Lacidipine prevents endothelial dysfunction in salt-loaded stroke-prone hypertensive rats

Endothelium-dependent vasorelaxation is defective in hypertensive rats, especially in conduit arteries. In the stroke-prone spontaneously hypertensive rat, impaired endothelium-dependent vasorelaxation appears to contribute to the pathogenesis of stroke independent of blood pressure. Because treatment with lacidipine, a long-acting calcium channel blocker, protects against stroke and cardiovascular remodeling in this model, we investigated the effect of this treatment on endothelium-dependent vasorelaxation in the aorta. Stroke-prone rats were exposed to a salt-rich diet (1% NaCl in drinking water) with or without lacidipine (1 mg. kg(-1). d(-1)) for 6 weeks. A high-sodium diet (1) increased systolic blood pressure, aortic weight, and wall thickness and plasma renin activity (P<0.05); (2) markedly reduced nitric oxide (NO)-mediated, endothelium-dependent relaxation of aortic rings to acetylcholine and the sensitivity to the relaxing effect of S-nitroso-N-acetylpenicillamine, an NO donor (P<0.001); and (3) induced an elevation of preproendothelin-1 mRNA levels in aortic tissue (P<0.01) without affecting endothelial NO synthase mRNA levels. Lacidipine treatment prevented the salt-dependent functional and structural alterations of the aorta, including the overexpression of the preproendothelin-1 gene, and increased endothelial NO synthase mRNA levels in aortic tissue (P<0.01). In conclusion, lacidipine protects stroke-prone hypertensive rats against the impairment of endothelium-dependent vasorelaxation evoked by a salt-rich diet, and this effect may contribute to its beneficial effect against end-organ damage and stroke.     

卡维地洛、氯沙坦合用防治大鼠心肌梗死左室重构对比

目的对比卡维地洛、氯沙坦及其合用防治大鼠急性心肌梗死(AMI)左室重构(LVRM)的作用.方法雌性SD大鼠分为AMI对照、卡维地洛 (1 mg·kg-1·d-1)、氯沙坦(3 mg·kg-1·d-1)和卡维地洛(1 mg·kg-1·d-1)+氯沙坦(3 mg·kg-1·d-1)组,另设假手术组对照.给药4周后行血流动力学测定和病理分析.结果 AMI各组间梗死面积差异均无显著性(45.8%～46.7%,P值均>0.05).与假手术组相比,AMI组的左室舒张末压(LVEDP)、容积(LVV)、重量(LVW)、室间隔厚度(STh)和右室重量(RVW)均显著增加(P值均<0.01),左室内压最大上升和下降速率(±dp/dp)及其校正值(±dp/dt/LVSP)均显著降低(P值均<0.01).与AMI组相比,卡维地洛、氯沙坦以及合用组的LVEDP、LVV、LVW、STh和RVW均显著降低或减轻(P值均＜0.01),±dp/dt及±dp/dt/LVSP均显著升高(P＜0.05～0.01),且LVEDP和STh在合用组较卡维地洛组降低更显著(P值均<0.01).结论卡维地洛和氯沙坦单用与合用均能有效抑制大鼠AMI后的左室重构,改善血流动力学和左室功能,且以合用更佳.     

The effects of combined versus selective adrenergic blockade on left ventricular and systemic hemodynamics, myocardial substrate preference, and regional perfusion in conscious dogs with dilated cardiomyopathy.

OBJECTIVES: Given that adverse effects of chronic sympathetic activation are mediated by all three adrenergic receptor subtypes (beta1, beta2, alpha1), we examined the effects of standard doses of carvedilol and metoprolol succinate (metoprolol controlled release/extended release [CR/XL]) on hemodynamics, myocardial metabolism, and regional organ perfusion. BACKGROUND: Both beta1 selective and combined adrenergic blockade reduce morbidity and mortality in heart failure. Whether there are advantages of one class over the other remains controversial, even in the wake of the Carvedilol Or Metoprolol European Trial (COMET). Similarly, the mechanistic basis for the relative differences is incompletely understood. METHODS: Thirty-three conscious, chronically instrumented dogs with pacing-induced (240 min(-1) for 4 weeks) dilated cardiomyopathy (DCM) were randomized to carvedilol (25 mg twice daily, Coreg, Glaxo Smith Kline, Research Triangle, North Carolina) or metoprolol succinate (100 mg qd, Toprol XL, Astra Zeneca, Wilmington, Delaware). Left ventricular and systemic hemodynamics, myocardial substrate uptake, and norepinephrine spillover were measured before and after three days of treatment. Regional (renal, hepatic, skeletal muscle) blood flows were measured using neutron-activated microspheres. RESULTS: Both agents had comparable heart rate effects. However, carvedilol-treated dogs showed significantly greater increases in stroke volume and cardiac output and decreases in left ventricular end-diastolic pressure and systemic vascular resistance. Carvedilol increased renal, hepatic, and skeletal muscle blood flow. Carvedilol increased myocardial glucose uptake and suppressed norepinephrine and glucagon. Carvedilol antagonized the response to exogenous norepinephrine to a greater extent than metoprolol CR/XL. CONCLUSIONS: At doses inducing comparable heart rate reductions, short-term treatment with carvedilol had superior hemodynamic and metabolic effects compared with metoprolol CR/XL. These data suggest important advantages of blocking all three adrenergic receptor subtypes in DCM.     

