Discovery and in Vivo Evaluation of Potent Dual CYP11B2 (Aldosterone Synthase) and CYP11B1 Inhibitors

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Hyperuricemia as a risk factor for cardiovascular disease

Chronic activation of the renin–angiotensin–aldosterone system (RAAS) plays a key role in the development of hypertension, and cardiac and renal diseases. RAAS inhibitors, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), improve cardiovascular and renal outcomes. However, studies have shown that residual morbidity and mortality remains high, despite current optimal treatment. More comprehensive control of the RAAS might provide additional reductions in morbidity and mortality. Direct renin inhibitors offer the potential for enhanced RAAS control as they target the system at the point of activation, thereby reducing plasma renin activity (PRA); by contrast, ARBs and ACE inhibitors increase PRA. Elevated PRA is independently associated with cardiovascular morbidity and mortality. A single-pill combination of the direct renin inhibitor, aliskiren, and the ARB, valsartan, at once-daily doses of 150/160 mg and 300/320 mg, has recently been approved by the US FDA for the treatment of hypertension in patients not adequately controlled on aliskiren or ARB monotherapy, and as initial therapy in patients likely to need multiple drugs to achieve their blood pressure goals. This article examines the efficacy, safety and tolerability of aliskiren/valsartan combination therapy, and considers the evidence for the potential organ-protection benefits of this treatment.     

Hypertension and left ventricular hypertrophy in autosomal dominant polycystic kidney disease

Hypertension is a common problem in patients with autosomal dominant polycystic kidney disease affecting both renal and patient survival. Activation of the renin–angiotensin–aldosterone system due to cyst expansion and local renal ischemia has been proposed to play an important role in the development of hypertension in autosomal dominant polycystic kidney disease. Left ventricular hypertrophy, a major cardiovascular risk factor, is also common in patients with autosomal dominant polycystic kidney disease. Both hypertension and the activation of the renin–angiotensin–aldosterone system play a role in the development of left ventricular hypertrophy in these patients. Prospective randomized results indicate that aggressive control of blood pressure is important for the optimal reversal of left ventricular hypertrophy, thereby diminishing a major risk factor for cardiovascular morbidity and mortality of patients with autosomal dominant polycystic kidney disease. There is also substantial epidemiological support for aggressive control of blood pressure in slowing renal disease progression in autosomal dominant polycystic kidney disease patients. Blockade of the renin–angiotensin–aldosterone system should be the initial approach in the treatment of hypertension in these patients.     

New clinical concepts after the ONTARGET trial

Some aspects of the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) study are briefly commented on in this article. The three main topics of interest related to the study that require further analysis are the following: the influence of blood pressure control, and in particular, the target blood pressure for patients with established cardiovascular disease such as those admitted in the ONTARGET study, the renal aspects of the study, which are of great interest but do not adequately clarify, in particular, concerns over the dual blockade of the renin–angiotensin–aldosterone system (RAAS) with telmisartan and ramipril, and finally, and probably most importantly, the role of statins in the outcome of the study. A high percentage of patients receiving this type of therapy at the end of the study, which probably contributed to obtaining a residual risk similar to that in the Heart Outcomes Prevention Evaluation (HOPE) study in the absence of treatment with RAAS blockers in approximately two-thirds of patients included in the ONTARGET trial.     

The role of renin–angiotensin– aldosterone system inhibition in chronic kidney disease

Chronic kidney disease (CKD) is emerging as a new health pandemic. Underlying the global rise in CKD is an increase in diabetes, hypertension and other cardiovascular risk factors leading to progressive renal dysfunction. Emerging evidence strongly suggests that achieving target blood pressure goals via inhibition of the renin–angiotensin–aldosterone system confers significant renal and cardioprotection for patients with CKD. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) lower blood pressure, reduce proteinuria and reduce both the progression of CKD and adverse cardiovascular events. The role of aldosterone inhibition and combination therapy, such as ACEI/ARB, in CKD are under investigation. As our understanding of the basic mechanisms underlying CKD progression advances, novel therapies targeting post-translational endothelial and mesangial messengers downstream from angiotensin II and aldosterone may become available for clinical use.     

