Comparison of angiotensin II type 1 receptor antagonists in the treatment of essential hypertension

Hypertension is a major health problem worldwide, yet remains under-diagnosed and under-treated. Angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) are highly effective at reducing blood pressure (BP), exhibit renoprotective properties and have placebo-like tolerability. However, it is unclear whether there are clinical differences in efficacy and tolerability between the available ARBs. A review of published, randomized, comparative clinical trials suggests that differences in BP-lowering efficacy and 24-hour BP control may exist between ARBs, although it appears that there is no evidence for important differences in tolerability between ARBs. Few studies have assessed attainment rates for important combined systolic BP (SBP)/diastolic BP (DBP) goals recommended in treatment guidelines. Likewise, few studies have directly compared more than two agents or ARB/hydrochlorothiazide fixed-dose combinations, and most ARBs have not been compared across their full recommended dosage ranges. Overall, there is insufficient weight of evidence to allow definitive conclusions to be drawn regarding the comparative efficacy of the available ARBs. However, newer ARBs (e.g. olmesartan medoxomil and telmisartan) appear to be more effective than older ARBs (e.g. losartan and valsartan) in reducing DBP and/or SBP in some trials. In addition, olmesartan medoxomil treatment regimens resulted in high BP control rates in several trials, but head-to-head trials with other ARBs are required to put these control rates into perspective, especially for SBP control with various agents. The purpose of this review is to present published data from ARB efficacy trials for a comparison of various efficacy parameters among the agents within this drug class.     

Nonpeptide angiotensin II receptor antagonists

Substantial progress has been made recently in the development of nonpeptide angiotensin II receptor antagonists, a goal that has long remained an unmet challenge. Pieter Timmermans and colleagues review the pharmacology and the course of events that led to the identification of the lead compound and clinical candidate DuP753. Nonpeptide angiotensin II receptor antagonists represent novel therapeutic agents and are the preferred probes for exploring the (patho)physiological role(s) of angiotensin II. In addition, these compounds have provided evidence for the existence of different binding sites/receptors for angiotensin II.     

Economic benefits of treating high-risk hypertension with angiotensin II receptor antagonists (blockers)

Hypertension is one of the leading risk factors for cardiovascular disease and represents a major health and economic burden. Most patients with high- or very high-risk hypertension have multiple cardiovascular risk factors with or without accompanying subclinical organ damage or established cardiovascular or renal disease. Patients with severe hypertension or with moderate hypertension and one to two additional risk factors have absolute 10-year risks of cardiovascular disease of 21-30% and 15-20%, respectively. Current European treatment guidelines recommend that antihypertensive therapy be initiated rapidly and aggressively in patients with high-risk hypertension. Most patients require two or more antihypertensive agents to achieve the strict blood pressure target of <130/80 mmHg. This article reviews the existing cost-effectiveness data on the use of angiotensin II receptor antagonists (blockers) [ARBs] in patients with high-risk hypertension. Aggressive ARB treatment of patients in the early (microalbuminuric) stages of diabetic nephropathy has a significant renoprotective effect, delaying the onset of overt (proteinuric) nephropathy. By slowing the progression of these patients to end-stage renal disease, substantial cost savings can be made. There is a paucity of cost-effectiveness data regarding the use of fixed-dose ARB plus thiazide diuretic combination therapies. Longitudinal cost-benefit studies of this attractive and efficacious first-line treatment option are needed.     

The role of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists in the management of diabetic complications

Evidence suggests that ACE inhibitors can be advantageous for prevention and halting progression of both micro- and macrovascular complications in patients with diabetes mellitus. ACE inhibitors are useful antihypertensive agents in both type 1 and type 2 diabetes; however, ACE inhibitor therapy often needs to be supplemented with calcium channel antagonists, beta-blockers or diuretics to achieve good blood pressure control. ACE inhibitors are also indicated in non-hypertensive patients with type 1 and type 2 diabetes who have micro- or macroalbuminuria. The effect of ACE inhibitors in halting the development and progression of retinopathy and, potentially, neuropathy needs further proof in large-scale studies. More recently, angiotensin II receptor antagonists are emerging as drugs with the potential to be successfully included in the management of diabetic complications, especially when ACE inhibitors are not suitable because of adverse effects.     

