How to Explain the Differences Between Renin Angiotensin System Modulators

Fucoidan improves bioactivity and vasculogenic potential of mesenchymal stem cells in murine hind limb ischemia associated with chronic kidney disease

Finerenone—A New Frontier in Renin-Angiotensin-Aldosterone System Inhibition in Diabetic Kidney Disease

The renin-angiotensin system (RAS) has long been regarded as a classical hormonal system, with angiotensin II (ANG II) being the circulating effector peptide. In recent years, evidence for additional RAS in various organs, including vascular wall, kidney, adrenal gland, heart, and brain, has been obtained. Drugs interfering with the RAS such as the converting enzyme (CE) inhibitors may, therefore, not only inhibit the plasma RAS but also inhibit these tissue RAS. Such a "tissue" RAS inhibition has been repeatedly demonstrated in animal experiments, and in some cases it correlated better with the cardiovascular actions of the CE inhibitors than did inhibition of plasma RAS. In the vascular wall, a local inhibition of ANG II synthesis may contribute not only to the reduction of vascular tone but also to the marked regression of media hypertrophy seen after CE inhibitor treatment. Vascular ANG II generation by CE appears to occur almost exclusively at the luminal surface of the endothelium. Locally formed ANG II may then contribute to the pool of circulating ANG II (endocrine ANG II) or feed back to adjacent cells without being transported by the blood (paracrine ANG II). Thus, CE inhibitors may not have to penetrate into deeper layers of the vascular wall to inhibit the vascular RAS, but may rather prevent the paracrine actions of locally generated ANG II.

The beneficial effects of blood pressure-lowering treatments on the risks of major cardiovascular events are well established [1]. Interruption of the renin–angiotensin system (RAS) with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) has been shown to be an effective strategy for lowering blood pressure. Randomized trials have shown that ACEi can lower blood pressure by an average of 5/2 mmHg and reduce the risks of cardiovascular events and cardiovascular mortality by ∼20% (and total mortality by 10%) [2–6]. ARBs produce similar reductions in blood pressure and vascular events (although fewer patients have received them in randomized trials) [7–9]. Further, RAS blockade has been reliably shown to reduce the risk of kidney disease progression [10–15]. A meta-analysis of ACEi and ARB monotherapy in diabetic nephropathy demonstrated reductions in end-stage renal disease (ESRD) of around one-quarter for both treatments [16]. Similarly, an individual patient data meta-analysis of ACEi in non-diabetic kidney disease showed a relative risk reduction of 31% (95% CI 5–49%). The major trials of ACEi or ARB monotherapy in various patient populations are summarized in Table 1. As shown in Table 1, among patients at a low risk of renal progression ESRD occurs rarely, and only after many years or even decades. This probably explains the lack of renal benefit reported in large general population trials and meta-analyses of such trials [17–19]. Furthermore, there is some evidence that even the relative benefit might depend on baseline risk, making it even less likely that any true benefit could be detected in existing trials [10]. Whether the observed benefits of RAS blockade are only mediatedbytheirbloodpressure-loweringeffectorwhether other effects also play a role remains controversial; there is some evidence that interruption of the RAS provides more benefit than would simply be expected by the degree of blood pressure reduction alone [5,7,20]. It has been suggested that incomplete blockade of the RAS with ACEi or ARB monotherapy can cause a phenomenon called ‘aldosterone escape’, in which the lack of negative feedback from end-products of the RAS causes a reactive increase in renin and consequent increases in angiotensin I and II concentrations which overwhelm the pharmacological blockade [21]. Dual blockade would therefore be attractive as ACEi and ARB inhibit the RAS at different steps. However, there is continuing uncertainty about the balance of benefits and harms of dual RAS blockade, both in terms of cardiovascular risk and progression of kidney disease. This question will be discussed here in the context of recent evidence from randomized controlled trials.

