Inhibition of renin: an updated review of the development of renin inhibitors

As an important cascade involved in the regulation of blood pressure and volume homeostasis, the renin-angiotensin system (RAS) has been targeted for blood pressure control. In the last decades, the most successful strategy to control the RAS has been the inhibition of the angiotensin-converting enzyme (ACE) and the angiotensin type 1 (AT(1)) receptor. Small-molecule inhibitors targeting these steps have been widely used clinically. However, complete inhibition of the RAS is not achievable by blocking the ACE or the AT(1) because of the compensatory rise in plasma renin activity, which limits the efficacy of many RAS drugs. Direct inhibition of renin, the first and rate-limiting step in the RAS cascade, is the preferred strategy for controlling the RAS, and much progress has been made in the research and development of renin inhibitors. This review covers the evolution of renin inhibitors and discusses the advantages of renin inhibition at the enzymatic and biosynthetic levels for blood pressure control.     

Renin inhibition with aliskiren

1. Initial attempts to inhibit renin in humans have faced numerous difficulties. Molecular modelling and X-ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors, such as aliskiren. 2. Aliskiren has a low bioavailability (between 2.6 and 5.0%) compensated by its high potency to inhibit renin (IC50: 0.6 nmol/L) and a long plasma half-life (23-36 h), which makes it suitable for once-daily dosing. 3. The once-daily administration of aliskiren to hypertensive patients lowers BP as strongly as standard doses of established angiotensin II type 1 (AT1) receptor blockers (losartan, valsartan, irbesartan), hydrochlorothiazide, angiotensin converting enzyme inhibitors (ramipril and lisinopril) or long acting calcium channel blockers (amlodipine). In combination therapy, aliskiren further decreases blood pressure when combined with either hydrochlorothiazide, amlodipine, irbesartan or ramipril. 4. The biochemical consequences of renin inhibition differ from those of angiotensin I-converting enzyme (ACE) inhibition and Ang II antagonism, particularly in terms of angiotensin profiles and interactions with the bradykinin-nitric oxide-cyclic guanosine monophosphate pathway and possibly the (pro)renin receptor. 5. Blockade of the renin angiotensin system (RAS) with ACE inhibitors, AT1 receptor blockers or a combination of these drugs has become one of the most successful therapeutic approaches in medicine. However, it remains unclear how to optimize RAS blockade to maximize cardiovascular and renal benefits. In this context, renin inhibition to render the RAS fully quiescent is a new possibility requiring further study.     

Can the renin-angiotensin system protect against stroke? A focus on angiotensin II receptor blockers

From a patient's perspective, stroke is the most devastating form of cardiovascular disease, representing the number one cause of permanent disability in the United States. Treatment of hypertension significantly reduces the risk of stroke; however, it is unclear whether all antihypertensive agents are equivalent in this regard. Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce the risk of cardiovascular events, including stroke. Although attenuation of the renin-angiotensin system (RAS) is often credited with the blood pressure-independent effects of this class of agents, this hypothesis has not been confirmed with regard to the end point of stroke. In fact, drugs that activate the RAS, such as diuretics and dihydropyridine calcium channel blockers, are as effective or superior to ACE inhibitors for stroke prevention. Angiotensin II receptor blockers (ARBs) selectively block the angiotensin II subtype I receptor, which results in a reflexive increase in levels of angiotensin II and unopposed activation of angiotensin II subtype 2 receptors. Clinical trials comparing ARBs with active controls have reported significant reductions in stroke in ARB-treated patients. Data on ARBs and other drugs that activate the RAS (diuretics and dihydropyridine calcium channel blockers) support a potential role for the RAS in protecting against stroke. Ongoing trials with ARBs are evaluating stroke as a primary end point, and results should help to further elucidate the role of ARBs in this disease. Until then, it is prudent to treat hypertension with an agent or combination of agents that are likely to result in a rapid and sustained reduction in blood pressure, taking into consideration patient characteristics, comorbidities, tolerability, and cost.     

Can dual blockade of the renin-angiotensin system reduce progression of kidney disease beyond monotherapy?

