Recent changes in the landscape of combination RAS blockade

The renin–angiotensin system (RAS) is a prime target for cardiovascular drug therapy. Inhibition of the RAS lowers blood pressure and confers protection against cardiovascular and renal events. These latter benefits cannot be entirely attributed to blood pressure lowering. Angiotensin-converting enzyme (ACE)-inhibitors and angiotensin receptor blockers (ARBs) have been studied extensively and, while there is irrefutable evidence that these agents mitigate the risk for cardiovascular and renal events, their protection is incomplete. In outcomes studies that have employed ACE-inhibitors or ARBs there has been a relatively high residual event rate in the treatment arm and this has been ascribed, by some, to the fact that neither ACE-inhibitors nor ARBs completely repress RAS. For this reason, combined RAS blockade with an ACE-inhibitor and ARB has emerged as a therapeutic option. In hypertension, combined RAS blockade elicits only a marginal incremental drop in blood pressure and it does not further lower the risk for cardiovascular events. In chronic heart failure and proteinuric renal disease, combining these agents in carefully selected patients is associated with a reduction in clinical events. Irrespective of the setting, dual RAS blockade is associated with an increase in the risk for adverse events, primarily hyperkalemia and worsening renal function. The emergence of the direct renin inhibitor, aliskiren, has afforded clinicians a new strategy for RAS blockade. Renin system blockade with aliskiren plus another RAS agent is the subject of ongoing large-scale clinical trials and early studies suggest promise for this strategy. Currently, combined RAS blockade with an ACE-inhibitor and an ARB should not be routinely employed for hypertension; however, the combination of an ACE-inhibitor or ARB with aliskiren might be considered in some patients given the more formidable blood pressure-lowering profile of this regimen. In carefully selected patients with heart failure or kidney disease, combination therapy with two RAS inhibitors should be considered.     

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.     

The role of renin inhibition in treating the hypertensive patient with diabetes: a summary of preclinical and clinical evidence

Comorbid hypertension and diabetes is common and associated with substantially greater cardiovascular and renal risk relative to hypertension alone. Tissue renin-angiotensin system (RAS) overactivity is a hallmark of diabetes and contributes to target organ damage. Treatment guidelines recommend angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) for reducing cardiorenal risk in patients with hypertension plus diabetes. However, these agents only partially prevent cardiovascular and renal morbidity/mortality. Further attempts to improve clinical outcomes have focused on the use of an ACE inhibitor plus an ARB, but this combination has not demonstrated a favorable risk-benefit profile. Direct renin inhibitors provide a more comprehensive blockade of the RAS compared with ACE inhibitors or ARBs, and may be of particular benefit in counteracting tissue RAS overactivity. In this article, the role of the RAS in diabetic hypertension and the preclinical and clinical effects of direct renin inhibitor therapy on target organs are reviewed.     

Pharmacokinetic/pharmacodynamic modeling of renin biomarkers in subjects treated with the renin inhibitor aliskiren

A semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) model was developed to evaluate the effects of aliskiren on the renin-angiotensin system (RAS) in humans. Mean data were extracted from a three-way crossover, placebo-controlled study. Outcome measures included the time-course of plasma renin activity (PRA) and plasma concentrations of aliskiren, active renin (AR), angiotensin I (ANG I), and angiotensin II (ANG II). The disposition of aliskiren may be best described as a two-compartment model with nonlinear elimination and distribution. The four biomarkers of RAS inhibition were co-modeled, and the AR showed a dose-dependent increase after the administration of aliskiren. This effect was described in terms of an indirect stimulatory response model in conjunction with an empirical submodel of functional adaptation. The estimated concentration of aliskiren necessary for producing 50% inhibition of PRA is 0.66 ng/ml, which is similar to in vitro estimates (0.33 ng/ml) after correction for plasma protein binding. The final and reduced models test the current hypothesis that RAS is inhibited by direct renin antagonism, and also provide suitable platforms for future clinical study design and analysis.     

Effects of renin-angiotensin system inhibition on end-organ protection: can we do better?

