Effects of angiotensin-converting enzyme inhibitors on tissue renin-angiotensin systems.

The renin-angiotensin system (RAS) plays a major role in the control of blood pressure and cardiovascular homeostasis and is involved in the pathogenesis of a number of cardiovascular disorders. The efficacy of angiotensin-converting enzyme (ACE) inhibitors in the treatment of hypertension and congestive heart failure has led to the widespread clinical use of ACE inhibitors in primary or secondary prevention of heart disease. The demonstration of the expression of the components of the RAS in several extrarenal tissues, as well as local generation of angiotensin II, has confirmed the existence of a tissue RAS that may serve organ-specific functions and act independently from the plasma RAS. The concept of paracrine/autocrine functions of the local RAS has changed our understanding of the functions of the RAS and suggests that tissue ACE inhibition may be of greater importance than inhibition of circulating ACE in the treatment of congestive heart failure and other cardiovascular disorders. Whereas the circulating endocrine RAS appears to be responsible for mediation of acute effects, the tissue RAS seems to be involved in more chronic situations, such as secondary structural changes of the cardiovascular system, and therefore could contribute to the pathogenesis of hypertension as well as other cardiovascular disorders, such as cardiac hypertrophy, coronary artery disease, and atherosclerosis. Several experimental and clinical findings suggest that reversal of cardiovascular structural changes secondary to cardiovascular disease and enhancement of renal sodium excretion by ACE inhibitors are important long-term antihypertensive actions possibly mediated by inhibition of the tissue RAS.     

Effects of Chronic Administration of Angiotensin Converting Enzyme (ACE) Inhibitors on Blood Pressure and Tissue ACE Activity in the SHR

Although ACE inhibitors have proven clinically effective as antihypertensive agents, the mechanisms by which they lower blood pressure are not clearly understood. While inhibition of circulating enzyme has been thought to be of primary importance, reductions in circulating angiotensin II levels do not appear to mediate the antihypertensive effects of ACE inhibitors in hypertensive animals or man (1,2). As previously demonstrated, inhibition of tissue components of the renin-angiotensin system may be an important factor involved in blood pressure reduction (1,3). In this regard, we have shown in a comparative study of several ACE inhibitors that while inhibition of circulating ACE activity is not well correlated with antihypertensive effects in SHR, changes in aorta and/or brain may be necessary for the acute effects of these compounds (4). In the present study, we have compared the chronic effects of enalapril and two new ACE inhibitors, CGS 14824A and CGS 16617, on blood pressure, tissue ACE activity, and components of the renin-angiotensin system in conscious SHR. CGS 14824A, like enalapril, is an ester pro-drug, while CGS 16617 is a diacid which does not require hydrolysis for in vivo activity.     

Liver disease and the renin-angiotensin system: recent discoveries and clinical implications

The renin–angiotensin system (RAS) is a key regulator of vascular resistance, sodium and water homeostasis and the response to tissue injury. Historically, angiotensin II (Ang II) was thought to be the primary effector peptide of this system. Ang II is produced predominantly by the effect of angiotensin converting enzyme (ACE) on angiotensin I (Ang I). Ang II acts mainly through the angiotensin II type-1 receptor (AT₁) and, together with ACE, these components represent the 'classical' axis of the RAS. Drug therapies targeting the RAS by inhibiting Ang II formation (ACE inhibitors) or binding to its receptor (angiotensin receptor blockers) are now in widespread clinical use and have been shown to reduce tissue injury and fibrosis in cardiac and renal disease independently of their effects on blood pressure. In 2000, two groups using different methodologies identified a homolog of ACE, called ACE2, which cleaves Ang II to form the biologically active heptapeptide, Ang-(1–7). Conceptually, ACE2, Ang-(1–7), and its putative receptor, the mas receptor represent an 'alternative' axis of the RAS capable of opposing the often deleterious actions of Ang II. Interestingly, ACE inhibitors and angiotensin receptor blockers increase Ang-(1–7) production and it has been proposed that some of the beneficial effects of these drugs are mediated through upregulation of Ang-(1–7) rather than inhibition of Ang II production or receptor binding. The present review focuses on the novel components and pathways of the RAS with particular reference to their potential contribution towards the pathophysiology of liver disease.     

