Bradykinin May Not Be Involved in Improvement of Insulin Resistance by Angiotensin Converting Enzyme Inhibitor

We have previously demonstrated that captopril ameliorates glucose intolerance by partially preventing the reduction in postprandial skeletal muscle blood flow. The present study was designed to clarify the mechanism by which ACE inhibitors affect glucose metabolism in fructose (FRU)-fed Wistar rats with hypertension, glucose intolerance and hyperinsulinermia. Eight-week-old male rats (n=51) were divided into six groups. Controls were given a normal chow, while fructose-rich (55%) chow was administered to the remainder for eight weeks. The different groups were administered alacepril (ALA, 30 mg/kg/day) with or without a continuous infusion of Hoe 140, a kinin B₂ receptor antagonist (150 μ/kg/day), Hoe 140 alone or TCV-116 (1 mg/kg/day), an angiotensin II receptor antagonist, alone. After measuring the body weight and systolic bolld pressure (BP), steady-state plasma glucose (SSPG) levels were determined. FRU significantly increased BP from 141 mmHg in controls to 156 mmHg. ALA with or without Hoe 140 decreased BP to 124 mmHg or 117 mmHg, respectively, but Hoe 140 alone did not affect BP. TCV-116 also decreased BP to 11 6 mmHg. The SSPG levels increased from 7.58 mM in controls to 8.98 mM in FRU-fed rats. This was lowered with both ALA and TCV-116. Hoe 140 alone, however, did not affect SSPG levels. Hoe 140 did not show any effects on ALA-induced improvement of SSPG. These results suggest that the improvement in glucose tolerance observed with ACE inhibitors is not due to the kinins, and angiotensin II receptor antagonists also improve insulin sensitivity.     

Prospective and randomized study of the antihypertensive effect and tolerability of three antihypertensive agents,losartan, amlodipine,and lisinopril,in hypertensive patients

We prospectively evaluated the antihypertensive effect and tolerability of three different antihypertensive agents, losartan (angiotensin II receptor blocker), amlodipine (calcium channel blocker), and lisinopril (angiotensin-coverting enzyme inhibitor), in patients with mild-to-moderate hypertension. After a 2-week washout period, 121 patients were randomly allocated to three different groups for 12 weeks. Medications were titrated upward as necessary to achieve the goal office-recorded sitting diastolic blood pressure (SiDBP) (defined as SiDBP 90mmHg or SiDBP 900mmHg but with a 10mmHg drop from baseline). Efficacy and tolerability were assessed after 4, 8, and 12 weeks of therapy with each regimen. At 12 weeks, significant differences in SiDBP compared with data of baseline were noted in all three groups (P 0.001 in all comparisons). Similarly, significant differences in the sitting systolic blood pressure compared with baseline data were also seen for all three groups (P 0.001 in all comparisons). The number of patients reaching goal SiDBP were comparable for the three groups: 25 patients (62.5%) in the losartan group, 27 patients (67.5%) in the amlodipine group, and 22 patients (59.5%) in the lisinopril group (not significant). Amlodipine produced a more pronounced reduction in SiDBP than the other two medications, although without statistical significance. Patients receiving lisinopril showed a high incidence of coughing (31.7%). Low leg edema was noted only in the amlodipine group (7.5%). Compared with the amlodipine and lisinopril groups, the losartan group seemed to have relatively fewer episodes (7.5%), and fewer patients (three cases) experienced adverse effects. In conclusion, this study demonstrates that losartan has the same antihypertensive effect, but has superior tolerability compared with the other two drugs. Coughing was a common side effect of lisinopril therapy in our population.     

