原发性高血压患者血浆一氧化氮,内皮素变化

目的探讨原发性高血压患者血浆一氧化氮和其对应缩血管性物质内皮素含量变化及其临床意义。方法６０例原发性高血压患者，平均年龄５４．５±９．２岁，男性３１例，女性２９例，接受血浆比色法的硝酸根和放免法内皮素含量测定。结果患者血浆硝酸根含量明显低于正常人，而内皮素含量却明显高于正常人。这种变化和疾病严重程度相平行，而和病程无关。结论血管内皮细胞产生的这一对扩张和收缩血管的因子的失衡在高血压的发病上起重要作用。     

Bosentan and the endothelin system in congestive heart failure

The endothelin system appears to play an important role in the pathophysiology of congestive heart failure (CHF). Endothelin receptor antagonists represent a novel class of agents that are being evaluated for their potential benefits in treating various cardiovascular disorders. Bosentan is an orally active endothelin receptor antagonist that has been studied for the treatment of CHF. Early clinical experience with bosentan has confirmed some benefits on hemodynamic parameters in patients with CHF. Its role in slowing the progression of the disease and improving survival remains to be elucidated.     

Role of Endothelin in the Control of Peripheral Vascular Tone in Human Hypertension

Endothelins are potent 21 amino acid vasoconstrictor isopeptides produced in different vascular tissues, including vascular endothelium. Endothelin-1 is the main endothelin generated by the endothelium and probably the most important in the cardiovascular system. Endothelin-1 acts through specific receptors termed ET(A), represented only on smooth muscle cells and having the function of growth promotion and mediating contractions, and ET(B), located both on smooth muscle cells, where they evoke contractions, and on endothelial cells, inducing relaxation by production of the endothelium-derived relaxing factor nitric oxide. In physiological conditions endothelin-1 administration causes vasodilation and vasoconstriction at low and high concentrations, respectively. However, administration of mixed ET(A)/(B) receptor antagonists causes slight or absent vasodilation, indicating that the direct vasoconstrictor effect of the peptide is probably masked by ET(B)-induced NO-dependent vasodilation. In essential hypertensive patients, the activity of exogenous endothelin-1 is either increased, similar or decreased as compared to normotensive subjects, depending on which vascular district or scheme of administration is considered. But although available evidence does not indicate increased endothelin-1 plasma levels in patients with essential hypertension, simultaneous antagonism of ET(A)/(B) receptors causes a greater degree of vasodilation in hypertensives than in normotensive subjects. Moreover administration of a selective ET(B) receptor antagonist causes vasoconstriction in normotensive subjects and vasodilation in essential hypertensive patients. Finally, the vasodilating effect of a mixed ET(A)/(B) receptor antagonist is inversely related to NO availability. Taken together these findings suggest that essential hypertension is characterized by increased endothelin-1 vasoconstrictor tone. This alteration seems to be dependent on decreased endothelial ET(B)-mediated NO production attributable to impaired NO availability. In such conditions endothelial ET(B)-induced vasodilation no longer compensates for the direct classical endothelin vasoconstrictor effect mediated by smooth muscle cell ET(A) and ET(B) receptors. Therefore endothelin-1 could potentially be involved in the pathogenesis of essential hypertension or of its complications, and blockade of this system is a fascinating new target for therapeutic intervention in this disease.     