The metabolic syndrome: Role of skeletal muscle metabolism

Skeletal muscle constitutes the largest insulin‐sensitive tissue in the body and is the primary site for insulin‐stimulated glucose utilization. Skeletal muscle resistance to insulin is fundamental to the metabolic dysregulation associated with obesity and physical inactivity, and contributes to the development of the metabolic syndrome (MS). The inability to efficiently take up and store fuel, and to transition from fat to glucose as the primary source of fuel during times of caloric abundance (high insulin) or scarcity (low insulin) has been termed metabolic inflexibility which contributes to a whole body metabolic dysregulation and cardiovascular risk. Potential mechanisms contributing to reduced insulin signaling and action in skeletal muscle includes adipose tissue expansion and increased inflammatory adipokines, increased renin‐angiotensin‐aldosterone system (RAAS) activity, decreases in muscle mitochondrial oxidative capacity, increased intramuscular lipid accumulation, and increased reactive oxygen species. Future research is focused upon understanding these and other potential mechanisms in order to identify therapeutic targets for reducing MS risk. Strategies will include adequate physical activity and maintaining a healthy weight, but may also require specific pharmacologic interventions.     

Atrial Natriuretic Peptide in Transient Puerperal Hypertension

This study is the first approach to evaluate whether human atrial natriuretic peptide (hANP) is involved in the pathophysiology in transient puerperal hypertension (TPH). Five women who were normotensive throughout pregnancy, labor, and delivery developed hypertension between the first and sixth postpartum day. hANP (pg/ml) and plasma renin activity (PRA, ng/ml/h), angiotensin I, II (AI, II, pg/ml), and aldosterone (Aldo, pg/ml) in plasma were quantified by radioimmunoassay. Ten women without hypertension were also studied on hANP, PRA, AI, AII, and Aldo sequentially as the control group.

hANP was apparently lower in women with TPH than in normotensive women. The levels of PRA, AI, AII, and Aldo were also clearly decreased in women with TPH, whereas those values in normotensive women were not altered from nonpregnant levels.

Maternal natriuresis usually reaches the peak at 3–5 days postpartum. The decrease of hANP and PPA, AI, AII, and Aldo in TPH coincides with this natriuretic period. This observation suggests that hANP may serve an important role in the pathogenesis of TPH.     

Effects of prostacyclin on renal haemodynamics, renal tubular function and vasoactive hormones in healthy humans. A placebo-controlled dose–response study

Aims To investigate the acute effects of prostacyclin (Flolan^® ) on renal haemodynamics, renal tubular function, plasma concentration of angiotensin II (Ang II), aldosterone (Aldo), atrial natriuretic peptide (ANP), arginine vasopressin (AVP), mean arterial blood pressure (MBP), and heart rate (HR). Methods Thirteen healthy control subjects were investigated on two separate occasions in a placebo controlled, randomized, dose–response study of the effect of intravenous infusion of prostacyclin (PGI₂, Flolan^®, 2, 4 and 8 ng kg⁻¹min⁻¹ ). Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured by the use of constant infusion of []> ⁵¹Cr]-EDTA and [¹²⁵I]-hippurane. Urinary output, urinary sodium excretion, fractional sodium excretion, fractional lithium excretion were measured and hormones were measured using radioimmunoassay. Results During prostacyclin (PGI₂ ) infusion we observed a significant increase in RPF (PGI₂: 4.8%; 6.1% and 5.2%vs Plac: −1.5%; −1.9% and −5.8% for 2,4 and 8 ng kg⁻¹min⁻¹ respectively; P≤0.05 for 4 and 8 ng kg⁻¹min⁻¹ ) in Ang II (PGI₂: 20.0%; 42.9% and 88.9%vs Plac: 0.1%; 8.0% and 0.0%, P≤0.01 for 4 and 8 ng kg⁻¹ min⁻¹ ) in ANP (PGI₂: 13.6%; 12.7% and 37.5%vs Plac: −10.2%; −6.6% and −2.4%, P≤0.05 for 2 ng kg⁻¹min⁻¹ and P≤0.01 for 4 and 8 ng kg⁻¹min⁻¹ ), and in HR (PGI₂: 8.8%; 17.6% and 32.7%vs Plac: 0.8%; 4.1% and 3.5%, P≤0.05 for 2 and P≤0.01 for 4 and 8 ng kg⁻¹min⁻¹.). A significant decrease was observed in MBP (MBP:PGI₂: −1.7%; −1.9% and −5.6%vs Plac: −0.4%; −1.6% and +2.1%, P≤0.01 for 8 ng kg⁻¹min⁻¹ ). No significant changes were seen in the other effect variables. Conclusions Infusion of prostacyclin in healthy control subjects increases renal plasma flow, angiotensin II, atrial natriuretic peptide, and heart rate and decreases mean blood pressure. Furthermore prostacyclin infusion does not change net sodium excretion in healthy controls.     