The coexistence of hypercholesterolaemia and diabetes dramatically and synergistically increases the risk of microvascular and macrovascular complications in patients. A single unifying mechanism of increased production of reactive oxygen species (ROS) by angiotensin II (Ang II) may serve as a causal link between hyperglycaemia and hypercholesterolaemia and many of the major pathways responsible for atherogenic and diabetic disorders. Several lines of evidence suggest a crucial role for Ang II-mediated oxidative stress in the pathogenesis of hyperglycaemia- and hypercholesterolemia-associated endothelial dysfunction. Endothelial dysfunction in these scenarios may be due to impaired nitric oxide (NO) synthesis and/or inactivation of endothelium-derived NO by ROS. That Ang II plays an important role in the development of atherosclerosis and glomerulosclerosis is supported by numerous studies indicating that angiotensin receptor blockers (ARBs) retard the progression of these diseases in both experimental animal models and humans. Evidence indicates that Ang II contributes to atherogenesis at both transcriptional and translational levels by upregulating adhesion molecule mRNA and protein synthesis. The recent demonstration of Ang II AT(2) receptors in the adult kidney and their potential to oppose the vasoconstrictive, antinatriuretic, and profibrotic properties of AT(1) receptors suggests that the balance of intrarenal AT(1) and AT(2) receptors may be important in determining the cellular responses to Ang II in diabetic nephropathy. Results of these studies suggest that hypercholesterolaemia and hyperglycaemia can induce a pro-inflammatory response within coronary arteries and the kidney glomerulus. This response involves production of well described macrophage chemotactic and adhesion molecules, which results in macrophage recruitment and the development of acute and chronic injury. Glomerular macrophage recruitment in experimental diabetes occurs via Ang II-stimulated monocyte chemoattractant protein (MCP)-1 expression, suggesting that the renin-angiotensin system is an important regulator of local MCP-1 expression, and strongly implicating macrophage recruitment and activation in the pathogenesis of early diabetic glomerular injury. Diabetes-associated vascular complications may also involve an activation of the nuclear factor (NF)-kappaB by hyperglycaemia. NF-kappaB activation is related to AT(1) receptor-mediated pathways, and is believed to be dependent on activation of the Rho proteins belonging to the superfamily of low molecular weight guanosine triphosphatases (GTPases) that regulate intracellular signalling. Preincubation of vascular smooth muscle cells with insulin doubled NF-kappaB transactivation stimulated by Ang II and hyperglycaemia, suggesting a potential mechanism for crosstalk between the renin-angiotensin system and hyperglycaemia. Taken together, these data suggest that activation of the renin-angiotensin system is a mechanism for the initiation and progression of inflammatory cell infiltration found in early changes common to both hypercholesterolaemia and hyperglycaemia. While the base of information regarding ARBs in high-risk patients with diabetes and hypercholesterolemia is lacking, preclinical and pilot trial data suggest that the ARBs are reno- and vasculoprotective in these patients. Therapeutic blockade of Ang II AT(1) receptors in diabetic and hypercholesterolaemic humans by ARBs, with concomitant elevation in plasma and tissue Ang II levels, may provide vascular and renal protection not only by reducing AT(1) receptor-mediated pro-oxidative effects, but also by unopposed AT(2) receptor stimulation.

The potent converting enzyme inhibitor (CEI) SQ14,225, which is known to prevent the formation of angiotensin II (AII) has been used to evaluate the role of AII in the development and reversal of cardiac hypertrophy. The present study describes the effect of CEI on blood pressure (BP) and myocardial hypertrophy (prevention and reversal) in the spontaneously hypertensive rat (SHR). A group of 3-week- and 8-week-old male SHR was treated with CEI (30 mg/kg in drinking water) for 6 weeks. An additional group of SHR was also treated with a combination of CEI and a diuretic (hydrochlorothiazide, 500 mg/liter). Heart weight, BP, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), hydroxyproline, myocardial catecholamines, and plasma renin activity (PRA) were determined. In the prevention study, we found a significant reduction in the ratio of heart weight to body weight along with the prevention of hypertension (200 vs 145 mm Hg, p less than 0.001). Similar reductions in BP and heart weights were obtained with the reversal group. A better BP control was noted in the CEI and hydrochlorothiazide group. The reduction of heart weight was associated with a reduction in RNA and hydroxyproline content. In all groups, we found a significant increase in PRA (p less than 0.001) and a slight increase in tissue catecholamine concentration. No change in kidney weight was found in any group. Data clearly showed that oral administration of CEI prevented and reversed cardiac hypertrophy in SHR. Reversal was associated with a decrease in myocardial collagen content. These data indicate that prevention of AII formation in combination with BP control can prevent and reverse cardiac hypertrophy in SHR. Of course, whether or not CEI acts only through the renin angiotension system is still speculative.

Gangrene, revascularization, and limb function improved with E-selectin/adeno-associated virus gene therapy

Fetopathy associated with exposure to angiotensin converting enzyme inhibitors and angiotensin receptor antagonists

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.

Angiotensin-converting enzyme (ACE) inhibitors are potent members of the arsenal to treat chronic kidney disease (CKD). By reducing blood pressure (BP) and disproportionately decreasing intraglomerular pressure, this class of drugs also reduces proteinuria and slows progression of CKD (1,2). Given the high prevalence of cardiovascular disease in this population, it is noteworthy that ACE inhibitors also decrease the incidence of stroke, myocardial infarction (MI), and cardiovascular mortality in patients who are at high cardiovascular risk (3). More recently, data reporting similar benefits of angiotensin receptor blockers (ARB) support their use in the treatment of CKD as well, especially in individuals with type 2 diabetes (4). Furthermore, one sizable study suggested that the combination of an ACE inhibitor and ARB may be more effective than either agent alone (5). Parving and colleagues (6) called attention to the effects of high-dose ARB therapy, up to three times the recommended dose, as an additional means of effectively interrupting the renin-angiotensin-aldosterone system (RAAS). By logical extension, further blockade of the RAAS by direct antagonism of aldosterone also may prove beneficial. Indeed, aldosterone seems to be a potent effector of renal injury (7–9). In the rare cases of primary aldosteronism and its functional analogue, the even more rare Liddle’s syndrome, the observed renal injury probably is independent of the more proximal elements of the RAAS (10,11). Animal models provide an expeditious tool for assessing pathophysiologic change and the efficacy of intervention. The classic model of primary aldosteronism, the mineralocorticoid–nephrectomy–high-salt model of hypertension, develops systemic and glomerular capillary hypertension and sustains renal damage (12). In the remnant kidney model of CKD, ACE inhibitors and ARB attenuate renal injury (13). However, this protection, which is associated with suppression of aldosterone secretion, is abrogated by exogenous aldosterone infusion with return of …