Comparison of metoprolol with low, middle and high doses of carvedilol in prevention of postinfarction left ventricular remodeling in rats

The dose-related beneficial effects of carvedilol on survival in heart failure have been verified, however, the effects on left ventricular remodeling (LVRM) after acute myocardial infarction (AMI) have not been defined. This experiment was designed to compare the effects of low, middle, and high doses of carvedilol (LD-car, MD-car, and HD-car) with metoprolol (Meto) in preventing postinfarction LVRM in rats. After the left coronary artery was ligated, 177 surviving female SD rats were randomized to: (1) AMI (n = 35), (2) LD-car (0.1 mg x kg(-1) x d(-1), n = 35), (3) MD-car (1 mg x kg(-1) x d(-1), n = 35), (4) HD-car (10 mg x kg(-1) x d(-1), n = 37) and (5) Meto (2 mg x kg(-1) x d(-1), n = 35) groups. A sham-operated group (n = 16) was also randomly selected. Gastric gavage therapy lasted for 4 weeks. After hemodynamic studies, the rat hearts were fixed and pathologically analyzed. After exclusion of rats which died or had an infarct size < 35% or > 55%, complete data were obtained in 69 rats, comprising AMI (n = 11), LD-car (n = 11), MD-car (n = 12), HD-car (n = 12), Meto (n = 11) and sham (n = 12) groups. There were no significant differences in MI size among the five AMI groups (44.5-46.3%, all P > 0.05). Compared with the sham group, left ventricular (LV) end-diastolic pressure (LVEDP), volume (LVV), weight (LVW) and septal thickness (STh) were all significantly increased, while +/- dp/dt was significantly decreased in the AMI group (all P < 0.001). Compared with the AMI group, heart rate was significantly decreased in all except the LD-car treatment groups (P < 0.05-0.01); LVEDP, LVV, LVW, and STh in the four treatment groups were also significantly decreased (P < 0.05-0.001) except LVW and STh in the Meto group (both P > 0.05)(LVEDP: 14.5 +/- 4.6, 12.1 +/- 2.4, 7.7 +/- 1.9 and 13.0 +/- 6.7 mmHg vs 24.1 +/- 5.2 mmHg; LVV: 0.82 +/- 0.1, 0.79 +/- 0.1, 0.72 +/- 0.1 and 0.72 +/- 0.1 mL vs 0.92 +/- 0.1 mL; LVW: 666 +/- 57, 622 +/- 70, 589 +/- 57 and 699 +/- 78 mg vs 730 +/- 79 mg; STh: 1.14 +/- 0.12, 1.18 +/- 0.21, 1.19 +/- 0.15 and 1.35 +/- 0.20 mm vs 1.33 +/- 0.29 mm; P < 0.05-0.001); while +/- dp/dt was significantly increased in each therapy group (P < 0.05-0.001). There were dose-effect relations in LVEDP and LVV in the carvedilol groups. The results indicate that low, middle and high dose carvedilol has dose-related effects in the prevention of postinfarction LVRM with respect to volume expansion and segmental hypertrophy in rats, while metoprolol prevents only LV dilatation but not hypertrophy.     