It is well-accepted that therapies directed at the renin-angiotensin system (RAS) reduce the progression of chronic kidney disease. Angiotensin-converting enzyme (ACE) inhibitors and the angiotensin receptor blockers (ARBs) are currently available to interrupt this cascade. Their positive actions result from better blood pressure control, a reduction in glomerular capillary pressure and a decrease in proteinuria. Blockade of the RAS may also reduce renal scarring by blunting direct pro-fibrotic effects of angiotensin II and aldosterone. Although these drugs successfully reduce urinary protein excretion and improve renal survival, a significant number of patients continue to progress to end stage renal disease. It is possible, however, that dual blockade of the RAS with an ACE inhibitor and an ARB might offer further benefit beyond using either agent alone. Optimally, the goal should be to completely halt the progression of kidney disease. With these concepts in mind, this paper will review the RAS and its effects on the kidney. The efficacy and safety of dual RAS blockade in proteinuric renal diseases will be examined. Finally, recommendations for utilising combined therapy with ACE inhibitors and ARBs will be provided.     

The fight against COVID-19: Striking a balance in the renin–angiotensin system

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells by interacting with membrane-bound angiotensin-converting enzyme 2 (ACE2), a vital element in the renin–angiotensin system (RAS), which regulates blood pressure, fluid balance, and cardiovascular functions. We herein evaluate existing evidence for the molecular alterations within the RAS pathway (e.g., ACE2 and angiotensin II) during SARS-CoV-2 infection and subsequent Coronavirus Disease 2019 (COVID-19). This includes reports regarding potential effect of RAS blockade (e.g., ACE inhibitors and angiotensin II receptor blockers) on ACE2 expression and clinical outcomes in patients with co-morbidities commonly treated with these agents. The collective evidence suggests a dual role for ACE2 in COVID-19, depending on the stage of infection and the coexisting diseases in individual patients. This information is further discussed with respect to potential therapeutic strategies targeting RAS for COVID-19 treatment.     

Angiotensin antagonism in coronary artery disease: results after coronary revascularisation

The renin-angiotensin system (RAS) is an ancient and complex cascade of homeostatic reactions aimed at regulating primordial functions that ensure organ perfusion through the control of blood pressure and the regulation of renal-cardiac activity. However, the over-expression or lack of compensatory mechanisms of any of its components may initiate detrimental effects that potentially lead to disease, a balance that makes the RAS a sequence with a labile physiological equilibrium and with a strong harm potential. These characteristics of the RAS in general, and of the angiotensin converting enzyme (ACE) in particular, make it not only an important complex for the regulation of blood pressure and neuropeptide metabolism, but also a fascinating subject of study from a biochemical, evolutionary and genetic point of view.Pharmacological interventions that influence the RAS by inhibiting the ACE or the angiotensin II type 1 receptor (AT1R) have demonstrated sustained efficacy in reducing the incidence of cardiovascular events and, consequently, vascular mortality in several clinical situations.ACE inhibitors and angiotensin II receptor antagonists (ARAs) reduce blood pressure and have cardio- and vasculoprotective effects. Anti-atherosclerotic effects have also been attributed to these drugs. For these reasons, it has been hypothesised that RAS inhibitors could also reduce the recurrence of ischaemic events after myocardial revascularisation procedures, namely coronary artery by-pass graft surgery (CABG) or percutaneous coronary interventions (PCI).Information available on the effect of ACE inhibitors and ARAs in patients with coronary artery disease (CAD) previously treated with revascularisation techniques indicates a substantial reduction of mortality and infarction in these patients. However, data regarding the progression of CAD, restenosis or reocclusion of vascular conduits of the coronary circulation after myocardial revascularisation are inconsistent.In most studies, the administration of ACE inhibitors neither improved the ischaemic threshold nor reduced the need for new revascularisation procedures. On the contrary, ACE inhibitors have been associated with higher restenosis rates after PCI in some retrospective series. Conversely, a single, exploratory randomised trial demonstrated that the selective AT1R antagonist valsartan significantly reduced stent restenosis after PCI. In patients undergoing CABG, ACE inhibitors did not reduce the risk of graft degeneration or occlusion. Studies that evaluated a possible anti-atherosclerotic effect of ACE inhibitors (including some large randomised trials) have generally been negative.     