不同昼夜时点给药对高血压大鼠血压、血浆一氧化氮和内皮素的影响

目的　探讨不同昼夜时点给药对高血压大鼠血压、血浆一氧化氮 (nitricoxide,NO)和内皮素 (en dothelin ,ET)的影响。方法　 12只雄性SD大鼠分为三组 ,在经口NG硝基 L 精氨酸甲酯 (NG nitro L arginine methlester,L NAME)复制大鼠高血压模型的基础上 ,进行 2 4小时动态血压监测。应用余弦软件分析血压的昼夜节律 ,计算出血压的峰值、中值和谷值所对应的时间点。分别于各时点前三个小时给予依那普利 (10mg·kg-1·d-1) ,连续 2周。然后对大鼠血压进行 2 4小时动态监测 ,并经尾动脉采血 ,测定血浆中一氧化氮和内皮素含量。结果　峰值前、中值前和谷值前给予依那普利后 ,与治疗前比较 ,血压分别下降 12 2 %、8 2 %和 8 3% ;血浆中NO含量分别上升了 6 2 8%、36 5 %和 34 5 % ;血浆中ET含量分别下降了 6 5 %、9 7%和 9 8%。结论　依那普利能够降低L NAME引起的高血压 ;在抗高血压治疗中 ,峰值前给药能更有效地降低血压 ,提高血浆中NO含量     

一氧化氮和内皮素在高血压左室肥厚形成中的作用

目的 探讨一氧化氮（NO）和内皮素（ET）在高血压左室肥厚（LVH）形成中的作用。方法 采用放射免疫分析法（RIA）和硝酸还原酶法检测30例单纯原发性高血压（EH,观察Ⅰ组）、30名健康体检者（对照组）及20例EH伴LVH（观察Ⅱ组）患者降压治疗前后血清ET、NO水平。并对结果进行相关分析。结果 观察Ⅰ组血清ET明显高于对照组、NO明显低于对照组（P均〈0．01）;观察Ⅱ组血清ET明显高于观察Ⅰ组、NO明显低于观察Ⅰ组（P均〈0．01）,且ET与NO水平呈负相关（r=0．586,P〈0．01）;左心室重量指数（LVMI）与ET呈正相关（r=0．427,P〈0．05）、与NO呈负相关（r=0．653,P〈0．01）。观察Ⅱ组治疗后,血清ET水平明显低于治疗前、NO水平明显高于治疗前（p均〈0．01）。结论 ET和NO两者失衡可能参与了EH及LVH形成的病理生理过程。     

高血压患者内皮素和一氧化氮与血压节律相关性的研究

目的 :探讨高血压患者血浆内皮素 (ET)和血清一氧化氮(NO)与血压节律的相关性。方法 :2 8例高血压患者和 1 7例血压正常人进行动态血压监测和 ET,NO测定。结果 :高血压组 ET增加 ,NO下降。2 8例高血压患者按动态血压监测结果分为勺型和非勺型组 ,在非勺型组 ,ET明显增高(5 3.3± 1 9.1 vs37.8± 1 0 .0 ng/ L) ,NO明显降低 (33.4± 1 2 .7vs 48.4± 1 1 .1 mg/ L ) ;且夜间血压下降与 ET负相关 (r=- 0 .5 2 ,P<0 .0 5 ) ,NO正相关 (r=0 .5 4,P<0 .0 5 )。结论 :高血压病患者内皮素和一氧化氮水平可能参与昼夜血压节律的调节     

Role of Nitric Oxide in Cocaine-Induced Acute Hypertension

Cocaine causes acute hypertension by blocking catecholamine reuptake. There is evidence that it also impairs the peripheral endothelial nitric oxide system, which is normally vasodilatory. We further explored the role of nitric oxide in cocaine-induced vasoconstriction in anesthetized rats, and in vitro by using isolated carotid artery segments. Cocaine administered intravenously in rats increased mean arterial pressure by 30 to 40 mm Hg within 1 min. This effect was dose dependent and the maximum effect was observed at a dose of 1.25 mg/kg. The prototype catecholamine norepinephrine induced a similar increase in blood pressure. When rats were pretreated with N^G-monomethyl-l-arginine (L-NMMA, a blocker of nitric oxide) and challenged with cocaine, the increase in blood pressure was blocked by 80%, whereas pretreatment with L-NMMA did not block norepinephrine-induced vasoconstriction. Both cocaine and norepinephrine also induced an immediate vasoconstriction in isolated carotid artery preparations. The in vitro vasoconstriction induced by cocaine was blocked by pretreatment with L-NMMA, whereas L-NMMA did not block the norepinephrine-induced vasoconstriction in vitro. Furthermore, carotid artery stripped of endothelium responded to norepinephrine but failed to respond to L-NMMA or cocaine. S-nitroso-N-acetyl-d,l-penicillamine (SNAP)—a precursor of nitric oxide— stimulated nitric oxide production in control coronary artery fragments. When these fragments were incubated with cocaine there was a 20% reduction in the production of nitrite oxide. These results suggest that cocaine exerts its peripheral vasoconstriction at least in part by inhibiting local vasodilator nitric oxide.     