几种肾素-血管紧张素系统抑制剂对大鼠外周血内皮前体细胞作用的研究

目的:观察正常大鼠应用临床推荐剂量的血管紧张素转换酶抑制剂或血管紧张素受体拈抗剂后,外周血内皮前体细胞(EPCs)克隆数量、分泌一氧化氮能力、内皮型一氧化氮合酶(eNOS)及半胱氨酸天冬氨酸蛋白酶3(Caspase-3)蛋白水平.方法:48只雄性SD大鼠随机平均分为6组(每组8只),对照组给予生理盐水,余5组每日灌胃给药,血管紧张素转换酶抑制剂:培哚普利组给予培哚普利1.33 mg/(kg·d)、雷米普利组给予雷米普利1.67 mg/(kg·d)、福辛普利组给予福辛普利6.67 mg/(kg·d)、卡托普利组给予卡托普利25 mg(kg·d),血管紧张素受体拮抗剂:替米沙坦组给予替米沙坦13.33 mg/(kg·d),共2周.2周后取外周血体外培养EPCs.免疫荧光染色及实时聚合酶链反应鉴定细胞表面标志.计数细胞克隆,检测细胞培养液上清一氧化氮含量,免疫印迹杂交方法分析细胞eNOS及Caspaee-3表达.结果:各组细胞培养至10～14天形成"铺路石"样克隆,经鉴定符合晚期EPCs特点.各药物组与对照组相比,细胞克隆数均有增多趋势,但只有卡托普利组与对照组相比差异有统计学意义(P<0.05);各药物组间差异无统计学意义.雷米普利组、福辛普利组及替米沙坦组与对照组相比,细胞培养上清液中一氧化氮含量亦有升高,差异有统计学意义(P相似文献   

Role of the angiotensin II receptor blocker valsartan in heart failure

Despite an enormous amount of research carried out in the past 10 to 20 years, the role of the renin-angiotensin system in the development of heart failure is still not very well understood. This review looks at preclinical data on the role of angiotensin II as a circulating and local hormone, and the effects of stimulation of the respective receptors in heart tissue. Recent large scale clinical trials have begun to furnish evidence of the effects of blocking the renin-angiotensin system in patients with heart failure using angiotensin-converting enzyme inhibitors or, more recently, angiotensin II receptor blockers that act directly at the receptor level, independent of pathways for angiotensin II generation. Results so far indicate that there are benefits from optimizing the blockade, but open questions remain, such as the role of endothelin and bradykinins, and the extent of crosstalk between the different systems.     

Prevention of renal damage by angiotensin II blockade, accompanied by increased renal hepatocyte growth factor in experimental hypertensive rats.

Hepatocyte growth factor (HGF) is a unique growth factor that has many protective functions against renal damage. Our previous study demonstrated that HGF stimulated the growth of endothelial and epithelial cells without the replication of mesangial cells. Moreover, angiotensin (Ang) II significantly decreased local HGF production in mesangial cells. Therefore, we examined the effects of Ang II blockade on renal HGF expression and renal damage in experimental hypertensive rats. An angiotensin-converting enzyme inhibitor (cilazapril; 10 mg. kg(-1). d(-1)), an Ang II type 1 receptor antagonist (E-4177; 30 mg. kg(-1). d(-1)), hydralazine (8 mg. kg(-1). d(-1)), and vehicle were administered to 16-week-old stroke-prone spontaneously hypertensive rats (SHR-SP) for 3 weeks. Renal damage was evaluated with a computer analysis system, and renal HGF mRNA was measured by Northern blot analysis. Blood pressure of SHR-SP was significantly decreased by all drug treatments compared with vehicle. Moreover, cilazapril, E-4177, and hydralazine significantly decreased the thickening and necrosis of blood vessels compared with vehicle. Similarly, degeneration and necrosis of glomeruli were also markedly improved by cilazapril and E-4177 (P<0.01). We next examined the effects of Ang II blockade on renal HGF expression in SHR-SP. Renal HGF mRNA was markedly decreased in SHR-SP compared with Wistar-Kyoto rats, although Ang II blockade by cilazapril and E-4177 but not hydralazine significantly increased renal HGF mRNA in SHR-SP. Ang II blockade significantly increased renal HGF (a protective growth factor for tubular epithelial cells); thus, we examined tubular histological appearance. Degeneration and necrosis of tubules were significantly improved by cilazapril and E-4177 treatment (P<0.01). In addition, cell infiltration into the glomeruli and hemorrhage were also significantly reduced in SHR-SP treated with cilazapril or E-4177. The present data demonstrated the prevention of renal damage by Ang II blockade in SHR-SP, which was accompanied by a significant increase in renal HGF mRNA. Given the strong mitogenic activity and antiapoptotic actions of HGF on endothelial and epithelial cells, we believe that increased local HGF production by the blockade of Ang II may improve renal function in hypertension.     