Role of the RAS in pancreatic cancer

Angiotensin II (Ang II), a main effector peptide of the renin-angiotensin system (RAS), mediates a hormonal action in the maintenance of blood pressure and electrolyte levels, and thus fluid homeostasis. Ang II also mediates paracrine, autocrine and/or intracrine actions in the control of various specific functions of diverse tissue organs. In the pancreas, Ang II exerts a growth promoting, angiogenic influence via the mediation of angiotensin II type 1 receptor (AT1R). Recent studies have implicated inappropriate activation of the local RAS in pancreatic cancer, including upregulation of AT1R and the angiotensin-converting enzyme (ACE), which consequently enhance Ang II-induced tumour activity. In addition to acting in a classical antihypertensive capacity, RAS blockers (AT1R blockers or ACE inhibitors) may yield protective effects against pancreatic cancer, a highly aggressive malignancy that is intrinsically resistant to radiotherapy and chemotherapy. Substantial experimental data from studies using cell and animal models of pancreatic cancer support the notion that RAS regulates tumour growth, angiogenesis, and metastasis; and a convergence of such findings suggests that pharmacological RAS blockade could have therapeutic potential in the management of pancreatic cancer. This review critically appraises the current research progress on the role of RAS in pancreatic cancer, and discusses the potential for developing drugs that target RAS for treatment of pancreatic cancer.     

Stroke prevention with losartan in the context of other antihypertensive drugs

Several large clinical trials have demonstrated that successful control of blood pressure decreases the incidence of strokes. Also, drugs that stimulate the production of angiotensin II, such as diuretics, calcium channel blockers (CCBs) and angiotensin receptor blockers (ARBs), provide additional stroke reduction than drugs that suppress angiotensin II production such as beta-blockers and angiotensin converting enzyme (ACE) inhibitors. Since the stroke-protective effect of angiotensin II is mediated through stimulation of the AT2 receptors, drugs that selectively block the AT1, such as the ARBs, provide greater stroke protection than the other antihypertensive drugs. The blockade of the AT1 receptors lessens local brain ischemia, whereas the stimulation of the AT2 receptors increases local blood flow through recruitment of collateral vessels. Among the ARBs, losartan possesses certain unique properties not shared by other members of its class, which enhance its stroke-protective effects. These include the prevention of platelet adhesiveness and aggregation and the decrease of serum uric acid levels, which both lead to reduction in cardiovascular and cerebrovascular events. (     

Engagement of renin-angiotensin system in prostate cancer

Angiotensin II (Ang-II) plays a role not only as a vasoconstrictor in controlling blood pressure and electrolyte and fluid homeostasis, but also as a mitogenic factor through the Ang-II type-1 (AT1) receptor in cardiovascular cells. Since a low prevalence of cancer in hypertensive patients receiving angiotensin converting enzyme inhibitors has been reported, the molecular mechanisms of the renin-angiotensin system (RAS) in cancer cells have been elucidated. Interestingly, there is increasing evidence that the RAS is implicated in the development of prostate cancer. As previously reported, AT1 receptor blockers (ARBs), a class of antihypertensive agent, have the potential to inhibit the growth of prostate cancer cells and tumors through the AT1 receptor. This review highlights that the RAS plays a potential role in various aspects of prostate cancer, and ARBs could be useful for treatment of prostate cancer or its chemoprevention.     