肾性高血压大鼠血浆及血管组织中内皮素及基础NO的动态变化

目的：观察肾性高血压（ＲＨ）时，血浆及血管组织中内皮素（ｅｎｄｏｔｈｅｌｉｎ， ＥＴ）及基础ＮＯ的动态变化，探讨其在肾性高血压发生发展中的作用。方法：将体重为１６０～１８０ ｇ 雄性Ｗｉｓｔａｒ大鼠随机分为肾性高血压组及假手术组，术后饲养２，４，６ 周后测定大鼠血压的变化、血浆及主动脉中ＥＴ 含量、主动脉基础一氧化氮（ｎｉｔｒｉｃｏｘｉｄｅ， ＮＯ）释放量。结果：ＲＨ组术后２周时血压即已升高，４、６ 周时显著升高。ＲＨ组２，４，６周基础ＮＯ生成量显著低于同期Ｃ组，而血浆及主动脉中ＥＴ含量均显著高于同期Ｃ组。结论：肾性高血压时，血管内皮细胞功能紊乱，维持血管正常张力的基础ＮＯ生成减少，缩血管物质ＥＴ生成异常增多可能在肾性高血压的发生及发展中具有重要作用     

PDCD4在野百合碱诱导肺动脉高压大鼠的表达及波生坦的干预机制

目的研究凋亡相关基因程序性细胞死亡因子4（PDCD4）蛋白在野百合碱诱导肺动脉高压大鼠中的表达并探讨波生坦对其干预机制。方法 SD大鼠正常对照组（N组,n=9）,不做任何处理。14只SD大鼠通过腹腔内注射野百合碱（60mg/kg）两周后,随机将大鼠分成2组,肺动脉高压模型对照组（M组,n=7）和波生坦组（B组,n=7）,分别通过胃管予以安慰剂或波生坦[200mg/（kg.d）]治疗,每天1次,共3周。测量血流动力学参数,观测肺血管和右室组织病理学改变,Western blot法测定肺组织中PDCD4和p-ERK1/2蛋白的表达。结果与N组相比,M组大鼠肺组织PDCD4蛋白表达明显减少、p-ERK1/2蛋白表达明显增加（P均〈0.001）。与M组相比,B组的平均肺动脉压和肺小动脉中膜平滑肌厚度均明显减少,肺组织PDCD4蛋白表达明显增加、p-ERK1/2蛋白表达明显减少（P均〈0.01）。结论 PDCD4蛋白在野百合碱诱导肺动脉高压大鼠中的表达减少,而波生坦可能经p-ERK1/2信号途径增加PDCD4蛋白表达从而降低肺动脉高压、减轻血管平滑肌细胞增殖,逆转肺血管重构的发生。     