血管紧张素Ⅱ受体阻断剂抗肝纤维化的实验研究

目的 探讨血管紧张素Ⅱ１型受体阻断剂对四氯化碳（ＣＣｌ４）诱导的实验性肝纤维化大鼠血清层粘连蛋白等细胞外基质水平的影响。地大鼠肝实质损伤性肝纤维化模型由ＣＣｌ４诱导。５０只雄性ＳＤ大鼠被随机分为５组：对照组、模型组及治疗组（高、中、低剂量组）,每组１０只,除对照组外所有大鼠均给予皮下注射４０％ＣＣｌ４（精制橄榄油配制,每３日１次,共６周）,对照组注射等体积的精制橄榄油。治疗组同时给予血管紧张素Ⅱ受     

Role of angiotensin II type 2 receptor during electrophysiological remodeling of left ventricular hypertrophic myocardium in spontaneously hypertensive rats

The objective was to investigate the role of angiotensin II type 2 receptor during electrophysiological remodeling of left ventricular hypertrophic myocardium in spontaneously hypertensive rats (SHRs). A total of 36, aged 10 weeks, male SHRs were divided into three groups: control, valsartan, and valsartan + PD123319 groups (n = 12 in each). The systolic blood pressure, left ventricular mass index, ventricular effective refractory period, and ventricular fibrillation threshold (VFT) were also measured after 8 weeks. At the same time, I_Na, I_CaL, I_to, and membrane capacitance were measured in left ventricular myocytes by whole-cell patch-clamp. The VFT of valsartan was higher than that of control (valsartan vs. control: 17.4 ± 0.6 mA vs. 15.8 ± 0.5 mA, P < .05). The VFT of valsartan was higher than that of valsartan + PD123319 (valsartan vs. valsartan + PD123319: 17.4 ± 0.6 mA vs. 16.6 ± 0.9 mA, P < .05). The density of I_to of valsartan was higher than that of control (valsartan vs. control: 14.7 ± 0.42 pA/pF vs. 11.2 ± 0.15 pA/pF, P < .05). The density of I_to of valsartan was higher than that of valsartan + PD123319 (valsartan vs. valsartan + PD123319: 14.7 ± 0.42 pA/pF vs. 13.6 ± 0.30 pA/pF, P < .05). The density of I_CaL of valsartan was lower than that of control (valsartan vs. control: ?4.6 ± 0.2 pA/pF vs. ?6.9 ± 0.1 pA/pF, P < .05). The density of I_CaL of valsartan was lower than that of valsartan + PD123319 (valsartan vs. valsartan + PD123319: ?4.6 ± 0.2 pA/pF vs. ?5.4 ± 0.1 pA/pF, P < .05). These results demonstrated that the stimulation of angiotensin II type 2 receptor improved electrophysiological remodeling of left ventricular hypertrophic myocardium in SHR.     

Effects of angiotensin II receptor antagonists on [(123)I]metaiodobenzylguanidine myocardial imaging findings and neurohumoral factors in chronic heart failure