腰麻-硬膜外联合麻醉对剖宫产母婴肾素-血管紧张素-醛固酮系统的影响

目的 研究腰麻－硬膜外联合麻醉（CSEA）对剖宫产母婴肾素－血管紧张素－醋固酮系统（RAAS）的影响。方法 将60例ASA Ⅰ级行择期剖宫产的健康产妇随机分为硬膜外麻醉组（EA组，n＝30）和CSEA组（n＝30)。分别于注射局麻药前(T0)、切皮后即刻（T1）、胎儿晚出后即刻（T2）、术毕即刻（T3）和术后24h（T4）取母体静脉血和胎儿娩出后胎儿脐动、静脉血测定血清素活性（PRA）、血管紧张素Ⅱ（AT-Ⅱ）和醛固酮（ALD）浓度；评定麻醉效果，记录痛觉阻滞平面达T7水平的时间，注射局麻药至胎儿娩出时间（I－DI）及新生儿娩出1min、5min的Apgar评分。结果 两组术中SP、DP、HR、SpO2的变化及新生儿娩出1min、5min的Apgar评分。结果 两组术中SP、DP、HR、SpO2的变化及新生儿娩出1min、5min的Apgar评分差异无显著性（P＞0.05）。同EA组相比，CSEA组麻醉起效时间明显缩短（P＜0.01）。两组母体于T1、T2、T4的PRA、AT－Ⅱ、ALD值均比T0、T3值明显降低（P＜0.01），胎儿脐动、静脉血中三者值差异不明显，但明显低于母体T0、T3值（P＜0.01）。结论 CSEA用于剖宫产手术时，只要运用得当，不会对母婴AAS产生不良影响。     

氯沙坦治疗充血性心力衰竭及对血浆内皮素和醛固酮的影响

目的 :观察氯沙坦对充血性心力衰竭(CHF)的疗效及治疗前后血浆内皮素 (ET)和醛固酮 (Ald)水平的变化。方法 :4 5例CHF病人随机分为氯沙坦组 2 5例 ,以利尿剂、洋地黄和氯沙坦 (5 0mg ,qd)治疗 3wk ;对照组 2 0例 ,仅以利尿剂和洋地黄治疗。结果 :治疗 3wk后 ,2组血浆ET和Ald水平较 3wk前显著下降 ,差值分别为 (- 8.2± 2 .3)pmol·L- 1,(- 2 1± 3) pmol·L- 1;(- 19.3± 1.4 )pmol·L- 1,(- 38± 3) pmol·L- 1(P <0 .0 1) ,但氯沙坦组下降更明显 (P <0 .0 1) ,治疗后 2组SV ,EF ,CO和CI有显著提高 (P <0 .0 1) ,2组间比较差异亦非常显著 (P <0 .0 1)。结论 :氯沙坦可以增加CHF病人的SV ,EF ,CO和CI ,并可降低血浆内ET和Ald ,显著改善心功能