Renin-angiotensin system blockade at the level of the angiotensin converting enzyme or the angiotensin type-1 receptor: similarities and differences

The development of drugs which block the renin-angiotensin system (RAS) has been proven a major advance in cardiovascular medicine. Angiotensin converting enzyme (ACE) inhibitors, which block the formation of angiotensin II from the inactive angiotensin I, are widely used as first line treatment in hypertension, heart failure and diabetic nephropathy. More recently, selective antagonists of the angiotensin type-1 receptor (AT1R) have become available for clinical use. Accumulating evidence suggests that AT1R antagonists have similar effects to ACE inhibitors in hypertension, heart failure and diabetic nephropathy. Although ACE inhibitors and AT1R antagonists block the same system, experimental evidence suggest that their mechanisms of action differ in several respects, such as increased bradykinin and angiotensin 1-7 levels with ACE inhibitors and AT2R activation with AT1R antagonists. Nevertheless, the clinical significance of these differences remains largely unknown and, in practice, the only clear advantage of AT1R antagonists over ACE inhibitors is the absence of cough as a side effect. Recent clinical data suggest that combined ACE inhibition and AT1R antagonism offer additive effects in reducing blood pressure in hypertension, in reducing proteinuria in nephropathy and in improving prognosis in heart failure. Further evidence suggests that some hypertensive patients may have a good antihypertensive response with ACE inhibition but not with AT1R antagonism, or the reverse. These data suggest that these two drug classes have important similarities, because they act on the same system, but they also appear to have important differences, which are not only of theoretical but also of clinical importance.     

End-organ protection in patients with hypertension: focus on the role of angiotensin receptor blockers on renal function

The renin-angiotensin system (RAS) plays a key role in a number of pathophysiological mechanisms that are involved in the development and progression of cardiovascular and renal disease. For these reasons, pharmacological antagonism of this system, particularly the blockade of formation or the receptor antagonism of angiotensin II, has been demonstrated to be an effective and safe strategy to reduce the burden of cardiovascular disease. Among different drug classes, angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) have provided an excellent alternative to ACE inhibitors, representing a more selective and a better tolerated pharmacological approach to interfere with the RAS. Results derived from large, international, randomized clinical trials have consistently indicated that ARB-based therapeutic strategies may effectively provide cardiovascular and renal disease prevention and protection in different clinical conditions across the entire cardiovascular continuum. This article reviews the pathophysiological rationale of RAS involvement in the pathogenesis of renal diseases, focusing on the beneficial effects provided by ARBs in terms of renal protection.     

Aliskiren/amlodipine combination for the treatment of hypertension

The challenge of managing hypertension is exemplified by the limited success of monotherapy and necessity for multiple drug regimens targeting complimentary pathways. Recent evidence suggests that combination therapy including angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers (CCBs) provides blood pressure control while reducing cardiovascular mortality and morbidity over ACE inhibitor/diuretic therapy. However, CCBs, ACE inhibitors and angiotensin receptor blockers all increase plasma renin activity (PRA), promoting angiotensin I accumulation and angiotensin II production through alternative pathways. While the clinical ramifications of this and other compensatory pathways activating the renin-angiotensin-aldosterone system are unclear, the recently approved aliskiren/amlodipine antihypertensive combination pill has been shown to decrease PRA via aliskiren's direct inhibition of renin. The purpose of this monograph is to review the mechanisms of action, pharmacodynamics, and safety and efficacy profile of the aliskiren/amlodipine combination pill.     

Urinary albumin excretion and the renin–angiotensin system in cardiovascular risk management

Microalbuminuria has been shown to be a strong predictor of cardiovascular morbidity and mortality in diabetic and hypertensive patients, but also in the general population. Moreover, several reports suggest that reduction of urinary albumin excretion (UAE) is associated with improvement of cardiovascular prognosis. Reduction of UAE can be achieved by lowering arterial blood pressure, but blockers of the renin–angiotensin system (RAS) with their specific renal actions have demonstrated to be able to reduce UAE more than might be expected from reduction of blood pressure alone. Consequently, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may also provide superior cardiovascular protection, especially in subjects with higher levels of albuminuria, but evidence is still scarce. The ability of both angiotensin-converting enzyme inhibitors and angiotensin receptor blockers to reduce UAE and provide cardiovascular protection suggests that the RAS may play a central role. New developments in this area include the use of aldosterone antagonists in albuminuric/proteinuric subjects, and the development of oral renin inhibitors. Combinations of the aforementioned drugs may have the ability to fully block the RAS, potentially avoiding all detrimental effects of this hormonal cascade. However, combination therapy is expected to also increase the incidence of side effects, such as hyperkalaemia and acute renal insufficiency. The current knowledge of microalbuminuria represents the proverbial tip of the iceberg, and future studies should focus on the underlying pathophysiological mechanism of urinary albumin excretion in relation to cardiovascular protection. Only then can a better understanding of the problem be achieved and the optimal pharmacological approach be ascertained.     