 Previous studies have not investigated the ef-ficacy of angiotensin II (AII) receptor antagonists against cardiac sympathetic overactivity in patients with chronic heart failure (CHF) using [¹²³I]metaiodobenzylguanidine (MIBG) myocardial imaging. We studied 34 CHF patients with fractional shortening of the left ventricular (LV) diameter ≦25% or LV ejection fraction ≦45% in echocardiograms. An AII receptor antagonist (losartan or candesartan) was administered. Before and 6 months after the administration, MIBG myocardial imaging and echocardiography were performed, and neurohumoral factors were investigated. MIBG imaging revealed that the antagonist did not significantly change the heart-to-mediastinum ratio. However, the washout rate fell significantly (from 32.6% ± 7.6% to 28.2% ± 7.5%; P < 0.001). No significant changes occurred in LV diameter, fractional shortening, or LV ejection fraction. Circulating atrial (ANP) and brain natriuretic peptides (BNP), and aldosterone fell significantly. Changes in the MIBG washout rate correlated positively with changes in BNP (r = 0.35, P < 0.05). In 19 patients also being treated with angiotensin-converting enzyme (ACE) inhibitors, the MIBG washout rate also fell significantly with AII antagonists, as did BNP and aldosterone. The decreased MIBG washout and BNP in patients with CHF induced by the AII receptor antagonists suggests the efficacy of these agents in modifying cardiac sympathetic function and neurohumoral factors, even with ACE inhibition. Combination therapy with AII receptor antagonists and ACE inhibitors appears effective for CHF. Received: April 30, 2002 / Accepted: August 2, 2002 Correspondence to H. Shinohara     

Blood pressure variability,impaired autonomic function and vascular senescence in aged spontaneously hypertensive rats are ameliorated by angiotensin blockade

Objective

Elderly hypertensive patients are characterized by blood pressure (BP) variability, impaired autonomic function, and vascular endothelial dysfunction and stiffness. However, the mechanisms causing these conditions are unclear. The present study examined the effect of angiotensin receptor blockers (ARBs) on aged spontaneously hypertensive rats (SHR).

Methods

We surgically implanted telemetry devices in SHR and WKY at the age of 15 weeks (Young) and 80 weeks (Aged). Aged SHR were orally administered either olmesartan or valsartan once daily at 19:00 h (at the beginning of the dark period (active phase)) for 4 weeks to examine the effects on BP variability, impaired autonomic function, and vascular senescence.

Results

Aging and hypertension in SHR additively caused the following: increased low frequency (LF) power of systolic BP, a decreased spontaneous baroreceptor reflex gain (sBRG), increased BP variability, increased urinary norepinephrine excretion, increased vascular senescence-related beta-galactosidase positive cells and oxidative stress. Treatment with olmesartan or valsartan significantly ameliorated these changes in aged SHR. However, olmesartan ameliorated these changes in aged SHR better than valsartan. The reductions in BP caused by olmesartan in aged SHR were sustained longer than reductions by valsartan. This result indicates longer-lasting inhibition of the AT1 receptor by olmesartan than by valsartan.

Conclusion

ARBs ameliorated autonomic dysfunction, BP variability, and vascular senescence in aged SHR. Olmesartan ameliorated the aging-related disorders better than valsartan and was associated with longer-lasting AT1 receptor inhibition by olmesartan. Thus, the magnitude of improvement of these aging-related abnormalities differs for ARBs.     

血管紧张素II对培养的人脐静脉内皮细胞产生纤溶因子的影响

摘要：　目的 探讨血管紧张素II(angiotensin II，Ang II)对内皮细胞纤溶功能的影响及缬沙坦的干预作用。方法 用酶消化法收集并培养人脐静脉内皮细胞(human umbilical vein endothelial cells，HUVECs)，将10-6，10-7，10-8，10-9mol/L Ang II分别与HUVECs共同孵育12 h；10-7mol/L Ang II和HUVECs分别孵育0，2，6，12，24，48 h；10-7mol/L Ang II和10-5，10-6，10-7，10-8mol/L缬沙坦(与HUVECs孵育12 h；10-6mol/L缬沙坦与HUVECs孵育12 h。用酶联免疫吸附法测定上清液中组织型纤溶酶原激活物(tissue plasminogen activator，tPA)和1型纤溶酶原激活物抑制剂(plasminogen activator inhibitor-1，PAI-1)抗原浓度。结果 Ang II呈浓度依赖性升高HUVECs的PAI-1水平，最大效应浓度10-7mol/L；10-7mol/L AngII对HUVECs作用，孵育2 h PAI-1含量即升高，12 h达高峰 198μg/L；缬沙坦呈浓度依赖性降低Ang II促HUVECs分泌PAI-1，缬沙坦最大效应浓度10-6mol/L； AngII和缬沙坦对HUVECs分泌tPA没有明显影响。结论 AngII通过促进HUVECs分泌PAI-1而降低纤溶活性；缬沙坦通过抑制AngII的促PAI-1分泌作用而提高纤溶活性，提示有助于动脉粥样硬化血栓性疾病的防治。     