BACKGROUND: The renin-angiotensin system (RAS) is a major regulator of blood pressure (BP) and vascular response to injury. There is increasing evidence that RAS inhibition may provide end-organ protection independent of BP lowering. Two drug classes directly target angiotensin II through complementary mechanisms. Angiotensin-converting enzyme (ACE) inhibitors block the conversion of angiotensin I to the active peptide angiotensin II and increase the availability of bradykinin. Angiotensin receptor blockers (ARBs) selectively antagonize angiotensin II at AT 1 receptors and may also increase activation of the AT 2 receptor and modulate the effects of angiotensin II breakdown products. OBJECTIVES: This paper presents an overview of clinical data supporting the use of RAS inhibitors (ACE inhibitors and ARBs) as monotherapy or combination therapy based on the known role of the RAS in BP regulation and the vascular response to injury, and considers the implications of the data for future treatment. METHODS: Relevant experimental and clinical studies were identified by searching MEDLINE (1969-June 30, 2007) using the primary search terms renin-angiotensin system, angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, and dual RAS blockade. Trials included in the review were large (>200 patients), prospective, randomized controlled studies evaluating the effect of RAS inhibition on end-organ protection in various high-risk populations. RESULTS: Eleven clinical trials each were identified that evaluated the effect of ACE-inhibitor and ARB monotherapy on end-organ protection. Five trials were identified that evaluated the effects of combination therapy with an ACE inhibitor and an ARB compared with treatment with either agent alone in different patient populations using different end points. In hypertensive patients with type 2 diabetes and microalbuminuria, combination ACE-inhibitor/ARB therapy resulted in better BP control than either agent alone (mean difference, 11.2 mm Hg systolic [P = 0.002], 5.9 mm Hg diastolic [P = 0.003]), as well as greater reductions in microalbuminuria (mean difference in albumin:creatinine ratio, 34%; P = 0.04). Compared with monotherapy, dual RAS inhibition reduced the occurrence of a doubling of the serum creatinine concentration or end-stage renal disease by 60% to 62% in patients with nondiabetic renal disease (P = 0.018 vs ACE inhibitor alone; P = 0.016 vs ARB alone). A recently published study reported a nonsignificant benefit for combination therapy over monotherapy only in a subset of hypertensive patients with high levels of microalbuminuria at baseline (58.1% vs 43.4% reduction, respectively). In patients with heart failure and left ventricular ejection fraction 相似文献   

The impact of age and sex on the reporting of cough and angioedema with renin–angiotensin system inhibitors: a case/noncase study in VigiBase

The purpose of this study was to assess the impact of age and sex on the reporting of cough and angioedema related to renin–angiotensin system (RAS) inhibitors. A case/noncase study was performed in VigiBase. Two case groups were identified, reports of cough and reports of angioedema, and noncases were all reports of all other adverse events. Logistic regression analysis was used to assess the association between reporting of cough and angioedema with each class of RAS inhibitors stratified by age/sex and to control for confounding. The reporting of cough with angiotensin‐converting enzyme (ACE) inhibitors was significantly higher in women than in men [adjusted reporting odds ratio (ROR): 44.0, 95% CI (43.2–44.8) for women vs. 29.2, 95% CI (28.5–29.9) for men]. There was no difference in reporting of cough linked to angiotensin receptor blockers (ARBs) and aliskiren between men and women. In contrast, the reporting of angioedema with ACE inhibitors and ARBs was significantly higher in men than in women, but for aliskiren, women had a significantly higher ROR than men [adjusted ROR: 5.20, 95% CI (4.18–6.46) for women vs. 3.04, 95% CI (2.30–4.02) for men]. The reporting of cough with ACE inhibitors was increased with age until reaching a plateau at middle adulthood (40–59 years) and the reporting of angioedema with ACE inhibitors was increased with age until elderly (60–79 years). Age had only a slight effect on the reporting of cough and angioedema with ARBs and aliskiren. Both age and sex have substantial effects on the reporting of cough and angioedema with RAS inhibitors and in particular ACE inhibitors. Further study is needed to determine whether these differences mainly express different adverse drug reaction risks in subgroups or also can be explained by factors influencing reporting.     