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the coronavirus disease 2019 (COVID-19) pandemic, uses the surface angiotensin-converting enzyme 2 (ACE2) receptor as the site of entry into host cardiac, respiratory, intestinal, renal, and nervous system cells. Predisposing risk factors such as cardiovascular disease increase the risk of developing severe disease. Hypertension is characterized by the stimulation of the renin-angiotensin-aldosterone system (RAAS). Angiotensin-converting enzyme inhibitors (ACEis) and angiotensin 2 receptor blockers (ARBs), medications used to treat hypertension, inhibit RAAS and its downstream effects; however, they have also been shown to upregulate ACE2 receptors. In this review, we aim to evaluate the effectiveness of ACEi/ARBs as an adjunct therapy in patients with SARS-CoV-2 as well as examine the possible protective effects and impact on infection rate and disease severity. A PubMed literature search excluding sources outside the United States and duplicates was performed using the following search criteria: "COVID-19 AND cardiovascular disease AND ACEi AND ARB", "SARS-COVID-19 OR COVID-19, AND ACEi AND ARB AND Infection rate", "COVID-19 AND ACEi and ARB", "Omicron BA.1 and BA.2 AND ACE2 OR ARBs", "Omicron AND ACEi AND ARBs". This resulted in 33 final sources. The review concluded that ACEi/ARB therapy may continue to improve COVID-19 survival as previous treatment is associated with positive clinical outcomes. Patients taking ACEis or ARBs were found to have a decreased risk of hospitalization, reduced severity of COVID-19 pneumonia, a lesser need for mechanical ventilation, and an overall reduction in mortality rate. No statistically significant association between ACEi/ARB use and enhanced COVID-19 infectivity was found. The Omicron variant is theoretically more infectious and was associated with increased negative clinical outcomes in those undertreated with ACEis/ARBs. The majority of the literature supports the current guidelines from the American College of Cardiology (ACC), American Heart Association (AHA), European Society of Cardiology (ESC), and Heart Failure Society of America (HFSA), which state that ACEi and ARB medications should not be withdrawn from or initiated on patients with cardiovascular disease who are infected with SARS-CoV-2. More research needs to be conducted on the association between the emerging COVID-19 variants and ACEis/ARBs to give clinicians confidence when treating patients within this subgroup of the population.

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.

The pathophysiological roles of the angiotensin II type 2 receptor (AT(2)) in cardiac hypertrophy remain unclear. By the targeted deletion of mouse AT(2) we were able to prevent the left ventricular hypertrophy resulting from pressure overload, while cardiac contractile functions remained normal. This implies that AT(2) is a mediator of cardiac hypertrophy in response to increased blood pressure. The effects of AT(2) deletion were independent of activation of embryonic genes for cardiac hypertrophy. However, p70(S6k), one of the key factors in cardiac hypertrophy, was markedly and specifically reduced in the ventricles of Agtr2(-)/Y mice. We propose that p70(S6k) plays a major role in AT(2)-mediated ventricular hypertrophy. This article may have been published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org.

Angiotensin receptor blockers (ARBs) were developed to providean alternative approach to interrupting the renin–angiotensin system(RAS), which was pharmacologically distinct from that ofangiotensin converting enzyme (ACE) inhibitors. By selectivelyblocking the angiotensin II type 1 (AT1) receptor, ARBs werethought to offer the potential for more complete blockade of theRAS. Evidence had accumulated that angiotensin II could be generatedthrough enzymes other than ACE (e.g. chymase) and ARBsblock the action of angiotensin II, regardless of its source, at thereceptor level. Another fundamental difference betweenthe two approaches is the lack of effect of ARBs on bradykininwhich is metabolized by ACE (also known as kininase II).Accumulation of bradykinin with ACE inhibitors is responsible forcough and angioedema. Consequently, it was hoped that ARBswould be better tolerated than ACE inhibitors. Bradykinin, however, may also have beneficial effects, including vasodilatation,antithrombotic activity, and inhibition of pathological tissueremodelling. This latter perspective, that bradykinin might have beneficial actions, underpinned the hypothesis that the combinationof an ACE inhibitor and ARB might be better than an ACEinhibitor alone in heart failure (HF). In other words, the ARBwould maximize RAS inhibition and the ACE inhibitor wouldaugment bradykinin.

Angiotensin receptor blockers (ARBs) but not angiotensin converting enzyme inhibitors (ACE-Is) are associated with lower osteoclast activity and higher bone mineral density: Results from the TUDA study.