Treating patients for cardiovascular protection: combination therapy to achieve complete renin-angiotensin system blockade

Inhibition of the renin-angiotensin system (RAS) with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) is a proven antihypertensive strategy. Understanding of the pathophysiologic effects of chronic RAS activation and clinical data indicate that RAS inhibition may exert beneficial effects in addition to blood pressure reduction. Studies indicate that monotherapy with ACE inhibitors and ARBs slows progression of diabetic and non-diabetic renal disease. Vascular protective effects of RAS inhibition have also been demonstrated in patients at high risk for cardiovascular events in the absence of significant blood pressure elevation or left ventricular dysfunction. Combining the complementary effects of ACE inhibitors and ARBs to achieve more complete RAS blockade is a promising approach to further reducing cardiovascular risk. This review will present the rationale for dual RAS inhibition, clinical data relating to its efficacy, and ongoing studies designed to evaluate its utility in patients at high risk for cardiovascular events.     

Renin-angiotensin system revisited

New components and functions of the renin-angiotensin system (RAS) are still being unravelled. The classical RAS as it looked in the middle 1970s consisted of circulating renin, acting on angiotensinogen to produce angiotensin I, which in turn was converted into angiotensin II (Ang II) by angiotensin-converting enzyme (ACE). Ang II, still considered the main effector of RAS was believed to act only as a circulating hormone via angiotensin receptors, AT1 and AT2. Since then, an expanded view of RAS has gradually emerged. Local tissue RAS systems have been identified in most organs. Recently, evidence for an intracellular RAS has been reported. The new expanded view of RAS therefore covers both endocrine, paracrine and intracrine functions. Other peptides of RAS have been shown to have biological actions; angiotensin 2-8 heptapeptide (Ang III) has actions similar to those of Ang II. Further, the angiotensin 3-8 hexapeptide (Ang IV) exerts its actions via insulin-regulated amino peptidase receptors. Finally, angiotensin 1-7 (Ang 1-7) acts via mas receptors. The discovery of another ACE2 was an important complement to this picture. The recent discovery of renin receptors has made our view of RAS unexpectedly complex and multilayered. The importance of RAS in cardiovascular disease has been demonstrated by the clinical benefits of ACE inhibitors and AT1 receptor blockers. Great expectations are now generated by the introduction of renin inhibitors. Indeed, RAS regulates much more and diverse physiological functions than previously believed.     

Angiotensin receptor blockers: evidence for preserving target organs

Hypertension is a major problem throughout the developed world. Although current antihypertensive treatment regimens reduce morbidity and mortality, patients are often noncompliant, and medications may not completely normalize blood pressure. As a result, current therapy frequently does not prevent or reverse the cardiovascular remodeling that often occurs when blood pressure is chronically elevated. Blockade of the renin-angiotensin system (RAS) is effective in controlling hypertension and treating congestive heart failure. Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) inhibit the activity of the RAS, but these two classes of antihypertensive medications have different mechanisms of action and different pharmacologic profiles. Angiotensin-converting enzyme inhibitors block a single pathway in the production of angiotensin II (Ang II). In addition, angiotensin I is not the only substrate for ACE. The ACE inhibitors also block the degradation of bradykinin that may have potential benefits in cardiovascular disease. Bradykinin is, however, the presumed cause of cough associated with ACE inhibitor therapy. Data from clinical trials on ACE inhibitors serve to support the involvement of the RAS in the development of cardiovascular disease. Angiotensin receptor blockers act distally in the RAS to block the Ang II type 1 (AT1) receptor selectively. Thus, ARBs are more specific agents and avoid many side effects. Experimental and clinical trials have documented the efficacy of ARBs in preserving target-organ function and reversing cardiovascular remodeling. In some instances, maximal benefit may be obtained with Ang II blockade using both ARBs and ACE inhibitors. This review describes clinical trials that document the efficacy of ARBs in protecting the myocardium, blood vessels, and renal vasculature.     