ACE and AT1R gene polymorphisms and hypertension in Indian population

The renin angiotensin system (RAS) controls intrarenal blood pressure and sodium balance, and is an important target for antihypertensive therapy. Several polymorphisms have been identified within genes encoding RAS that may contribute to the development of elevated blood pressure. The relevance of these polymorphisms in hypertension remains controversial. In this study we have examined 105 hypertensive subjects and 192 controls from the Indian population for I/D polymorphism of angiotensin I converting enzyme (ACE) and A(1166)C polymorphism of angiotensin II type I receptor (AT1R) genes by polymerase chain reaction (PCR) and PCR-based restriction enzyme analysis method, respectively. There was no significant difference in the distribution of ACE (I/I, I/D, and D/D) and AT1R (A/A and A/C) genotypes between controls and hypertensive subjects. D allele was significantly associated with an early onset of hypertension and although nonsignificant, the frequency was high in subjects with family history of cardiovascular disorders. C(1166) allele of AT1R did not correlate with the age of onset of hypertension and the frequency was low in subjects with family history. Thus no association was found between ACE and AT1R genotypes and hypertension. However the D allele can be used as a predictor of risk of hypertension in the Indian population.     

What is the role of direct renin inhibitors in the treatment of the hypertensive diabetic patient?

The renin-angiotensin system (RAS) is the most important mechanism leading to cardiovascular and renal damage in diabetic patients. Studies conducted until now have unequivocally demonstrated that antihypertensive treatment with RAS blockers (angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers) improve the prognosis of patients with diabetes, by reducing rates of cardiovascular events and preventing or delaying the progression of diabetic nephropathy. However, despite the benefits of such treatment, cardio-renal events are still very frequent in diabetics. Several strategies for reducing this cardiovascular and renal risk have been proposed, but among them, a more complete blockade of the RAS seems the most attractive. Direct renin inhibitors are RAS blockers with some particularities, such as their ability to reduce plasma renin activity or the possibility to modulate tissue and intracellular RAS, which could represent a theoretical advantage when treating diabetic patients. In experimental and clinical studies conducted until now, aliskiren is able to reduce blood pressure in diabetics, alone or in combination with ACE inhibitors or angiotensin-receptor blockers. Moreover, aliskiren reduces markers of cardiac and renal disease, such as left ventricular hypertrophy or post-infarction ventricular remodeling, as well as proteinuria in diabetics already treated with other RAS blockers. The translation of these promising results to the clinical arena is currently being investigated in the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE), where more than 8600 diabetic patients with chronic kidney disease and at high-risk of cardio-renal events are treated with aliskiren or placebo added to the current treatment consisting of another RAS blocker. If positive, aliskiren will be the treatment of choice in the prevention of cardiorenal disease in diabetics.     

Combination therapy with aliskiren and amlodipine in hypertension: treatment rationale and clinical results

Optimal antihypertensive therapy requires a multimodal approach based on lifestyle modification and, for most individuals, combination drug therapy. Recommendations from experts suggest that a combination of an agent that blocks the renin–angiotensin system (RAS), together with a vasodilator (generally a calcium-channel blocker or a thiazide-type diuretic), is most likely to control blood pressure and provide the widest overall cardiovascular protection. Understanding the opportunities afforded by the combination of RAS blockade with a calcium-channel blocker requires a discussion of basic and clinical science data. One new concept is that of ‘global’ or total RAS blockade. The impact of the RAS can be diminished or blocked by several different classes of drugs (central sympatholytics, β-blockers, renin inhibitors, ACE inhibitors or ARBs); what is most important is how effectively the overall impact of angiotensin II is blunted. A second new concept is that the complementary actions of RAS blockers and calcium-channel blockers are best explained on the basis of diminished intracellular calcium availability in excitable tissue (sympathetic neurons and vascular smooth muscle cells) via parallel actions that reduce angiotensin II type-1 receptor stimulation and L-channel-mediated calcium flux. Aliskiren is the first of the direct renin inhibitors, the newest subclass of RAS blockers. In both short- and long-term studies, aliskiren has been shown to be similar in efficacy and tolerability compared with other RAS blockers, with the added benefit that its effects persist longer. Outcome studies with aliskiren are currently underway.     