Eprosartan for the treatment of hypertension

Antihypertensive agents are proven to reduce the cardiovascular risk of stroke, coronary heart disease and cardiac failure. The ideal antihypertensive agent should control all grades of hypertension and have a placebo-like side effect profile. Angiotensin II (AII) receptor antagonists are a relatively new class of antihypertensive agent that block AII Type 1 (AT(1)) receptors, and reduce the pressor effects of AII in the vasculature. By this mechanism, they induce similar pharmacological effects compared with angiotensin-converting enzyme (ACE) inhibitors, resulting in a lowering of blood pressure. However, AII receptor blockers differ from ACE inhibitors with respect to side effects, and induce less cough, a side effect which may be related to bradykinin or other mediators such as substance P. Within the class of AII blockers, eprosartan differs from other currently available agents in terms of chemical structure, as it is a non-biphenyl, non-tetrazole, non-peptide antagonist with a dual pharmacological mode of action. Eprosartan acts at vascular AT(1) receptors (postsynaptically) and at presynaptic AT(1) receptors, where it inhibits sympathetically stimulated noradrenaline release. Its lack of metabolism by cytochrome P450 enzymes confers a low potential for metabolic drug interactions and may be of importance when treating elderly patients and those on multiple drugs. In clinical trials, eprosartan has been demonstrated to be at least as effective in reducing blood pressure as the ACE inhibitor enalapril, and has significantly lower side effects. Eprosartan is safe, effective and well-tolerated in long-term treatment, either as a monotherapy or in combination with other antihypertensive drugs such as hydrochlorothiazide.     

Substituted benzimidazole derivatives as angiotensin II-AT1 receptor antagonist: a review

The renin angiotensin system (RAS) plays an important role in regulation of blood pressure and fluid-electrolyte homeostasis. The renin-angiotensin system consists of a cascade of enzymatic reactions producing angiotensin II (Ang II). Ang II is a vasoconstrictive peptide hormone that exerts a wide variety of physiological actions on cardiovascular, renal, endocrine and central nervous systems. The RAS can be inhibited at various points to control pathogenesis of hypertension. Renin inhibitors and angiotensin-converting enzyme (ACE) inhibitors were the earliest RAS blocking agents. A relatively new class of compounds known as Ang II receptor antagonists (SARTANs) is developed for the treatment of hypertension. They exert their action by blocking the binding of Ang II on AT(1) receptor. Angiotensin converting enzyme (ACE) inhibitors are associated with incident of side effects such as cough and angioedema while clinical trials with Ang II receptor antagonists have confirmed that these drugs are safe and efficacious for the treatment of hypertension. Based upon the understanding of molecular interaction of Ang II receptor antagonists with AT(1) receptor some of the common structural features have been identified, such as a heterocyclic (nitrogen atom) ring system, an alkyl side chain and an acidic tetrazole group. Research efforts for development of new molecules with similar structural features have led to the discovery of various non-peptidic Ang II receptor antagonists with different substituted heterocyclic such as imidazole (losartan) and benzimidazole (candesartan and telmisartan). In this study we have critically reviewed various benzimidazole substituted compounds as Ang II-AT(1) receptor antagonists and explored other potential clinical uses for this class of compounds.     