血管紧张素-(1-7)对腹主动脉缩窄大鼠的抗心肌肥厚效应

目的　探讨血管紧张素 (1 7)能否预防和减轻腹主动脉缩窄所诱导的大鼠心肌肥厚。方法　 45只大鼠随机分为假手术组、腹主动脉缩窄组、腹主动脉缩窄 +血管紧张素 (1 7)治疗组 ,每组 15只。在腹主动脉缩窄术后 1d开始 ,腹主动脉缩窄血管紧张素 (1 7)治疗组大鼠经置入式微量泵持续颈静脉给予血管紧张素 (1 7) ,给药剂量 2 5μg·kg- 1 ·h- 1 ,假手术组及腹主动脉缩窄组经微量泵只给予同量的生理盐水 ,4周后检测颈动脉血压、心率、血浆和心肌血管紧张素Ⅱ浓度、左心室重量指数和心肌胶原容积分数。结果　腹主动脉缩窄可导致颈动脉血压升高、心率加快、心肌血管紧张素Ⅱ浓度升高、左心室重量指数和心肌胶原容积分数增加 ;血管紧张素 (1 7)不改变腹主动脉缩窄所诱导增高的血压、心率和心肌血管紧张素Ⅱ浓度 ,但能明显减轻腹主动脉缩窄所诱导增高的左心室重量指数和心肌胶原容积分数。结论　外源性血管紧张素 (1 7)能减轻腹主动脉缩窄所诱导的大鼠心肌肥厚。其机制不是通过改变血流动力学或心肌血管紧张素Ⅱ浓度所致 ,可能与它抑制血管紧张素Ⅱ的细胞内信号转导有关。     

卡维地洛对原发性高血压心肌组织特征及部分血管活性肽水平的改变

目的:应用超声声学密度技术探讨卡维地洛治疗原发性高血压患者左心室心肌组织密度的变化,分析治疗后部分血管活性肽心钠素、脑钠素、内皮素-1(ET-1)、降钙素基因相关肽(CGRP)、胰岛素样生长因子-1(IGF-1)水平的改变及其与心肌组织密度变化的关系。方法:将入选对象101例分为无左心室肥厚组56例及伴左心室肥厚组45例,应用超声声学密度技术测量治疗前后左心室心肌不同切面的平均声学密度(AII％);测量治疗前后部分血管活性肽心钠素、脑钠素、ET-1、CGRP、IGF-1水平,分析治疗前后其变化规律及与心肌声学密度变化的关系。结果:卡维地洛治疗后原发性高血压左心室各室壁AII％之和(SUM)较治疗前有显著性下降(P<0．05)。心钠素、脑钠素、IGF-1在无左心室肥厚组有下降的趋势(P>0．05),ET-1有显著性下降(P<0．05)。在伴左心室肥厚组心钠素、ET-1、IGF-1有显著性下降(P<0．05),脑钠素有下降趋势(P>0．05)。CGRP水平治疗后无左心室肥厚组有升高趋势(P>0．05),伴左心室肥厚组有显著性升高(P<0．05)。伴左心室肥厚组心肌各切面室壁SUM在治疗前后的变化ΔSUM与ΔET-1、Δ心钠素、ΔIGF-1等各因子水平呈正相关,与ΔCGRP水平呈负相关。结论:卡维地洛能降低原发性高血压左心室心肌组织密度;能使原发性高血压左心室肥厚两组心钠素、ET-1、CGRP、IGF-1等部分血管活性肽向有利于维持正常血压水平的方向改变。     

Cardioprotection by long-term ET(A) receptor blockade and ACE inhibition in rats with congestive heart failure: mono- versus combination therapy

OBJECTIVES: We investigated the effects of long-term endothelin A (ET(A)) receptor blockade and ACE inhibition, either alone or in combination, on the hemodynamics, neurohormonal activation and cardiac remodeling in rats with congestive heart failure (CHF) after extensive myocardial infarction (MI). METHODS: Rats were treated with placebo, the ET(A) antagonist LU135252 (30 mg/kg/d), the ACE inhibitor trandolapril (0.3 mg/kg/d), or a combination of both for 11 weeks, starting 7 days after MI. RESULTS: Despite comparable effects on left ventricular (LV) systolic pressure among all drug treatments, only combined ET(A) and ACE inhibition significantly reduced LV end-diastolic pressure (P<0.01), improved LV dP/dt(max) (P<0.01) and normalized sympathetic activation (P<0.05) in rats with CHF. The combination therapy was more effective in reducing type I and III collagen mRNA levels, MMP-2 zymographic activity and collagen accumulation in the surviving LV myocardium. Moreover, the increases in cardiac beta-myosin heavy chain and skeletal alpha-actin mRNAs, markers of hypertrophy or failure, were attenuated to a greater degree by the combination therapy than monotherapy, whereas right ventricular hypertrophy and ANF mRNA upregulation were significantly (P<0.01) prevented only by combined ET(A) and ACE inhibition. CONCLUSION: Long-term combined ET(A) receptor and ACE inhibition improved cardiac failure after extensive MI more effectively than monotherapy. We show additive effects on LV fibrosis and fetal gene expression. ET(A) receptor antagonists could be a therapeutical option in CHF in addition to an ACE inhibitor.     