Spectrum of use for the angiotensin-receptor blocking drugs

The renin-angiotensin system (RAS) plays an important role in regulating blood pressure, and maintaining fluid and electrolyte balance. Angiotensin II is the principal mediator of the RAS and has been implicated in the development of hypertension as well as other forms of cardiovascular and renal disease. Angiotensin II-receptor antagonists are a new class of drugs that inhibit the RAS by selectively blocking the AT₁ receptor. These compounds therefore provide more specific and thorough blockade of the RAS by inhibiting the deleterious actions of angiotensin II at the receptor level, irrespective of how this peptide is formed. The increased specificity of action of angiotensin II-receptor antagonists may also circumvent unwanted side-effects normally associated with angiotensin-converting enzyme (ACE) inhibitors (eg, cough and angioedema) as these agents do not interfere with the metabolism of other peptides (eg, bradykinin, substance P, etc.). There is still some concern with angiotensin II-receptor antagonists and the long-term effects of hyper-stimulation of the unopposed AT₂ receptor that is caused by elevated levels of angiotensin II. However, it appears that stimulation of the AT₂ receptor may actually contribute to the beneficial effects of angiotensin II-receptor antagonists by counteracting the effects mediated by the AT₁ receptor. Angiotensin II-receptor antagonists display great therapeutic promise in the field of cardiovascular medicine and are currently being exploited as new antihypertensive agents. These drugs have demonstrated safety, efficacy, and tolerability; however, morbidity and mortality data are still lacking. Nonetheless, it is likely that angiotensin II-receptor antagonists will become part of the medical arsenal against cardiovascular and renal disease, thus consideration should be given to their future use as first-line antihypertensive agents.     

Renin inhibition: A new modality for hypertension management

Renin is the first and rate-limiting step cleaving angiotensinogen to angiotensin I, thus influencing angiotensin II (Ang II) formation. Inhibition of the renin-angiotensin system (RAS) with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) is effective in management of several cardiovascular diseases; however, control continues to be difficult and requires multiple drug therapy. Use of RAS inhibitors does not totally prevent Ang II formation, which could continue to contribute to development of end-organ damage. Over the past two decades, renin inhibition seemed to be an attractive approach for complete blockade of the RAS. Recently, aliskiren, a renin inhibitor, was approved as the first of a new class of antihypertension drugs. Clinical trials demonstrated significant blood pressure reduction in hypertensive patients with aliskiren used alone or combined with hydrochlorothiazide, ACE inhibitors, or ARBs. Studies are in progress to evaluate the potential role for renin inhibition in management of kidney and cardiac diseases.     

Why blockade of the renin-angiotensin system reduces the incidence of new-onset diabetes

Recent trials have suggested that inhibitors of the renin-angiotensin system (RAS), such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), may reduce the incidence of new-onset diabetes in patients with or without hypertension and at high risk of developing diabetes. In this review, we critically evaluate the evidence from recent clinical trials for such a potential preventive effect of ACE inhibitors and ARBs, including a meta-analysis of these recent trials. The reduced incidence of diabetes in patients at high risk of developing diabetes by ACE inhibitors or ARBs has been explained by haemodynamic effects, such as improved delivery of insulin and glucose to the peripheral skeletal muscle, and non-haemodynamic effects, including direct effects on glucose transport and insulin signalling pathways, all of which decrease insulin resistance. There is now evidence that the pancreas may contain an in situ active RAS, which appears to be upregulated in an animal model of type 2 diabetes. Thus, ACE inhibitors and ARBs may act by attenuating the deleterious effect of angiotensin II on vasoconstriction, fibrosis, inflammation, apoptosis and beta-cell death in the pancreas, thereby protecting a critical beta-cell mass essential for insulin production. New evidence is presented that ACE inhibitors and ARBs may delay or prevent the development of insulin resistance and diabetes, for which novel mechanisms are suggested. The actions of agents that interrupt the RAS on insulin resistance, obesity and diabetes warrant further investigation in other animal models. Prospective clinical studies with the primary endpoint of the prevention of diabetes are now indicated to (i) further explore whether the inhibitors of the RAS are superior compared to other antihypertensive agents such as calcium channel blockers (CCBs) and (ii) to evaluate the potential beneficial effects of combination antihypertensive regimens on the development of diabetes.     