Endothelin and pulmonary arterial hypertension

BACKGROUND AND OBJECTIVES: Pulmonary arterial hypertension (PHT) is a potentially fatal disease. The purpose of this article is to review the current knowledge of the role played by endothelin (ET) in PHT and the relevant drug regimens used in the treatment of this condition. METHODS: A detailed search via MEDLINE (PubMed) was performed by using PHT and ET as the key terms. RESULTS: PHT could be a primary or a secondary diagnosis associated with various heart and lung diseases. PHT appears during the late stage of systemic sclerosis and may complicate other systemic diseases such as systemic lupus erythematosus. The vascular endothelium and activation of various mediators and growth factors such as the ET system are thought to play a crucial role in the development of this condition. The pathologic process progresses very rapidly from vasoconstriction to widespread pulmonary vascular obstruction. The use of high doses of calcium channel blockers is of limited value. Life-long anticoagulant therapy is recommended for the treatment of PHT. Currently, the drug being used in PHT therapy is continuous central-venous prostacyclin infusion. Prostacyclin is a strong vasodilator with antiaggregate and antifibrotic properties and has the potential to reduce endothelial injury and to induce vasculature remodeling. This treatment results in improved functional status and increased life span. Unfortunately, its use is accompanied by various side effects, technical difficulties, and high cost. The role of other therapeutic modalities (inhaled prostacyclin, subcutaneous treprostinil, oral beraprost, sildenafil) in vascular remodeling, and the improvement in functional capacity and survival of patients with PHT, are currently under investigation. Bosentan, administered orally, is a recently developed active ET receptor antagonist. It is a promising new therapeutic tool in the treatment of PHT because of its potent vasodilator, antiproliferative, and vascular remodeling activity. CONCLUSIONS: The revolutionary conceptual shift in understanding the pathogenesis of PHT from a vasoconstrictive process to a vasoproliferative one, has led to a modification in the treatment of this disease from the use of vasodilators to the use of drugs with antiproliferative and vascular remodeling activity. Until now, prostacyclin was the only drug of this type available for the treatment of PHT. ET blockade seems to be a reasonable and potential therapeutic option.     

罗格列酮对糖尿病合并高血压大鼠血压的影响及其机制

目的探索罗格列酮对糖尿病合并高血压大鼠血压的影响及其可能的机制。方法选择自发性高血压大鼠24只,采用链脲佐菌素腹腔注射的方法建立糖尿病合并高血压模型,造模后,随机分为对照组12只,治疗组12只(罗格列酮灌胃),治疗4周,观察血压变化,检测血清NO和一氧化氮合成酶(NOS)含量,用免疫组织化学染色检测血管内皮素受体A(ETRA)和内皮素受体B(ETRB)表达变化。结果与对照组比较,治疗组大鼠血压明显降低(P<0.05);血清NO和NOS含量均明显增高[(29.98±4.86)μmol/L vs(38.68±4.57)μmol/L,P<0.01;(15.53±1.19)U/ml vs(17.51±1.48)U/ml,P<0.01];心肌ETRA水平无明显变化(P>0.05),而ETRB表达水平显著升高(P<0.01)。结论罗格列酮能明显降低糖尿病合并高血压大鼠的血压,产生降压现象的机制可能是通过选择性的上调ETRB表达,提高NOS活性,进而增加NO合成,促进血管舒张实现的。     

高血压病患者血浆一氧化氮和内皮素的变化

目的探讨一氧化氮(NO)和内皮素(ET)与高血压病的发病关系及其临床意义.方法采用重氮反应法和放射免疫法检测40例高血压病(EH)患者和36例正常对照者治疗前后的血浆NO和ET浓度的变化.结果①EH患者NO浓度为(15.28±2.36)μmol/L,明显低于正常组的(21.76±2.59)μmol/L(P＜0.01);治疗后EH患者的NO浓度明显增高,但仍低于正常组(P＜0.01).②EH患者ET浓度为(59.71±22.77)ng/L,明显高于正常组的(37.36±13.27)ng/L(P＜0.01);治疗后EH组患者ET浓度明显降低,但仍高于正常组(P＜0.01).结论血管内皮细胞产生的这一对舒缩血管因子的失衡在EH的发生和发展上起着重要作用.     

Chronic Antagonism of the Mineralocorticoid Receptor Ameliorates Hypertension and End Organ Damage in a Rodent Model of Salt-Sensitive Hypertension

We investigated the effects of chronic mineralocorticoid receptor blockade with eplerenone on the development and progression of hypertension and end organ damage in Dahl salt-sensitive rats. Eplerenone significantly attenuated the progressive rise in systolic blood pressure (SBP) (204 ± 3 vs. 179±3 mmHg, p < 0.05), reduced proteinuria (605.5 ± 29.6 vs. 479.7 ± 26.1 mg/24h, p < 0.05), improved injury scores of glomeruli, tubules, renal interstitium, and vasculature in Dahl salt-sensitive rats fed a high-salt diet. These results demonstrate that mineralocorticoid receptor antagonism provides target organ protection and attenuates the development of elevated blood pressure (BP) in a model of salt-sensitive hypertension.     