卡维地洛长期治疗对原发性高血压左心室肥厚及室性心律失常干预的对比研究

目的探讨β及α受体阻滞剂卡维地洛对原发性高血压(EH)患者左心室肥厚(LVH)及室性心律失常(VA)的干预作用。方法入选经超声心动图、心电图、动态心电图检查证实为EH伴LVH及VA患者72例,随机分配到卡维地洛组(口服25~50mg/d)或卡托普利组(口服25~75mg/d),治疗8个月,治疗前后各检查超声心动图、心电图、动态心电图,对比分析组内治疗前后左心室重量指数及VA变化和两组间的差异。结果①与治疗前比较,EH患者在卡维地洛或卡托普利治疗8个月后,两组收缩压与舒张压明显下降(166/104mmHg至135/86mmHg;162/103mmHg至138/87mmHg)(P均<0.01)。②卡维地洛组治疗后,左心室后壁与室间隔厚度较治疗前显著下降(P<0.05),左心室重量及左心室重量指数下降更显著(P均<0.01);卡托普利组治疗后左心室后壁与室间隔厚度及左心室重量及左心室重量指数下降显著(P均<0.05)。③卡维地洛组治疗后VA及复杂性室性VA的控制率为91.67%(33/36);卡托普利组治疗后VA及复杂性VA的控制率为36.1%(13/36),两组间差异有显著性(P<0.01)。结论EH伴LVH及VA患者在卡维地洛治疗8个月后LVH显著逆转,卡维地洛对VA的干预明显优于卡托普利。     

Regression of left ventricular hypertrophy in hypertensive elderly patients with carvedilol

In hypertensive patients, the development of left ventricular hypertrophy seems to increase the risk of cardiovascular death although some antihypertensive agents have been associated with regression in left ventricular hypertrophy. A few studies have evaluated the carvedilol, a new drug having a balanced pharmacology of vasodilatation and beta-receptor blockade, particularly in elderly hypertensive patients. To test its effects on left ventricular hypertrophy, patients with essential hypertension and left ventricular hypertrophy were studied before and at the end of 6 months of therapy with 25 mg of carvedilol daily. Candidates had to have moderate, uncontrolled essential hypertension with echocardiographically documented left ventricular hypertrophy (left ventricular mass index > 130 g/m2 for men and > 110 g/m2 for women). Of 26 patients selected, 4 dropped out. The remaining 22 patients successfully completed 6 months of therapy. The average age was 69 +/- 8 years. Carvedilol caused a significant reduction of mean systolic blood pressure from 175 to 145 mmHg (p < 0.001), of diastolic blood pressure from 102 to 82 mmHg (p < 0.001), of left ventricular mass index from 148 +/- 24 g/m2 (p < 0.003), and a non significant change of the mean heart rate from 78 to 72 beats/min. In our study, carvedilol was well tolerated in patients with essential hypertension and left ventricular hypertrophy.     

Effect of selective and nonselective beta-blockers on resting energy production rate and total body substrate utilization in chronic heart failure

BACKGROUND: In chronic heart failure (CHF) beta-blockers reduce myocardial oxygen consumption and improve myocardial efficiency by shifting myocardial substrate utilization from increased free fatty acid oxidation to increased glucose oxidation. The effect of selective and nonselective beta-blockers on total body resting energy production rate (EPR) and substrate utilization is not known. METHODS: Twenty-six noncachectic patients with moderately severe heart failure (New York Heart Association class II or III, left ventricular ejection fraction < 0.40) were treated with carvedilol (37.5 +/- 13.5 mg/12 h) or bisoprolol (5.4 +/- 3.0 mg/d) for 6 months. Indirect calorimetry was performed before and after 6 months of treatment. RESULTS: Resting EPR was decreased in carvedilol (5.021 +/- 0.803 to 4.552 +/- 0.615 kJ/min, P <.001) and bisoprolol group (5.230 +/- 0.828 to 4.978 +/- 0.640 kJ/min, P <.05; nonsignificant difference between groups). Lipid oxidation rate decreased in carvedilol and remained unchanged in bisoprolol group (2.4 +/- 1.4 to 1.5 +/- 0.9 mg m(2)/kg min versus 2.7 +/- 1.1 to 2.5 +/- 1.1 mg m(2)/kg min, P <.05). Glucose oxidation rate was increased only in carvedilol (2.6 +/- 1.4 to 4.4 +/- 1.6 mg m(2)/kg min, P <.05), but did not change in bisoprolol group. CONCLUSIONS: Both selective and nonselective beta-blockers reduce total body resting EPR in noncachectic CHF patients. Carvedilol compared to bisoprolol shifts total body substrate utilization from lipid to glucose oxidation.     