Levels of vascular endothelial growth factor and hepatocyte growth factor in sera of patients with rheumatic diseases

 Angiogenesis plays an important role in the progression of rheumatic disease. We measured the levels of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in sera from patients with rheumatic diseases and investigated whether these angiogenic factors would be useful in the evaluation of rheumatic diseases. Serum VEGF and HGF levels were determined using ELISA in 128 patients with rheumatic diseases and in 11 healthy controls. Serum VEGF and HGF levels were significantly higher in patients with rheumatic diseases compared to healthy controls [VEGF, 312 ± 20 pg/ml versus 61 ± 8 pg/ml (mean ± SE), P < 0.001; HGF, 935 ± 36 pg/ml versus 413 ± 49 pg/ml, P < 0.01]. Serum VEGF and HGF levels were significantly elevated in patients with adult Still's disease (VEGF, 1021 ± 258 pg/ml; HGF, 1500 ± 295 pg/ml) and were relatively increased in patients with active rheumatoid arthritis (RA) (VEGF, 359 ± 94 pg/ml) and systemic sclerosis (SSc) (VEGF, 356 ± 43 pg/ml; HGF, 1294 ± 224 pg/ml). HGF levels correlated with the clinical course and disease severity in rheumatic disease patients. VEGF levels correlated with the presence of Raynaud's phenomenon (P < 0.05), interstitial lung disease (ILD) (P < 0.05), and serum KL-6 levels (P < 0.01), whereas HGF levels correlated with cryoglobulinemia (P < 0.05), ILD (P < 0.05), serum C-reactive protein (CRP) (P < 0.05), thrombomodulin (P < 0.05), and KL-6 levels (P < 0.05) in rheumatic disease patients. VEGF levels correlated with the skin scores and KL-6 levels in SSc patients and also correlated with the disease activity of RA patients. These data suggest that serum VEGF and HGF levels are related to rheumatic disease activity and the presence of complications. Analysis of VEGF and HGF may be useful in the clinical evaluation of rheumatic disease patients. Received: February 19, 2002 / Accepted: August 13, 2002 Acknowledgment We are grateful to Ms. Aki Nomura for assistance with the ELISA of VEGF and HGF.     

Changes in protein and gene expression of angiotensin II receptors (AT1 and AT2) in aorta of diabetic and hypertensive rats

Diabetes and hypertension have been associated with cardiovascular diseases and stroke. Some reports have related the coexistence of hypertension and diabetes with increase in the risk of developing vascular complications. Recently some studies have shown results suggesting that in the early stages of diabetes and hypertension exist a reduced functional response to vasopressor agents like angiotensin II (Ang II), which plays an important role in blood pressure regulation mechanism through the activation of its AT₁ and AT₂ receptors. For that reason, the aim of this work was to study the gene and protein expression of AT₁ and AT₂ receptors in aorta of diabetic SHR and WKY rats. Diabetes was induced by the administration of streptozotocin (60?mg/kg i.p.). After 4 weeks of the onset of diabetes, the protein expression was obtained by western blot and the mRNA expression by RT-PCR. Our results showed that the hypertensive rats have a higher mRNA and protein expression of AT₁ receptors than normotensive rats while the AT₂ expression remained unchanged. On the other hand, the combination of diabetes and hypertension increased the mRNA and protein expression of AT₁ and AT₂ receptors significantly. In conclusion, our results suggest that diabetes with hypertension modifies the mRNA and protein expression of AT₁ and AT₂ receptors. However, the overexpression of AT₂ could be associated with the reduction in the response to Ang II in the early stage of diabetes.     