Cozaar降压疗效及对靶器官的保护作用

目的探讨血管紧张素Ⅱ受体拮抗剂－Ｃｏｚａａｒ（科素亚）的降压疗效及对心肾靶器官的影响。方法６０例高血压病Ⅱ期患者服用Ｃｏｚａａｒ５０ｍｇ／ｄ～１００ｍｇ／ｄ治疗八周。结果Ｃｏｚａａｒ不仅使血压持续下降,并且逆转心脏左室肥厚,改善心功能,降低尿蛋白排泄量及血尿β２－ＭＧ含量水平（Ｐ＜０．０１）。结论Ｃｏｚａａｒ降压疗效肯定及对高血压靶器官具有保护作用。     

Ketanserin in the Treatment of Hypertension: A Multicentre Dose-Finding Study in China

The effect of ketanserin at 5 mg, 10 mg and 20 mg twice daily for 3 months was studied in Chinese patients with hypertension. Both 10 mg and 20 mg doses twice daily effectively reduced systolic and diastolic pressures, while 5 mg twice daily was not effective. The 20 mg regimen was more effective than 10 mg in reducing diastolic, but not systolic pressures. Blood pressure reduction was progressive up to 1 month of treatment but not thereafter. Neither first-dose hypotension nor postural hypotension were seen. There were no effects on body weight or heart rate. A nominally significant 6 msec increase in QTc was seen with 10 mg, but not with 5 or 20 mg twice daily; this could be a chance finding. The side-effect burden was light, and decreased with time.     

Pulmonary Expression of iNOS and HO-1 Protein Is Upregulated in a Rat Model of Prehepatic Portal Hypertension

Portal hypertension is associated with a wide range of pulmonary pathophysiologies, ranging from portopulmonary hypertension to hepatopulmonary syndrome. Although the clinical and pathological features of pulmonary dysfunction in this setting have been extensively characterized, the underlying biology is not well understood. Specifically, the role of mediators that regulate mesenteric vascular hemodynamics in portal hypertension, such as nitric oxide and endothelin, have not been studied in the lung. Using a rat model of prehepatic portal hypertension with preserved hepatic function, we examined pulmonary elaboration of endothelial nitric oxide synthase (NOS), inducible NOS, heme oxygenase- 1 (HO-1), heme oxygenase-2 (HO-2), endothelin-1 mRNA, and protein. In comparison to sham controls, portal hypertensive animals exhibited significantly increased pulmonary iNOS and HO-1 mRNA and protein. Cyclic GMP was significantly increased in portal hypertensive lung tissue, suggesting activation of guanylyl cyclase by the endproducts of iNOS and/or HO-1 activity. Using immunohistochemical analysis, iNOS expression was localized to the vascular endothelium, while HO-1 localized to bronchiolar epithelium and macrophages. These results suggest that production of nitric oxide and carbon monoxide may contribute to the pulmonary pathology associated with portal hypertension.     

Potential Role of Endothelin Receptor Antagonists in the Setting of Cardiopulmonary Bypass: Relevance to Myocardial Performance

The ET system is activated in cardiac surgical setting as evidenced by elevated systemic and myocardial ET-1 levels after coronary bypass grafting surgery which requires hypothermic cardioplegic arrest and cardiopulmonary bypass. Increased ET-1 may influence a number of clinical parameters in this setting. First, ET-1 may directly modulate myocardial contractile performance in the early postoperative period resulting in LV dysfunction and a complex postoperative course. Second, elevated ET-1 levels may exacerbate increased pulmonary vascular resistance and contribute to the development of transient pulmonary hypertension following bypass. Finally, augmented postoperative ET-1 levels could contribute to changes in the caliber and flow of vascular conduits used for coronary bypass. In this review, a current perspective on the ET system in the setting of cardiopulmonary bypass grafting surgery is provided and the potential use of ET receptor antagonists in this setting is discussed.     