Extracellular matrix proteins in cardiac fibroblasts derived from rat hearts with chronic pressure overload: effects of beta-receptor blockade

Left ventricular hypertrophy (LVH) is accompanied by progressive accumulations of extracellular matrix proteins. They are produced predominantly by cardiac fibroblasts that surround the cardiac myocytes. The aim of this study was to emphasize the role of a combined approach using both in vivo and in vitro studies to elucidate the effects of carvedilol on cardiac remodeling. We therefore used an established model of supravalvular aortic banding and cardiac fibroblasts. LVH was induced by banding of the ascending aorta. Male Wistar rats were allocated to four groups: sham-operated, sham+carvedilol, aortic stenosis (AS), and AS+carvedilol. Treatment time was four weeks. Fibroblasts were isolated from the entire left ventricle of sham and AS rats. Carvedilol/metoprolol/prazosin were added (0.1, 1.0 and 10 microM; 24 h). In addition, interferon- gamma was applied for 24 h (10, 100 and 1000 IU). AS rats revealed increased LV weights (+27%) and cardiomyocyte widths as compared to sham-operated rats (1.6-fold, P<0.01). Carvedilol reduced LVH by 20%. This finding was accompanied by a decrease of laminin, fibronectin, collagen I and III in vivo. Collagen I/III and fibronectin were increased in fibroblasts of AS v sham rats (P<0.0001, each). Carvedilol reduced collagen I, III and fibronectin by 40/60/35% (0.1 microM; P<0.001) irrespective of LVH. Carvedilol had no effects on collagen IV and laminin. Carvedilol dose-dependently reduced the proliferation rate by 20% at 0.1 microM(P<0.0001). Metoprolol and prazosin had no effect on the expression of extracellular matrix proteins and on the proliferation of the cells of either origin. Interferon- gamma blunted the proliferation rate of cultured fibroblasts and lead to a significant decrease in extracellular matrix deposits. These results indicate that the effects of carvedilol may be due to the antiproliferative or antioxidative properties of this unselective beta-adrenergic receptor antagonist. These changes of the extracellular matrix represent a new mechanism of carvedilol that may contribute to the observed beneficial effects in congestive heart failure.     

卡维地洛和美托洛尔对大鼠急性心肌梗死后胶原重构影响的对比研究

目的　对比研究非选择性 β受体阻滞剂卡维地洛及选择性 β1 受体阻滞剂美托洛尔对大鼠心肌梗死后胶原的影响 ,以了解卡维地洛改善心室重构及心功能的机制。方法　将梗死后 4 8h存活大鼠分为心肌梗死对照组、美托洛尔组 (15mg·kg- 1 ·d- 1 )、低剂量卡维地洛组 (1mg·kg- 1 ·d- 1 )和高剂量卡维地洛组 (10mg·kg- 1 ·d- 1 )。另设假手术组。给药 6周后 ,测量血流动力学参数及心功能。取血测量血浆内皮素及血管紧张素Ⅱ。测量心肌梗死区及非梗死区的总间质胶原容积分数 (ICVF)及Ⅰ、Ⅲ型胶原的ICVF。结果　美托洛尔及卡维地洛均可减低左心室舒张末压、增加左心室内压最大上升和下降速率 ,以高剂量卡维地洛组效果最好。与心肌梗死对照组比较 ,高剂量的卡维地洛可减轻心肌非梗死区尤其是右心室的ICVF及Ⅰ、Ⅲ型胶原的ICVF。低剂量卡维地洛及美托洛尔对间质胶原影响不明显。结论　卡维地洛可抑制非梗死区胶原增生 ,减少心肌纤维化 ,而美托洛尔无此作用。卡维地洛对心肌纤维化的抑制可能较美托洛尔能更好地改善心肌梗死后心室重构及心功能     