Comparative properties of angiotensin-converting enzyme inhibitors: relations with inhibition of tissue angiotensin-converting enzyme and potential clinical implications.

This review summarizes the evidence indicating that local synthesis of angiotensin II, and interference with this process by inhibition of angiotensin-converting enzyme (ACE), may be important in the treatment of hypertension. Inhibition of tissue converting enzyme generally has a stronger correlation with the hemodynamic effects of ACE inhibitors than inhibition of ACE in plasma. Reported differences in the ability of ACE inhibitors to penetrate tissues and to bind to the converting enzyme may be closely related to the relative lipophilicity of these agents. Finally, correlation of data from clinical studies with results provided by laboratory experimentation suggests that the efficacy of different ACE inhibitors in hypertensive patients may be predicted from differences among the actions of these drugs in vitro and in whole animals.     

Physiologic evidence of renoprotection by antihypertensive therapy

PURPOSE OF REVIEW: Hypertension is vastly prevalent worldwide and constitutes the second leading cause of end-stage renal disease. Therefore, treating hypertension and protecting the kidney from deterioration are exceedingly important. Although previous studies have explored the renal effects of various antihypertensive drugs in animal models and humans, recent clinical trials are all the more convincing. This review summarizes the latest data demonstrating the physiologic evidence of renoprotection by antihypertensive therapy. RECENT FINDINGS: Experimental studies in various models of hypertension with renal injury have demonstrated clearly that angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor blockers, or aldosterone antagonists promote beneficial renal actions, through hemodynamic and nonhemodynamic mechanisms. Of particular significance, recent clinical trials have demonstrated renoprotection by angiotensin II inhibition in patients with hypertension and chronic kidney disease. Angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade have provided equivalent renal benefits, and their dual action seems to confer greater renoprotection. The available data on the renal outcomes of other antihypertensive drugs such as calcium antagonists have been inconsistent. SUMMARY: The results of the numerous experimental and clinical studies have established the renoprotective properties of renin-angiotensin-aldosterone inhibitors, which confer greater benefit by virtue of their effects over and beyond blood pressure reduction. These findings provide the convincing basis for the recommendation of angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor blockers, or both as first-line therapy in hypertension with chronic kidney disease.     

Converting enzyme inhibition: search for additional mechanisms of action

Although the therapeutic usefulness of angiotensin converting enzyme (ACE) inhibitors in patients with hypertension and congestive heart failure has been clearly demonstrated, important unanswered questions remain about these drugs, including patient selection criteria, side effects, long-term effects, and especially their precise mechanism of action. The principal explanation of the effect of ACE inhibitors remains the inhibition of the renin-angiotensin system (RAS). However, in chronic treatment with ACE-inhibitory drugs, this relationship may not held true. Additional mechanisms of action postulated to explain the effect of ACE-inhibitors include inhibition of angiotensin II formation in the central RAS, neutralization of renin activity in the vascular wall, blockade of vasoconstrictor response to sympathetic nerve stimulation, and possible involvement of prostaglandins linked, for instance, to bradykinin accumulation. The search for additional mechanisms of action should lead to clinically important findings, provide a better understanding of the pathophysiology of cardiovascular disease, and improve patient treatment with ACE inhibitory drugs.     