The use of renin angiotensin system inhibitor on mortality in patients with coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis

Backgroundand Aims; To investigate the association between use of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin-receptor blocker (ARB) and outcomes of hypertensive COVID-19 patients, a systematic review and meta-analysis were performed.MethodsWe systematically searched PubMed, EuropePMC, ProQuest, and Cochrane Central Databases using the terms “(COVID-19 OR SARS-CoV-2) AND (angiotensin converting enzyme OR angiotensin receptor blocker)”. The primary and second outcomes were mortality (non-survivor) and severe COVID-19, respectively.ResultsTotally, 7410 patients were included from 15 studies. Pooled analysis showed that the use of ACEI/ARB was not associated with mortality (OR 0.73 [0.38, 1.40], p = 0.34; I²: 81%) and severity (OR 1.03 [0.73, 1.45], p = 0.87; I²: 65%). Pooled adjusted OR showed no risk/benefit associated with ACEI/ARB use in terms of mortality (OR 0.83 [0.54, 1.27], p = 0.38; I²: 0%). Subgroup analysis showed that the use of ARB was associated with reduced mortality (OR 0.51 [0.29, 0.90], p = 0.02; I²: 22%) but not ACEI subgroup (OR 0.68 [0.39, 1.17], p = 0.16; I²: 0%). Meta-regression showed that the association between ACEI/ARB use and mortality in patients with COVID-19 do not varies by gender (p = 0.104). GRADE showed a very low certainty of evidence for effect of ACEI/ARB on mortality and severity. The certainty of evidence was very low for both ACEI and ARB subgroups.ConclusionAdministration of a renin angiotensin system (RAS) inhibitor, was not associated with increased mortality or severity of COVID-19 in patients with hypertension. Specifically, ARB and not ACEI use, was associated with lower mortality.     

血管紧张素II和缬沙坦对人脐静脉内皮细胞血凝素样氧化低密度脂蛋白受体表达的影响

目的　研究血管紧张素II(AngII)和AngIII型受体 (AT1)拮抗剂缬沙坦对人脐静脉内皮细胞 (HUVECs)血凝素样氧化低密度脂蛋白受体 (LOX 1)基因转录和蛋白表达的影响 ,以进一步探讨AngII和LOX 1在动脉粥样硬化 (AS)中的地位和相互关系 ,以及缬沙坦可能的抗AS作用。方法　将不同浓度AngII(1× 10 -5～ 1× 10 -10 mol/L)与HUVECs共孵育 2 4h ,以及将 1× 10 -6mol/L浓度的AngII与HUVECs作用不同时间 (0、3、6、12、2 4、36、4 8h)后 ,用细胞酶联免疫法和半定量RT PCR分别检测LOX 1蛋白和mRNA表达的情况 ,并观察缬沙坦对此的影响。结果　AngII呈浓度依赖方式诱导HUVECsLOX 1蛋白和mRNA表达增加 ;10 -6mol/L的AngII作用 3h ,内皮细胞LOX 1蛋白和mRNA表达即有显著增高 (P <0 0 0 1) ;随着时间延长 ,LOX 1蛋白和mRNA表达量逐渐增加 ,至 2 4～ 36h达最高峰。缬沙坦可显著抑制AngII诱导的HUVECsLOX 1表达 ,使LOX 1表达接近于正常水平。结论AngII能明显增强HUVECs表达LOX 1,并呈浓度和时间依赖性 ,这可能是AngII促进动脉粥样硬化发生、发展的机制之一 ;此作用可被AT1拮抗剂缬沙坦阻断 ,从而产生可能的抗AS作用。     

Expression of angiotensin II type 1 receptor in human cirrhotic livers: Its relation to fibrosis and portal hypertension.