血管紧张素Ⅱ受体阻断剂对慢性肾脏病患者肾素-血管紧张素系统表达的影响

目的：研究血管紧张素Ⅱ受体阻断剂（angiotensinⅡ receptor blocker,ARB）对慢性肾脏病（chronic kidney disease,CKD）患者循环和肾脏肾素-血管紧张素系统（renin-angiotensin system,RAS）表达的影响。方法：行肾脏活组织检查且2个月内未曾服用血管紧张素转换酶抑制剂的CKD患者,其中2周内ARB治疗的患者17例（ARB治疗组）,另选取2周内未应用ARB治疗的患者17例（空白对照组）,根据年龄、性别、血压、估算肾小球滤过率（eGFR）、24h尿蛋白、尿钠等进行配对。采用放射免疫法和酶联免疫吸附分析（ELISA）方法测定血、尿RAS组分的浓度,并采用免疫组织化学方法评价肾脏肾素、血管紧张素原（AGT）、血管紧张素Ⅱ（AngⅡ）和血管紧张素Ⅱ受体的表达。分析ARB对血、尿和肾组织RAS表达的影响。结果：ARB治疗组与空白对照组在性别、年龄、eGFR、24h尿蛋白、尿钠和血压等方面均显著差异。ARB治疗组血浆AngⅡ高于空白对照组[（63.09±15.14）pg/mL比（53.66±8.33）pg/mL,P〈0.05],肾内肾素免疫组织化学染色面积高于空白对照组[（48.65±19.58）%比（30.29±24.98）%,P〈0.05]。ARB治疗组肾内AGT、AngⅡ和血管紧张素Ⅱ1型受体免疫组织化学染色面积略低于空白对照组,但差异无统计学意义。结论：ARB治疗对循环和肾脏局部RAS表达的影响不同,可使循环AngⅡ升高,并可能抑制肾脏局部AngⅡ的表达。     

The benefits of angiotensin II receptor blockers in patients with renal insufficiency or failure

Hypertension occurs frequently in patients with renal disease and contributes to the development of end-stage renal disease. Because the renin angiotensin system (RAS) influences hypertension and renal disease, angiotensin-converting enzyme (ACE) inhibitors have been used successfully to treat and reduce renal consequences of hypertension. This review assesses how angiotensin II (A-II) influences renal disease and explores the effectiveness of losartan, a selective A-II receptor blocker, in patients with renal disease. Clinical trials have demonstrated that losartan is a safe and effective treatment for hypertension in renally impaired patients and produces renal hemodynamic effects akin to those seen with ACE inhibitors. However, losartan demonstrates a greater uricosuric effect than ACE inhibitors and does not produce cough, a significant side effect frequently associated with ACE inhibitors. Further studies will determine whether combination therapy with an ACE inhibitor and A-II receptor blocker will provide additional RAS blockade and synergistic benefits in patients with renal disease.     

Combination therapy with aliskiren and amlodipine in hypertension: treatment rationale and clinical results

Optimal antihypertensive therapy requires a multimodal approach based on lifestyle modification and, for most individuals, combination drug therapy. Recommendations from experts suggest that a combination of an agent that blocks the renin-angiotensin system (RAS), together with a vasodilator (generally a calcium-channel blocker or a thiazide-type diuretic), is most likely to control blood pressure and provide the widest overall cardiovascular protection. Understanding the opportunities afforded by the combination of RAS blockade with a calcium-channel blocker requires a discussion of basic and clinical science data. One new concept is that of 'global' or total RAS blockade. The impact of the RAS can be diminished or blocked by several different classes of drugs (central sympatholytics, β-blockers, renin inhibitors, ACE inhibitors or ARBs); what is most important is how effectively the overall impact of angiotensin II is blunted. A second new concept is that the complementary actions of RAS blockers and calcium-channel blockers are best explained on the basis of diminished intracellular calcium availability in excitable tissue (sympathetic neurons and vascular smooth muscle cells) via parallel actions that reduce angiotensin II type-1 receptor stimulation and L-channel-mediated calcium flux. Aliskiren is the first of the direct renin inhibitors, the newest subclass of RAS blockers. In both short- and long-term studies, aliskiren has been shown to be similar in efficacy and tolerability compared with other RAS blockers, with the added benefit that its effects persist longer. Outcome studies with aliskiren are currently underway.     