拉西地平对高血压大鼠血管平滑肌细胞CRT和caspase12表达变化的影响

目的 探讨压力负荷高血压大鼠动脉血管平滑肌细胞内质网应激相关因子钙网蛋白（calreticulin,CRT）和caspase-12的表达变化及药物拉西地平对其的影响.方法 将30只成年雄性SD大鼠随机等分为对照组（sham组）、模型组（TAC组）和拉西地平组（lacidipine组）.Sham组分离腹主动脉但不行狭窄术,TAC组行腹主动脉狭窄术,lacidipine组行腹主动脉狭窄术并给予拉西地平0.5 mg/（kg·d）,喂养8周用颈动脉插管法测定各组大鼠的平均动脉压（MAP）;利用图像分析软件测量血管中层的厚度;用免疫组织化学法和western-blot法检测CRT和caspase-12的表达水平;TUNEL荧光法检测血管平滑肌细胞的凋亡率.结果 ①TAC组大鼠MAP均值显著高于sham组（P＜0.01＝和lacidipine组（P＜0.05＝;lacidipine组大鼠MAP均值高于sham组（P＜0.05＝;②TAC组大鼠血管平滑肌中层厚度均值大于sham组和lacidipine组均有统计学意义（P＜0.05＝,lacidipine组和sham组大鼠血管平滑肌中层厚度比较,差异无统计学意义（P＞0.05）;③TAC组的CRT和caspase-12蛋白表达量均值高于sham组和lacidipine组,lacidipine组CRT和caspase-12蛋白表达量均值高于sham组（P＜0.05＝;④TAC组大鼠血管平滑肌凋亡率高于sham组和lacidipine组（P＜0.05＝,lacidipine组大鼠血管平滑肌凋亡率高于sham组（P＜0.05＝.结论 腹主动脉狭窄致高血压可引起血管平滑肌细胞内质网应激反应,导致CRT表达增加及caspase-12的活化增高;拉西地平通过下调内质网应激水平,逆转高血压所致的血管平滑肌细胞的损伤作用,对血管平滑肌细胞具有保护作用.     

Effects of antihypertensive drugs on alcohol-induced functional responses of cultured human endothelial cells.

Alcohol-induced endothelial changes might contribute to an increase in blood pressure in regular alcohol consumers. Some antihypertensive drugs affect oxidative stress and endothelial function and might counteract the effects of alcohol at the cellular level. The aim of this study was to investigate in vitro the effects of three different types of antihypertensive agents on alcohol-induced endothelial responses and oxidative stress. Cultured human endothelial cells were exposed to increasing concentrations (1, 10, 60 micromol/L) of zofenoprilat, carvedilol, and lacidipine in the absence and in the presence of ethanol (140 mmol/L). Concentrations of endothelin (ET) and nitric oxide (NO) were measured in the culture media as markers of endothelial function, and malondialdehyde (MDA) and intracellular glutathione (GSHi) were measured as markers of oxidative stress. Exposure to alcohol increased the levels of ET, NO, and MDA, and decreased GSHi. Carvedilol and zofenoprilat were more effective than lacidipine in counteracting the effects of alcohol on ET production. Alcohol-induced NO production was enhanced by carvedilol, whereas zofenoprilat and lacidipine did not have a significant effect. The alcohol-induced increase in MDA concentrations was blunted by all three drugs, but only carvedilol restored a normal response. All three drugs increased GSHi levels, with the effect being greater for carvedilol and lacidipine than zofenoprilat. Carvedilol is more effective than zofenoprilat and lacidipine in counteracting alcohol-induced endothelial responses in vitro and in decreasing oxidative stress. These effects might be particularly beneficial in patients with alcohol-related hypertension.     

Release of preformed Ang II from myocytes mediates angiotensinogen and ET-1 gene overexpression in vivo via AT1 receptor

The role of angiotensin II in pressure overload is still debated because notwithstanding its effects on myocyte contractility angiotensin II is not an obligatory factor for the development of hypertrophy. To define the role of angiotensin II in acute pressure overload we studied the effects of AT1 blockade (valsartan 80mg per day) on myocardial contractility, cardiac growth factor gene expression, and myocardial hypertrophy in aortic banded (60mmHg) pigs. Acute pressure overload caused an abrupt reduction of myocardial contractility, measured by the end-systolic stiffness constant, and a sharp increase in end-systolic stress which rapidly normalized (within 12h) in the placebo group. In AT1-blocked animals end-systolic stiffness constant remained significantly depressed up to 24h and end-systolic stress was still elevated up to 48h (both P<0.05 vs placebo). In both groups confocal microscopy revealed that granular staining of angiotensin II in cardiomyocyte cytoplasm disappeared after 30min of pressure overload. AT1 blockade abolished following cardiac overexpression of angiotensinogen and endothelin-1 genes as shown in RT-PCR studies and the consequent angiotensin II and endothelin-1 release in the coronary circulation. Conversely, insulin-like growth factor-I and ACE mRNA overexpression, as well as the onset of left ventricular mass increase, were not significantly affected by AT1 blockade. In conclusion: (1) mechanical stress releases preformed angiotensin II from myocyte in vivo; (2) the AT1 blockade abolishes cardiac angiotensin II and endothelin-1 production with delayed recovery of myocardial contractility; whereas (3) the overexpression of insulin-like growth factor-I gene and the development of myocardial hypertrophy are not angiotensin II-mediated effects.     

Comparative effects of carvedilol and losartan alone and in combination for preventing left ventricular remodeling after acute myocardial infarction in rats.