Upregulation of hepatic angiotensin-converting enzyme 2 (ACE2) and angiotensin-(1-7) levels in experimental biliary fibrosis

BACKGROUND/AIMS: Angiotensin-converting enzyme 2 (ACE2), its product, angiotensin-(1-7) and its receptor, Mas, may moderate the adverse effects of angiotensin II in liver disease. We examined the expression of these novel components of the renin angiotensin system (RAS) and the production and vasoactive effects of angiotensin-(1-7) in the bile duct ligated (BDL) rat. METHODS: BDL or sham-operated rats were sacrificed at 1, 2, 3 and 4 weeks. Tissue and blood were collected for gene expression, enzyme activity and peptide measurements. In situ perfused livers were used to assess angiotensin peptide production and their effects on portal resistance. RESULTS: Hepatic ACE2 gene and activity (P<0.0005), plasma angiotensin-(1-7) (P<0.0005) and Mas receptor expression (P<0.01) were increased following BDL compared to shams. Perfusion experiments confirmed that BDL livers produced increased angiotensin-(1-7) (P<0.05) from angiotensin II and this was augmented (P<0.01) by ACE inhibition. Whilst angiotensin II increased vasoconstriction in cirrhotic livers, angiotensin-(1-7) had no effect on portal resistance. CONCLUSIONS: RAS activation in chronic liver injury is associated with upregulation of ACE2, Mas and hepatic conversion of angiotensin II to angiotensin-(1-7) leading to increased circulating angiotensin-(1-7). These results support the presence of an ACE2-angiotensin-(1-7)-Mas axis in liver injury which may counteract the effects of angiotensin II.     

Tissue angiotensin converting enzyme inhibition. Relevant to clinical practice?

Accumulating data indicate that tissue and systemic renin-angiotensin systems may coexist. Evidence supporting the existence of local regulatory systems derives from several sources. Firstly, it has been clearly demonstrated that all components of the renin-angiotensin system are detectable in the tissues of organs such as the brain, heart, lung, kidney, testis, and blood vessels. Secondly, many diverse actions of angiotensin II have been defined in different tissues, all of which have a common mechanism: maintaining or increasing vascular tone, blood volume, or both. Evidence supporting the concept that the local and systemic renin-angiotensin systems are functionally independent includes the discrepancy in the time courses of hemodynamic changes and enzyme inhibition following administration of angiotensin-converting enzyme (ACE) inhibitors; and the observation that ACE inhibitor treatment results in decreases in blood pressure in anephric subjects, who have extremely low circulating concentrations of angiotensin II. These and other data suggest that inhibition of tissue ACE may be as, or more, important than its effects on the more easily measured circulating ACE. This raises the question of whether there are differences among ACE inhibitors in their selectivity for one or more organ systems. Some experimental data indicate that the binding affinity and time course of ACE inhibition can vary from one tissue to another, and among individual agents.(ABSTRACT TRUNCATED AT 250 WORDS)     

Angiotensin-converting enzyme in cardiovascular and adrenal tissues and implications for successful blood pressure management.

Components of the renin-angiotensin system, and the ability to synthesize these components locally, have been demonstrated in cardiovascular tissues. Locally generated angiotensin II may affect vascular tone, regional blood flow, cardiac contractility, and vascular and cardiac growth. Local renin-angiotensin systems may exert autocrine and paracrine functions, whereas the circulating system serves an endocrine function. Use of angiotensin-converting enzyme (ACE) inhibitors has provided further clarification of the activities of local renin-angiotensin systems. Tissue and systemic effects of these agents may prove equally important in determining their clinical efficacy. Experiments with quinapril demonstrated that inhibition of vascular ACE was a significant component of the antihypertensive effect of the drug. Differences at the tissue level may have implications for the efficacy and tolerability of a particular agent. Improved individualization of therapy may be accomplished by the use of newer ACE inhibitors with very favorable side effects profiles and tissue specificity. The newest agent, quinapril, appears to exert an important effect on vascular converting enzyme.     

Plasma angiotensin II and the antihypertensive action of angiotensin-converting enzyme inhibition

The measurement of immunoreactive "angiotensin II" in plasma cannot provide an accurate reflection of the efficacy of angiotensin-converting enzyme (ACE) inhibition because different angiotensin fragments interfere in all radioimmunoassays available so far. More complex methods are necessary in order to measure specifically angiotensin-(1-8)octapeptide. With such methodology it can be shown that no tolerance develops to the angiotensin II-reducing effect of ACE inhibitors after prolonged administration. Marked reduction of angiotensin II levels can be shown even in patients with primary aldosteronism. At peak blockade, the level of plasma angiotensin II is still related to circulating active renin and angiotensin I. Accordingly, because ACE inhibitors raise circulating angiotensin I in a dose-dependent fashion, this should be taken into account when dosing ACE inhibitors. The hypothesis that tissue renin-angiotensin systems play an important independent role in determining vasomotor tone is very interesting. However, any discussion on whether tissue or plasma renin determines the pharmacological effect of ACE inhibitors should be based on the simultaneous measurement of true angiotensin II in tissue and plasma under steady-state conditions.     