ACEI/ARB therapy for IgA nephropathy: a meta analysis of randomised controlled trials

Background: Published reports examining the efficacy of RAS blockers: angiotensin converting‐enzyme inhibitor (ACEI) and angiotensin II receptor blocker (ARB) agents for preserving renal function in IgA nephropathy (IgAN) have yielded conflicting results. To evaluate systematically the effects of ACEI/ARB agents on IgAN, we conducted a meta analysis of published randomised controlled trials (RCTs). Methods: MEDLINE, EMBASE, the Cochrane Library and article reference lists were searched for RCTs that compared ACEI/ARB with placebo and any other antihypertensive agents or non‐immunosuppressive agents for treating IgAN. The quality of the studies was evaluated with the method of intention to treat analysis and allocation concealment, as well as with the Jadad method. Meta analyses were performed on the outcomes of proteinuria and renal function in patients with IgAN. Results: Eleven RCTs involving 585 patients were included in the review. Seven trials used placebo/no treatment as controls. Four trials used other antihypertensive agents as controls. Overall, ACEI/ARB agents had statistically significant effects on protecting renal function(p < 0.00001) and reduction of proteinuria (p < 0.00001) when compared with control group. Tests for heterogeneity showed no difference in effect among the studies. Systolic and diastolic blood pressure, glomerular filtration rate (GFR), age, did not influence treatment response. ACEI/ARB agents were well tolerated. Conclusions: The current cumulative evidence suggests that ACEI/ARB agents had statistically significant effects on protecting renal function and reduction of proteinuria in patients with IgAN when compared with control groups. ACEI/ ARB agents are a promising medication and should be investigated further.     

Clinical role of direct renin inhibition in hypertension

Treatment strategies to improve blood pressure control, reduce end-organ damage, and improve cardiovascular outcomes are more important today than ever before. Most patients will require combination therapy to achieve target blood pressure; early initiation of combination therapy may help patients achieve blood pressure control more rapidly. Low-dose combinations may be more effective with fewer adverse effects than higher doses of single agents. Dysregulation of the renin-angiotensin-aldosterone system (RAAS) is an important contributor in the pathogenesis of hypertension and its sequelae. Treatment with a direct renin inhibitor blocks the rate-limiting step in the RAAS, resulting in decreased angiotensin I and II production and decreased urinary aldosterone excretion. Like the angiotensin converting enzyme inhibitors and angiotensin II receptor blockers, treatment with a direct renin inhibitor increases plasma renin concentration, but unlike the other RAAS inhibitors, treatment with a direct renin inhibitor decreases plasma renin activity. This unique combination of effects on the RAAS make a direct renin inhibitor an attractive option to combine with other antihypertensive agents for the management of hypertension and its comorbidities. Clinical studies have shown that combining the direct renin inhibitor, aliskiren, with drugs representing each of the major classes of antihypertensive agents (thiazide diuretics, beta blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, and calcium-channel blockers) reduces blood pressure, improves markers for cardiovascular outcomes, or does both. Results of several ongoing randomized clinical trials should provide additional insights into the potential of therapeutic combinations that include aliskiren to improve cardiovascular morbidity and mortality in patients with hypertension and related comorbidities.     

