings suggest that NA release can be enhanced by activation of prejunctional β₂-adrenoceptors in vivo.