Renin inhibitors: discovery and development. An overview and perspective

Pharmacological suppression of the renin angiotensin system (RAS) by inhibiting angiotensin-converting enzyme (ACE), both as monotherapy and in conjunction with other conventional agents, has been proven to be an effective therapeutic approach to the treatment of hypertension and congestive heart failure. Renin is the enzyme that catalyzes the first and rate limiting step, preceding the involvement of ACE, in the production of the potent pressor hormone angiotensin II (Ang II). Unlike ACE, which has multiple substrates, renin is selective for a single naturally occurring substrate, angiotensinogen. Interruption of the generation of ANG II by renin inhibitors at the highly specific, initial step of the cascade may have therapeutic advantages over ACE inhibitors and other antihypertensive agents with less precise mechanisms of action, by producing fewer clinical side effects. Exciting advances in the discovery of renin inhibitors have led to the synthesis of potent, dipeptide inhibitors of renin, which have been shown in the laboratory to be efficacious hypotensive agents when administered intravenously. Although there are recently reported compounds that demonstrate some degree of oral activity, efforts to enhance bioavailability are presently underway in order to develop orally active therapeutic agents. The development of renin inhibitors will provide target-specific agents for the treatment of various cardiovascular disorders, and will serve as invaluable tools to study the role of the RAS in regulating blood pressure and fluid volume. An overview of the progress in the discovery and development of renin inhibitors is presented.     

The use of knockout mouse technology to achieve tissue selective expression of angiotensin converting enzyme

The resin angiotensin system (RAS) plays an essential role in blood pressure regulation and electrolyte homeostasis. The effecter peptide of the RAS, angiotensin II, is produced by angiotensin converting enzyme (ACE) in multiple tissues. Genetic deletion of ACE in mice resulted a phenotype of low blood pressure, anemia and kidney defects. However, it is not clear whether the lack of the systemic or the local production of angiotensin II caused these defects. To understand the role of local angiotensin II production, we developed a method to achieve tissue specific ACE expression through homologous recombination. In this review, we discuss mouse models in which endothelial ACE was eliminated and replaced by hepatic ACE. These studies suggest that both circulating angiotensin II and local angiotensin II production play a role in angiotensin II generation; the elimination of local angiotensin II generation up-regulates systemic production and maintains physiologic homeostasis.     

Why not prescribe the best drugs for hypertension now?

As Westernised societies have become more affluent, the attitudes of the population have become more risk-aware. People are now intolerant of small risks as well as the physical or mental discomforts from drug side effects. Safety and tolerability are now major forces driving the development of new medicines for the treatment of chronic illnesses and the prevention of increasingly rare events. For example, over the past decades, lower and lower treatment thresholds have been recommended in hypertension. Public perception of risk strongly influences the acceptability of lifetime treatment, especially for mild hypertension. This era has also witnessed great advances in the development of antihypertensive drugs that combine efficacy with unsurpassed tolerability. However, the philosophy of Scottish teachers of Materia medica still appears to be followed-'never be the first or the last to prescribe a new drug'. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists are as safe and as efficacious as other antihypertensive medications and better tolerated. Large trials (HOT, HOPE, UKPDS and PROGRESS) point to the need for rigorous control of blood pressure particularly in high-risk individuals. Antihypertensive drugs that act on the renin-angiotensin system will probably impact significantly on achieving optimal blood pressure levels. Should it not now be accepted that high-risk patients should have ACE inhibitors and angiotensin II receptor antagonists prescribed as first-line agents? We review the evidence for the use of ACE inhibitors and angiotensin II receptor antagonists as antihypertensive agents.