Current strategies to achieve further cardiac and renal protection through enhanced renin-angiotensin-aldosterone system inhibition

An incomplete inhibition of the renin angiotensin aldosterone system (RAAS) may be responsible for the residual organ damage and event rate that still occur in spite of an apparent blood pressure control in patients with hypertension, diabetes, chronic kidney disease and heart failure treated with angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Additional antiproteinuric effect in diabetic and non diabetic chronic kidney disease, and reduction in hospitalizations in patients with heart failure already receiving a single RAAS antagonist, has been achieved by incremental inhibition of the RAAS with dual therapy or uptitration of an individual agent above conventional dosages. However, the synergistic increase in plasma renin activity (PRA) and the angiotensin II escape could reduce the expected benefit obtained with dual therapy. Results from ONTARGET showing a lack of additional outcome benefit over monotherapy, with a concomitant increase risk of hyperkalemia, renal impairment, and hypotension, discourage the use of the ACEI/ARB combination in patients at high risk of cardiovascular events. This occured despite a lower albumin excretion in dual versus single RAAS blockade, indicating that an incremental antiproteinuric effect is not automatically translated into clinical outcome benefits. The efficacy and safety of ACEI/ARB combination versus monotherapy in patients with overt proteinuria is currently evaluated by LIRICO and VA NEPHRON-D clinical trials. The long lasting direct renin inhibitor aliskiren, acting at the first and rate limiting step of the RAAS cascade, prevents the reactive increase in PRA when combined with ACEIs, ARBs or diuretics. The ASPIRE HIGHER programme, involving more than 35,000 patients with hypertension, heart failure, kidney disease and diabetes, is currently evaluating the efficacy and safety of aliskiren on top of standard therapy. The clinical benefit of adding mineralocorticoid receptor blockers (MRBs) in the control of resistant hypertension, proteinuric kidney diseases, and prevention of mortality in patients with heart failure on top of conventional treatment, evidences the pathogenic role of inadequately suppressed aldosterone as a cause of suboptimal response to conventional RAAS inhibition. The present review will focus on the pathophysiological ground, and the evidence provided by clinical trials assessing the efficacy and safety of recent strategies for the prevention of cardiovascular events and target organ damage progression via enhanced RAAS inhibition.     

Plasma renin and the antihypertensive effect of the orally active renin inhibitor aliskiren in clinical hypertension

BACKGROUND: Aliskiren is the first in a new class of orally effective renin inhibitors for the treatment of hypertension. METHODS: In 569 patients with mild-to-moderate hypertension, blood pressure (BP), plasma renin activity (PRA) and plasma renin concentration (PRC) were measured before and after 8 weeks of double-blind treatment with once-daily oral doses of aliskiren (150, 300 or 600 mg), irbesartan 150 mg or placebo. RESULTS: Aliskiren 150, 300 and 600 mg and irbesartan 150 mg significantly reduced mean cuff sitting systolic BP (SBP) from baseline (p < 0.001 vs. placebo). Aliskiren 150, 300 and 600 mg significantly reduced geometric mean PRA by 69%, 71% and 75% from baseline respectively (p < 0.05 vs. placebo). Irbesartan 150 mg significantly increased PRA by 109% (p < 0.05 vs. placebo). Aliskiren dose-dependently increased PRC from baseline by 157%, 246% and 497%, at 150, 300 and 600 mg respectively, compared with a 9% decrease with placebo (p < 0.05). PRC increased significantly more with aliskiren 300 and 600 mg compared with irbesartan 150 mg (105%; p < 0.05). Regression analysis showed no significant correlations between baseline PRA and changes in SBP in any of the treatment groups, but interestingly, the slopes of the regression lines between changes in SBP and log-transformed baseline PRA were +2.0 for placebo and -1.5, -1.8 and -2.3 for aliskiren 150, 300 and 600 mg respectively. The slope for irbesartan 150 mg (-1.4) was similar to that for aliskiren 150 mg. CONCLUSIONS: Aliskiren reduces SBP and PRA and increases PRC dose-dependently. In contrast, irbesartan reduces SBP but increases both PRC and PRA. As PRA is a measurement of angiotensin I-generating capacity, PRA can be used for measuring the ability of an antihypertensive agent to prevent the generation or action of Ang II, either directly (renin inhibitors, beta-blockers, central alpha(2)-agonists) or indirectly (AT(1)-receptor blockers, ACE inhibitors).     