Urinary albumin excretion and the renin-angiotensin system in cardiovascular risk management

Microalbuminuria has been shown to be a strong predictor of cardiovascular morbidity and mortality in diabetic and hypertensive patients, but also in the general population. Moreover, several reports suggest that reduction of urinary albumin excretion (UAE) is associated with improvement of cardiovascular prognosis. Reduction of UAE can be achieved by lowering arterial blood pressure, but blockers of the renin-angiotensin system (RAS) with their specific renal actions have demonstrated to be able to reduce UAE more than might be expected from reduction of blood pressure alone. Consequently, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may also provide superior cardiovascular protection, especially in subjects with higher levels of albuminuria, but evidence is still scarce. The ability of both angiotensin-converting enzyme inhibitors and angiotensin receptor blockers to reduce UAE and provide cardiovascular protection suggests that the RAS may play a central role. New developments in this area include the use of aldosterone antagonists in albuminuric/proteinuric subjects, and the development of oral renin inhibitors. Combinations of the aforementioned drugs may have the ability to fully block the RAS, potentially avoiding all detrimental effects of this hormonal cascade. However, combination therapy is expected to also increase the incidence of side effects, such as hyperkalaemia and acute renal insufficiency. The current knowledge of microalbuminuria represents the proverbial tip of the iceberg, and future studies should focus on the underlying pathophysiological mechanism of urinary albumin excretion in relation to cardiovascular protection. Only then can a better understanding of the problem be achieved and the optimal pharmacological approach be ascertained.     

Endogenous angiotensin II levels and the mechanism of action of angiotensin-converting enzyme inhibitors and angiotensin receptor type 1 antagonists

1. Modification of endogenous angiotensin II (AngII)-mediated processes by inhibitors of the angiotensin-converting enzyme (ACE) and antagonists of the angiotensin type 1 (AT(1) ) receptor is dependent upon both the levels of each agent in the plasma and tissues and on the concomitant changes in plasma and tissue AngII levels. 2. Both ACE inhibitors and AT(1) receptor antagonists increase renin secretion and angiotensin peptide formation in plasma and extrarenal tissues. Clinical doses of ACE inhibitors produce incomplete inhibition of ACE and the increased AngI levels act to restore AngII towards basal levels. Clinical doses of AT(1) receptor antagonists produce incomplete blockade of AT(1) receptors and the increased AngII levels in plasma and extrarenal tissues counteract (to an unknown degree) the effects of the antagonist. 3. The effects of ACE inhibitors and AT(1) receptor antagonists on AngII levels show tissue specificity. Angiotensin II-mediated processes in the kidney are most sensitive to inhibition by these agents. ACE inhibitors reduce renal AngII levels at doses much less than those required to reduce AngII levels in plasma and other tissues. Moreover, in contrast to increased AngII levels in plasma and extrarenal tissues, renal AngII levels do not increase in response to AT(1) receptor antagonists. The inhibition of AngII-mediated processes in the kidney may, therefore, play a primary role in mediating the effects of ACE inhibitors and AT(1) receptor antagonists on blood pressure and other aspects of cardiovascular function and structure. 4. Combination of an ACE inhibitor with an AT(1) receptor antagonist prevents the rise in plasma AngII levels that occurs with AT(1) receptor antagonism alone. This combination would, therefore, be predicted to produce more effective inhibition of endogenous AngII-mediated processes than either agent alone. We must await further studies to determine whether the combination of ACE inhibition and AT(1) receptor antagonism results in superior clinical outcomes.     

Perindopril versus angiotensin II receptor blockade in hypertension and coronary artery disease: implications of clinical trials

The renin-angiotensin-aldosterone system (RAAS) is now known to play a key role in the pathogenesis of hypertension and a range of other cardiovascular diseases. Two groups of drugs, the ACE inhibitors and angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) have been developed with the aim of improving clinical outcomes by regulating the RAAS in patients with cardiovascular disease. Initial assumptions were that these two drug types might be interchangeable, but ongoing research has revealed differences between them in terms of pharmacology and outcomes in clinical trials. Although both groups of drugs lower blood pressure, studies of the ACE inhibitor perindopril have revealed preservation of beneficial vascular and endothelial effects mediated by bradykinin and nitric oxide. The selective blockade exerted by ARBs is not associated with these effects. Furthermore, examination of clinical endpoints in major clinical trials has provoked discussion about outcomes comparing ACE inhibitors and ARBs, with recent debate focusing on the incidence of myocardial infarction (MI) in patients receiving these agents. Whether there is an actual difference in protection from MI remains unresolved, although available data confirm the benefit and safety of ACE inhibitors, in particular perindopril, for myocardial protection.