Experience with angiotensin II antagonists in hypertensive patients

1. The availability of orally active specific angiotensin receptor antagonists (AT(1) antagonists) has opened new therapeutic choices and provided probes to test the specific role of the renin-angiotensin system in the pathogenesis of cardiovascular disease. 2. The data available so far suggest that the antihypertensive efficacy of angiotensin receptor antagonists is comparable to that of angiotensin-converting enzyme (ACE) inhibitors. This provides further evidence that this latter class of drugs exerts its effect mainly through blockade of the renin-angiotensin enzymatic cascade. As expected, the association of a diuretic exerts an equally strong additive effect to the antihypertensive efficacy of both classes of drugs. 3. The most common side effect of ACE inhibitors, dry cough, does not occur with AT(1) antagonists, which confirms the long-held view that this untoward effect of the ACE inhibitors is due to renin-angiotensin-independent mechanisms. 4. Long-term studies with morbidity/mortality outcome results are needed, before a definite position can be assigned to this newcomer in the orchestra of modern antihypertensive drugs. Notwithstanding, this new class of agents already represents an exciting new addition to our therapeutic armamentarium.     

Telmisartan has the strongest binding affinity to angiotensin II type 1 receptor: comparison with other angiotensin II type 1 receptor blockers

There is a growing body of evidence that the renin-angiotensin system (RAS) plays a pivotal role in the pathogenesis of cardiovascular diseases. Indeed, large clinical trials have demonstrated a substantial benefit of the blockade of this system for cardiovascular-organ protection. Although several types of angiotensin II type 1 (AT1) receptor blockers (ARBs) are commercially available for the treatment of patients with hypertension, comparisons of the binding affinity to AT1 receptor among them remain to be elucidated. In this study, we examined the dissociation rate of several ARBs from AT1 receptor in vitro. Angiotensin II time-dependently dissociated telmisartan, olmesartan, candesartan, valsartan, losartan and an active metabolite of losartan, EXP3174, from membrane components containing human AT1 receptor The dissociation rate constant of each ARB was 0.003248, 0.004171, 0.005203, 0.009946, 0.01027 and 0.008561 min(-1), with corresponding half-lives of 213, 166, 133, 70, 67 and 81 min, respectively. These results demonstrate that telmisartan has the strongest binding affinity to AT1 receptor among various ARBs examined herein. The rank order of affinity was telmisartan > olmesartan > candesartan > EXP3174 > or = valsartan > or = losartan. The present findings suggest that telmisartan (Micardis) may have long-lasting blood pressure-lowering effects and superior cardioprotective properties in patients with hypertension due to its strongest AT1 receptor antagonistic ability.     

Therapeutic potential of angiotensin II receptor antagonists

The circulating renin-angiotensin system plays an important role in cardiovascular homeostasis. More importantly, the local tissue renin angiotensin plays a pivotal role in cell growth and remodelling of cardiomyocytes and on the peripheral arterial vasculature. In addition, the renin angiotensin system is related to apoptosis, control of baroreflex and autonomic responses, vascular remodelling and regulation of coagulation, inflammation and oxidation. The cardioprotective and vascular protective effects of the angiotensin receptive blockade appears to be related to selective blockade of the angiotensin II (A-II) Type I (AT₁) receptors. However, there is now growing evidence showing that some of the effects of AT-II receptor blockers (ARBs) are related to the activation of the kinin pathways. This paper will review some of the recent mechanisms related to the cardiovascular effects of angiotensin and more specifically of ARBs. This paper will present the novel data on the role of ARB in the development of atherosclerosis, vascular remodelling, coagulation balance and autonomic regulation. Finally, the role of ARBs, used alone or in combination with ACE inhibitor in patients with heart failure, will be discussed.     