Renininhibitor Aliskiren als Antihypertensivum

Blockade of the renin-angiotensin system in the pharmacological treatment of high blood pressure has proven worthwhile. ACE inhibitors and angiotensin receptor blockers as the agents of first choice effectively reduce blood pressure, prevent the progression or initiate the regression of end-organ damage, and decrease cardiovascular morbidity and mortality. The new strategy of direct renin inhibition appears to be a promising therapeutic approach in this context because it inhibits the first and rate-limiting step in the renin-angiotensin system. In the sense of optimal cardiovascular protection, “low renin activity” and “low angiotensin status” should be the goals in patients with arterial hypertension. For this reason, the concept of direct renin inhibition is very promising. Data gathered to date show aliskiren to be a potent antihypertensive agent with a low side effect profile. Its application in the management of hypertension appears to be indicated both in monotherapy and in combination therapy with other antihypertensive drugs. Whether it will be effective in the treatment of cardiovascular end-organ damage and in primary and secondary prevention of cardiovascular diseases remains to be seen.     

Tissue gene expression of renin-angiotensin system in human type 2 diabetic nephropathy

OBJECTIVE: Recent studies have proved that blockade of the renin-angiotensin system (RAS) retards the progression of diabetic nephropathy, whereas hyporeninemia is known as a typical state in diabetic subjects. The purpose of this study is to determine whether expression levels of RAS differ between nondiabetic and diabetic renal tissues with accurate quantitative method. RESEARCH DESIGN AND METHODS: Subjects were 66 nondiabetic and 8 diabetic patients with biopsy-proven renal diseases. The eight diabetic subjects suffered from type 2 diabetes with overt proteinuria. Renal histology revealed typical diffuse or nodular lesions with linear IgG deposit on immunofluorescent staining and thickened basement membrane on electronic microscopy. Total RNA from a small part of the renal cortical biopsy specimens was reverse-transcribed, and the resultant cDNA was amplified for new major components of RAS (i.e., renin, renin receptor, angiotensinogen, ACE, ACE2, angiotensin II type 1 receptor, and angiotensin II type 2 receptor) and measured. RESULTS: Among these components, a significant upregulation was observed in the ACE gene in diabetic renal tissue. CONCLUSIONS: The results suggest that renal tissue RAS might be activated in the respect that ACE gene expression is upregulated in spite of a tendency to low renin expression in type 2 diabetic nephropathy.     

Effect of Direct Renin Inhibition on Renal Hemodynamic Function, Arterial Stiffness, and Endothelial Function in Humans With Uncomplicated Type 1 Diabetes: A pilot study

OBJECTIVE

Blockade of the renin-angiotensin system (RAS) plays an important role in preventing end-organ injury associated with diabetes. The recent development of direct renin inhibitors (DRIs) provides a new approach to block the RAS, but the effects of DRIs on renal and systemic vascular function in uncomplicated type 1 diabetes have not been elucidated.

RESEARCH DESIGN AND METHODS

Renal hemodynamic function (inulin and paraaminohippurate clearance), augmentation index and pulse wave velocity, endothelial dependent vasodilatation (flow-mediated dilation [FMD]), and endothelial independent vasodilatation (response to sublingual nitroglycerin) were evaluated before and after administration of aliskiren (300 mg daily for 30 days) in 10 adult subjects with uncomplicated type 1 diabetes during clamped euglycemia (4–6 mmol/l) and hyperglycemia (9–11 mmol/l).

RESULTS

In response to the DRI, plasma renin activity decreased (from 0.40 to 0.13 ng · ml⁻¹ · h⁻¹, P < 0.05) and plasma renin increased (from 5.2 to 75.0 ng/l, P < 0.05). Peripheral and central blood pressures decreased, and effective renal plasma flow and glomerular filtration rate increased during clamped euglycemia and hyperglycemia (P < 0.05). The carotid augmentation index during clamped euglycemia decreased (from 26 ± 6 to 20 ± 5%, P < 0.05) as did pulse wave velocity during clamped hyperglycemia (from 7.8 ± 0.6 to 6.8 ± 0.5 m/s, P < 0.05). In response to the DRI, FMD increased during both clamped euglycemia (from 1.92 ± 1.13 to 5.55 ± 0.81%) and hyperglycemia (from 1.86 ± 0.98 to 5.63 ± 0.62) as did the vasodilatory response to sublingual nitroglycerin.