It has been verified that losartan has beneficial effects on ventricular remodeling (VRM) after acute myocardial infarction (AMI), but the effects of carvedilol alone or in combination with losartan on this condition have not been defined. The present study used rats to compare the effects of carvedilol and losartan alone and in combination for preventing VRM after AMI. After ligation of the left coronary artery, 100 surviving female Sprague-Dawley rats were randomly assigned to 1 of 4 groups: (1) AMI control (n=25), (2) carvedilol (Car, 1 mg x kg(-1) x day(-1)) (n=25), (3) losartan (Los, 3 mg x kg(-1) x day (-1)) (n=25), and (4) Car (1 mg x kg (-1). day(-1)) + Los (3 mg x kg(-1) x day (-1)) (n=25). A sham-operated group (n=17) was also randomly selected. Drugs were administered by gastric gavage for 4 weeks. After hemodynamic studies, the hearts were fixed and analyzed pathologically. Exclusive of the rats that had died or had an infarct size <35% or >55%, complete data were obtained for 65 rats, comprising AMI control (n=13), Car (n=12), Los (n=13), combination (n=14), and sham (n=13) groups. There were no significant differences in the size of infarct among the 4 AMI groups (45.8 approximately 46.7%, all p>0.05). Compared with the sham group, left ventricular (LV) end-diastolic pressure (LVEDP), volume (LVV), weight (LVW) and septal thickness (STh) were all significantly increased (all p<0.001), whereas +/-dp/dt was significantly decreased (both p<0.001) in the AMI group. In comparison with the AMI group, LVEDP, LVV, LVW and STh were all significantly decreased (LVEDP: 12.7+/-2.3, 9.7+/-2.8, and 8.6+/-3.5 mmHg vs 20.6+/-2.7 mmHg, all p<0.001; LVV: 0.74+/-0.07, 0.76+/-0.07, and 0.70+/-0.09 ml vs 0.86+/-0.05 ml, all p<0.05; LVW: 668.4+/-52.0, 702.6+/-45.4, and 683.9+/-67.7 mg vs 787.3+/-76.7 mg, p<0.05 approximately 0.001; STh: 1.57+/-0.05, 1.48+/-0.07, and 1.46+/-0.07 mm vs 1.71+/-0.04 mm, all p<0.05), whereas +/-dp/dt was significantly increased (all p<0.05) in the Car, Los, and combination groups, with LVEDP decreasing more in both Los and the combination groups than in the Car group alone (p<0.05) and STh decreasing more in the combination group than in the Car group alone (p<0.05). Carvedilol and losartan alone and in combination all prevent VRM after AMI in rats, with almost equivalent effect.     

卡维地洛对兔缺血再灌注心律失常和梗死范围的影响

目的探讨卡维地洛对兔缺血再灌注性心律失常和心肌梗死(MI)范围的影响。方法新西兰大白兔50只,随机分为5组,每组10只;Ⅰ组:假手术组,Ⅱ组:急性心肌梗死(AMI)组,Ⅲ组:缺血再灌注组,Ⅳ组:利多卡因组,V组:卡维地洛组。Ⅱ、Ⅲ、Ⅳ、V组分别结扎冠状动脉左室支中点30 min再灌注120 min,观察室性期前收缩(PVC)、室性心动过速(VT)、心室颤动(Vf)的发生率和MI范围的变化。结果应用利多卡因和卡维地洛后,PVC、VT、Vf的发生率显著低于缺血再灌注组,利多卡因和卡维地洛两组之间差异无统计学意义。利多卡因能有效的减少缺血再灌注时心律失常的发生率,但对MI范围无影响,卡维地洛不仅有效的减少缺血再灌注时心律失常的发生率,而且能显著的缩小MI范围。结论卡维地洛能有效的减少缺血再灌注时心律失常的发生,明显缩小MI范围。     

Effects of endothelin-1 and endothelin-1 receptor blockade on cardiac output,aortic pressure,and pulse wave velocity in humans