Risk-benefit assessment of angiotensin II receptor antagonists

Inhibiting the renin-angiotensin-aldosterone system through the use of angiotensin-converting enzyme (ACE) inhibitors has proven very useful in the treatment of hypertension, congestive heart failure (CHF) and progressive renal failure. More recently, agents that directly block the angiotensin II Type 1 (AT(1)) receptor--angiotensin II receptor antagonists (AIIRAs)--have been developed. These agents are thought to have a more specific mechanism of action since they do not affect other hormone systems as do the ACE inhibitors. Whether such specificity results in a different efficacy profile is still being determined. However, these drugs are extremely well-tolerated and very safe. AIIRAs are effective in the reduction of both systolic and diastolic blood pressure and compare favourably to other classes of agents. Recent results indicate that at least one AIIRA has a favourable effect on stroke in hypertensive patients with left ventricular hypertrophy. Additional studies with other members of the class will provide further information on similar outcomes. In CHF patients, ACE inhibitors remain the drug of choice and AIIRAs are best utilised in patients who cannot tolerate an ACE inhibitor or in those receiving an ACE inhibitor who cannot tolerate a beta-blocker and need additional therapy. AIIRAs are effective in slowing the progression of renal failure in patients with Type II diabetes and may be effective in other proteinuric conditions. Whether they are more or less effective than ACE inhibitors is unknown. Overall, AIIRAs represent an important addition to the armamentarium of cardiovascular therapies with an excellent safety record and an emerging profile of utility in multiple cardiovascular conditions.     

Risk-benefit assessment of angiotensin II receptor antagonists

Inhibiting the renin-angiotensin-aldosterone system through the use of angiotensin-converting enzyme (ACE) inhibitors has proven very useful in the treatment of hypertension, congestive heart failure (CHF) and progressive renal failure. More recently, agents that directly block the angiotensin II Type 1 (AT₁) receptor – angiotensin II receptor antagonists (AIIRAs) – have been developed. These agents are thought to have a more specific mechanism of action since they do not affect other hormone systems as do the ACE inhibitors. Whether such specificity results in a different efficacy profile is still being determined. However, these drugs are extremely well-tolerated and very safe. AIIRAs are effective in the reduction of both systolic and diastolic blood pressure and compare favourably to other classes of agents. Recent results indicate that at least one AIIRA has a favourable effect on stroke in hypertensive patients with left ventricular hypertrophy. Additional studies with other members of the class will provide further information on similar outcomes. In CHF patients, ACE inhibitors remain the drug of choice and AIIRAs are best utilised in patients who cannot tolerate an ACE inhibitor or in those receiving an ACE inhibitor who cannot tolerate a β-blocker and need additional therapy. AIIRAs are effective in slowing the progression of renal failure in patients with Type II diabetes and may be effective in other proteinuric conditions. Whether they are more or less effective than ACE inhibitors is unknown. Overall, AIIRAs represent an important addition to the armamentarium of cardiovascular therapies with an excellent safety record and an emerging profile of utility in multiple cardiovascular conditions.     

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.     

ACE inhibitors and angiotensin II receptor antagonists

The biological actions of angiotensin II (ANG), the most prominent hormone of the renin-angiotensin-aldosterone system (RAAS), may promote the development of atherosclerosis in many ways. ANG aggravates hypertension, metabolic syndrome, and endothelial dysfunction, and thereby constitutes a major risk factor for cardiovascular disease. The formation of atherosclerotic lesions involves local uptake, synthesis and oxidation of lipids, inflammation, as well as cellular migration and proliferation--mechanisms that may all be enhanced by ANG via its AT1 receptor. ANG may also increase the risk of acute thrombosis by destabilizing atherosclerotic plaques and enhancing the activity of thrombocytes and coagulation. After myocardial infarction, ANG promotes myocardial remodeling and fibrosis, and its many pathological mechanisms deteriorate the prognosis of these high-risk patients in particular. Therapeutically, inhibitors of the angiotensin I-converting enzyme (ACEI) and AT1 receptor blockers (ARB) are available to suppress the generation and cellular signaling of ANG, respectively. Despite major differences in the efficacy of ANG suppression and the modulation of other hormones and receptors, both classes of drugs are generally effective in attenuating numerous pathomechanisms of ANG in vitro, and in diminishing the development of atherosclerotic lesions and restenosis after angioplasty in various animal models. In clinical therapy, ACEI and ACE are well-tolerated antihypertensive drugs that also improve the prognosis of heart failure patients. After myocardial infarction and in stable coronary heart disease, ACEI have been shown to reduce mortality in a manner independent of hemodynamic alterations. However, there is little evidence that inhibitors of the RAAS may be effective against arterial restenosis, and a possible benefit of these substances compared to other antihypertensive drugs in the primary prevention of coronary heart disease in hypertensive patients is still a matter of debate, possibly depending on the specific substance and condition being investigated. As such, the general clinical efficacy of ACEI and ARB may be due to a positive influence on hemodynamic load, vascular function, myocardial remodeling, and neuro-humoral regulation, rather than to a direct attenuation of the atherosclerotic process. Further therapeutic advances may be achieved by identifying optimum drugs, patient populations, and treatment protocols.     