Identifying and treating resistant hypertension in PRECISION: A randomized long‐term clinical trial with aprocitentan

The design and baseline data of the PRECISION study, which evaluates the effect of the dual endothelin receptor antagonist aprocitentan on blood pressure (BP) in patients with resistant hypertension (RHT) are presented. The study is a blinded, randomized, parallel‐group Phase 3 study and its three‐part design assesses the short‐term and sustained long‐term effects of aprocitentan on BP. Results are expected in 2022.Patients with uncontrolled BP (measured as unattended automated office BP) despite the use of three or more antihypertensive medications for at least 1 year were screened. They were switched to a single‐tablet triple fixed combination antihypertensive therapy for at least 4 weeks before entering a single‐blind placebo run‐in period. The 4‐week placebo run‐in period further excluded placebo responders. The randomization period consisted of three sequential parts: (1) a 4‐week double‐blind part with aprocitentan 12.5 mg, 25 mg, or placebo (1:1:1 ratio); (2) a 32‐week single‐blind part with aprocitentan 25 mg; and (3) a 12‐week randomized withdrawal part with aprocitentan 25 mg or placebo (1:1 ratio). The purpose was to demonstrate the BP lowering effect of aprocitentan in RHT (Part 1) and the persistence of this effect (Parts 2 and 3).Out of 1965 screened patients, 730 were randomized resulting in an overall inclusion failure rate of 62.8%. The most common reason for exclusion (44.4% of all screened patients) was failure to meet the BP inclusion criteria. These results underline the high proportion of pseudoresistant hypertension among patients referred for RHT.     

The Effect of a Combination of Inhaled Nitric Oxide and an Endothelin<Subscript>A</Subscript>-Receptor Antagonist onHemodynamic Dysfunction in Experimental AcutePulmonary Thromboembolism

Although either inhaled nitric oxide (NO) or endothelin_A receptor antagonist has been tried in the treatment of various forms of pulmonary hypertension, the effects of combination therapy have not been reported. We evaluated the effects of inhaled NO alone or a combination of inhaled NO and ZD2574 (an endothelin_A receptor antagonist) in an experimental canine acute pulmonary thromboembolism model. Forty parts per million of inhaled NO alone, or a combination of inhaled NO and 10 mg/kg of ZD2574 was administered 1 hour after embolization with an autologous blood clot. We compared the hemodynamic and gas exchange parameters between the two treatment groups. Two treatment regimens decreased mean pulmonary arterial pressure and pulmonary vascular resistance and attenuated decrease in cardiac output. Moreover, systemic arterial hypotension or worsening of hypoxemia did not occur in either of the treatment groups. In the combined group, more favorable hemodynamic outcomes were maintained than in the inhaled NO alone group. And hemodynamic deterioration shown after NO withdrawal was attenuated in the combined group. These findings suggest that when inhaled NO is concomitantly administered with an ET_A receptor antagonist, more favorable hemodynamic outcomes can be expected during and after NO inhalation in acute pulmonary thromboembolism.     

内皮型一氧化氮合酶基因多态性与原发性高血压的相关关系

目的 探讨内皮型一氧化氮合酶(eNOS)基因27bp数目可变的串联重复序列(VNTR)多态性与中国汉族人原发性高血压(EH)的相关性。方法 (1)聚合酶链反应(PCR)及琼脂糖凝胶电泳检测334例EH患者的基因型，同时进行基因测序。(2)硝酸还原酶法测定空腹血清一氧化氮代谢物(NOx)水平，用放射免疫法测定内皮素(ET)的水平。结果(1) EH组aa ab基因型和a等位基因频率显著高于对照组；(2)EH组内ab ab基因型空腹血清NOx、NOx／ET比明显低于bb基因型。结论 eNOS基因27bpVNTR的a等位基因与中国汉族人EH的发生相关，a等位基因携带者可能通过减少内皮：NO的释放、损害内皮功能参与EH发病。