Angiotensin II (ANG-II) and its receptor (AT1) have been potential targets of therapy for liver cirrhosis. However, AT1 expression in human cirrhotic livers has not been clarified. We studied AT1 and ANG-II generating enzymes in human autopsy (20 cirrhotics and 20 normal controls) and biopsy (10 cirrhotics) livers. AT1 immunoreactivity in tissue sections was quantified by computer-aided morphometry. AT1 protein and mRNA levels were assessed by Western blotting and real-time polymerase chain reaction. Concerning ANG-II generating system, angiotensin-converting enzyme (ACE) and mast cell chymase were examined. AT1 expression was seen not only in vascular smooth muscle cells, but also in activated stellate cells/myofibroblasts and liver parenchymal cells. AT1-positive vessels and myofibroblasts were significantly increased in fibrous septa of cirrhosis, although overall hepatic AT1 expression was reduced in the cirrhotic livers compared with the controls. Augmentation of AT1-positive vessels was related to severity of portal hypertension. Expressions of ACE and chymase were enhanced in the cirrhotic livers. These results suggest that hepatic AT1 expression is shifted to and concentrated in vessels and myofibroblasts in cirrhotic settings, and increased ANG-II generation by ACE and chymase contributes to portal hypertension and liver fibrosis via binding to AT1 expressed on vessels and myofibroblasts.     

The arterial length‐densities under preventive angiotensin‐converting‐enzyme inhibiting treatment in the myocardium of spontaneously hypertensive rats

The length density (L_V) of capillaries is known to be increased in the hearts of spontaneously hypertensive rats (SHR) after high‐dosed but also after low‐dosed subantihypertensive treatment with the ACE‐inhibitor Ramipril administered in utero and post partum. Under the same conditions in the present study only highdose Zabicipril caused an increase of capillary L_V. Under preventive ACE‐inhibition in both high‐dose groups L_V of myocardial arteries was significantly higher. In the low‐dose groups L_V was not significantly increased. The increased arterial L_V in the high‐dose‐group may result from the avoidance of angiotensin II‐induced overabundant growth of myocardial muscle‐mass. Changes in collagen could not be found in any of the experimental groups. (Basic Res Cardiol) Received: 7 April 1997, Returned for 1. revision: 9 June 1997, 1. Revision received: 12 September 1997, Returned for 2. revision: 29 October 1997, 2. Revision received: 31 October 1997, Accepted: 6 November 1997     

Comparison between angiotensin receptor antagonism and converting enzyme inhibition in heart failure

This study was designed to assess the influence of the activation status of the renin angiotensin system (RAS) on the hemodynamic effects of EXP 3174 (an angiotensin AT1 receptor antagonist) and enalaprilat (an angiotensin converting enzyme inhibitor) in tachycardia-induced heart failure. Thirteen dogs were chronically instrumented to measure left ventricular (LV) pressure, its first time derivative (LV dP/dt), atrial and aortic pressures, and cardiac output. EXP 3174 (0.1 mg/kg, iv) or enalaprilat (1 mg/kg, iv) were administered in conscious dogs with heart failure induced by right ventricular pacing (250 beats/min, 3 weeks). EXP 3174 and enalaprilat produced significant vasodilation but the effects of EXP 3174 on mean aortic pressure (MAP), cardiac output, and total peripheral resistance (TPR) were only 50% of those produced by enalaprilat. When dogs were grouped according to their baseline plasma renin activity (PRA) values, in dogs with normal PRA (0.5 ± 0.1 ng/ml/h) EXP 3174 did not produce significant change in MAP and TPR, while enalaprilat decreased significantly MAP and TPR. In contrast, in dogs with high PRA (6.7 ± 3.2 ng/ml/h), EXP 3174 produced significant reductions in MAP and TPR, which were similar to those produced by enalaprilat. Thus, in conscious dogs with heart failure, enalaprilat is effective whether the RAS is activated or not. In contrast, EXP 3174 is effective only when the RAS is activated. These results may help in the choice of inhibitors of the RAS in heart failure. Received: 22 September 1998, Returned for revision: 14 October 1998, Revision received: 23 November 1998, Accepted: 8 December 1998