Endothelin-1 (ET-1) is a potent vasoconstrictor. Its effect on arterial wave reflections and central pressure augmentation is unknown. We studied whether ET-1, in plasma concentrations present in disease, increases pulse wave velocity (PWV) and augmentation index (AIx) and therefore compromises cardiac output, and whether the ET-1 receptor blocker VML-588 (previously AXV-034343 and Ro 61-1790) prevents such effects. Nine healthy men received a 2-hour infusion with ET-1 (2.5 ng x kg(-1) x min(-1)) superimposed on vehicle or VML-588 (0.05, 0.20, or 0.40 mg x kg(-1) x h(-1)) (randomized order). Arterial tonometry and pulse wave contour analysis were used to assess aortic PWV and central aortic pressures and impedance cardiography for cardiac output. ET-1 slightly increased mean arterial pressure and peripheral resistance but had no significant effect on systolic blood pressure and pulse pressure. PWV increased from 5.4+/-0.2 to 5.7+/-0.3 m/s (P<0.05), AIx from 9.9+/-3.3 to 17.2+/-3.8 (P<0.05), central systolic blood pressure by 8.7+/-1.7 mm Hg (P<0.05), and central pulse pressure by 5.1+/-1.9 mm Hg (P<0.05). This was associated with a fall in cardiac output by approximately 18% (P<0.05). VML-588 caused a slight decrease in brachial mean arterial pressure, PWV, and AIx, and prevented the effects of ET-1 on central hemodynamics without a clear dose-response effect. In summary, ET-1 in plasma concentrations as found in renal failure and heart failure accelerates PWV, causes a disproportionate increase in central aortic systolic blood pressure and pulse pressure, and decreases cardiac output. These effects can be prevented with an ET-1 receptor blocker such as VML-588. This makes it worthwhile to focus on endothelin as a target to prevent ventricular hypertrophy and to maintain cardiac function in diseases associated with high ET-1.     

The effects of chronic carvedilol therapy on QT dispersion in patients with congestive heart failure.

BACKGROUND: Carvedilol therapy reduces mortality from sudden cardiac death and progressive pump failure in congestive heart failure (CHF). However, the effect(s) of carvedilol on ventricular repolarization characteristics is unclear. AIM: The aim of the study was to investigate the effects of chronic carvedilol therapy on ventricular repolarization characteristics as assessed by QT dispersion (QTd) in patients with CHF. METHOD: Nineteen patients (age 53+/-12 years; 16 male, three female) with CHF (eight ischemic, 11 non-ischemic dilated cardiomyopathy) were prospectively included in the study. Carvedilol was administered in addition to standard therapy for CHF at a dose of 3.125 mg bid and uptitrated biweekly to the maximum tolerated dose. From standard 12-lead electrocardiograms the maximum and minimum QT intervals (QTmax, QTmin), QTd, corrected QT intervals (QTcmax, QTcmin) and corrected QTd (QTcd) values were calculated at baseline, after the 2nd and the 16th month of carvedilol therapy. RESULTS: A significant reduction was noted in the QTd and QTcd values with carvedilol therapy after the 16th month (QTd: 81+/-22 ms vs. 40+/-4.3 ms P<0.001; QTcd: 91+/-25 ms vs. 51+/-7 ms P<0.001), but not after the 2nd month (P>0.05). The resting heart rate was also significantly reduced after a 16-month course of carvedilol therapy (78+/-13 bpm vs. 66+/-15 bpm, P<0.05). Carvedilol therapy did not alter QTmax and QTcmax intervals (P>0.05), however, QT min and QTcmin significantly increased with carvedilol at the 16th month (P<0.001 and P<0.01, respectively). CONCLUSION: Long-term carvedilol therapy was associated with a reduction in QTd, an effect that might contribute to the favorable effects of carvedilol in reducing sudden cardiac death in CHF.     

Effect of selective and nonselective β-blockers on resting energy production rate and total body substrate utilization in chronic heart failure

Background: In chronic heart failure (CHF) β-blockers reduce myocardial oxygen consumption and improve myocardial efficiency by shifting myocardial substrate utilization from increased free fatty acid oxidation to increased glucose oxidation. The effect of selective and nonselective β-blockers on total body resting energy production rate (EPR) and substrate utilization is not known. Methods: Twenty-six noncachectic patients with moderately severe heart failure (New York Heart Association class II or III, left ventricular ejection fraction < 0.40) were treated with carvedilol (37.5 ± 13.5 mg/12 h) or bisoprolol (5.4 ± 3.0 mg/d) for 6 months. Indirect calorimetry was performed before and after 6 months of treatment. Results: Resting EPR was decreased in carvedilol (5.021 ± 0.803 to 4.552 ± 0.615 kJ/min, P < .001) and bisoprolol group (5.230 ± 0.828 to 4.978 ± 0.640 kJ/min, P < .05; nonsignificant difference between groups). Lipid oxidation rate decreased in carvedilol and remained unchanged in bisoprolol group (2.4 ± 1.4 to 1.5 ± 0.9 mg m²/kg min versus 2.7 ± 1.1 to 2.5 ± 1.1 mg m²/kg min, P < .05). Glucose oxidation rate was increased only in carvedilol (2.6 ± 1.4 to 4.4 ± 1.6 mg m²/kg min, P < .05), but did not change in bisoprolol group. Conclusions: Both selective and nonselective β-blockers reduce total body resting EPR in noncachectic CHF patients. Carvedilol compared to bisoprolol shifts total body substrate utilization from lipid to glucose oxidation.