CONCLUSIONS

DRIs exert a renal vasodilatory effect and improve parameters of systemic vascular function, suggesting that blockade of the RAS with this new class of agents has important functional effects in subjects with uncomplicated type 1 diabetes.Diabetes renal complications are, in part, mediated by activation of the renin-angiotensin system (RAS), which leads to maladaptive renal and systemic hemodynamic responses including renal hyperfiltration, increased arterial stiffness, and endothelial dysfunction (1–3). More recently, a new class of RAS inhibitors, called direct renin inhibitors (DRIs), has become available. DRIs block the generation of angiotensin I from angiotensinogen, thereby preventing the generation of angiotensin II (one of the main effectors of the RAS). DRIs also mitigate the cellular effects of prorenin and renin on the prorenin receptor, thereby accounting for the prominent hemodynamic effects of DRIs in animals and humans (4). From a functional perspective, the addition of a DRI to an angiotensin receptor blocker (ARB) or ACE inhibitor (ACEI) provides additional antihypertensive effects (4). In humans with type 2 diabetes and clinical evidence of diabetic nephropathy, DRIs such as aliskiren (Rasilez; Novartis Pharmaceuticals Canada) exert antiproteinuric effects that are additive to those of ARBs, suggesting that DRIs may specifically enhance blockade of the intrarenal RAS in humans (5). Use of a DRI is therefore an attractive strategy to block the RAS in conditions in which the RAS is activated, such as diabetes, and may provide incremental protective hemodynamic effects in humans when added to ACEI or ARB therapy (4).However, the renal and peripheral vascular hemodynamic effects of DRI monotherapy have not been studied in human subjects with uncomplicated type 1 diabetes. Accordingly, the objective of this pilot study was to examine the renal hemodynamic and peripheral vascular effects of a DRI using aliskiren in subjects with uncomplicated type 1 diabetes, when RAS activation may promote the cellular and hemodynamic changes that contribute to the development of diabetic nephropathy and vascular complications (6).     

Novel and effective gene transfer technique for study of vascular renin angiotensin system.

Vascular renin angiotensin system (RAS) has been reported to exist in vascular wall. However, there is no direct evidence whether the vascular RAS per se can modulate growth of vascular smooth muscle cells (VSMC), because there is no suitable method to investigate the effect of endogenously produced vasoactive substances on growth of these cells. In this study, we transferred angiotensin-converting enzyme (ACE) and/or renin cDNAs into cultured VSMC using the efficient Sendai virus (hemagglutinating virus of Japan) liposome-mediated gene transfer method, to examine their relative roles in VSMC growth in vitro. Within 35 min or 6 h, the transfection of ACE cDNA into VSMC by hemagglutinating virus of Japan method resulted in a twofold higher ACE activity than control vector, whereas a cationic liposome (Lipofectin)-mediated method failed to show any effect. This in vitro system provided us with the opportunity to investigate the influence of endogenous vascular RAS on VSMC growth. Transfection of ACE or renin cDNA resulted in increased DNA and RNA synthesis, which was inhibited with the specific angiotensin II receptor antagonist (DuP 753: 10(-6) M). Angiotensin I added to ACE-transfected VSMC increased RNA synthesis in a dose-dependent manner. Cotransfection of renin and ACE cDNAs stimulated further RNA synthesis as compared to ACE or renin cDNA alone. These results showed that transfected components of RAS can modulate VSMC growth through the endogenous production of vascular angiotensin II, and that ACE as well as renin are rate limiting in determining the VSMC RAS activity. We conclude that the hemagglutinating virus of Japan liposome-mediated gene transfer technique provides a new and useful tool for study of endogenous vascular modulators such as vascular RAS.