Molecular activation of PPARgamma by angiotensin II type 1-receptor antagonists

OBJECTIVE AND DESIGN: Elevated blood pressure and insulin resistance are strongly associated in patients. We explored the potential for the anti-hypertensive angiotensin II type 1-receptor (ATR(1)) antagonists to improve insulin sensitivity through modulation of the nuclear receptor PPARgamma, in vitro and in vivo compared to the potent insulin sensitizer, rosiglitazone. METHODS: PPARgamma modulation by ATR(1) antagonists was measured first by direct recruitment of PGC-1, followed by trans-activation reporter assays in cells, and promotion of adipogenesis in fibroblast and pre-adipocyte cell lines. Improvement of insulin sensitivity was measured as changes in levels of glucose, insulin, and adiponectin in ob/ob mice. RESULTS: Telmisartan, candesartan, irbesartan, and losartan (but not valsartan or olmesartan) each served as bona fide PPARgamma ligands in vitro, with EC(50) values between 3 and 5 micro mol/l. However, only telmisartan, and to a lesser extent candesartan, resulted in significant PPARgamma agonism in cells. In vivo, although rosiglitazone significantly lowered both glucose (33%, p<0.01) and insulin (61%, p<0.01) levels and increased expression of adiponectin (74%, p<0.001), sartan treatment had no effect. CONCLUSIONS: Many members of the sartan family of ATR(1) antagonists are PPARgamma ligands in cell-free assays but their modulation of PPARgamma in cells is relatively weak. Furthermore, none appear to improve insulin sensitivity in a rodent model under conditions where other insulin sensitizers, including rosiglitazone, do. These results question whether reported effects of sartans on insulin sensitivity may be through other means, and should guide further efforts to develop dual agents to treat hypertension and insulin resistance.     

The role of angiotensin type 1 receptor in inflammation and endothelial dysfunction

Endothelial dysfunction plays an important role in all stages of atherosclerosis, and is characterized by an increased activity of vasoconstricting factors, proinflammatory and prothrombotic mediators. The aim of the review is to evaluate the role of angiotensin II (Ang II) and especially of angiotensin type 1 (AT1) receptor in inflammation and endothelial dysfunction. Ang II with AT(1) receptor are through several mechanisms implicated in the progression of atherosclerosis. Stimulation of AT(1) receptor increases oxidative stress especially through activation of NADH/NADPH oxidase in the vascular cells. Oxidative stress is associated with activation of the inflammatory processes. Ang II via AT(1) receptor increases expression of adhesion molecules and stimulates the induction of monocyte chemoattractant protein-1 (MCP-1). AT(1) receptor enhances the activation of nuclear factor NF-kappaB, which stimulates the production of proinflammatory cytokines. Proinflammatory cytokines on the other side may induce acute-phase response in the liver. Activation of AT(1) receptor via inducible cyclooxygenase (COX)-2 promotes biosynthesis of matrix metalloproteinases (MMPs). Ang II is implicated in the process of angiogenesis. Via AT(1) receptor takes part in the regulation of vascular endothelial growth factor (VEGF), which is one of the most angiogenic factors and stimulates the activity of endothelial progenitor cells (EPC). Recently some patents were reported discussing role of different compounds for the treatment of cardiovascular disease, renovascular disease nephropathy, peripheral vascular disease, portal hypertension and ophthalmic disorders, are cyclooxygenase-2 inhibitors.     

Comparative pharmacology of the angiotensin II receptor antagonists

The non-peptide angiotensin II (AII) receptor antagonists are a new class of compounds that are continuing to be developed as therapeutic agents for the treatment of hypertension, heart failure (HF) and chronic renal disease (CRD). Several of these compounds are currently available for therapeutic use in the USA and the European community with several more in clinical trials and in development. Compounds in this new class are as effective as angiotensin converting enzyme (ACE) inhibitors in treating hypertensive patients and appeared to have a similar therapeutic profile to ACE inhibitors in patients with HF and CRD. One clinical advantage of the AII receptor antagonists over ACE inhibitors is an improved side-effect profile with the absence of the persistent dry cough associated with ACE inhibitor therapy. To date, it is clear that the AII receptor antagonists are effective antihypertensive agents. Clinical trials are currently in progress to determine the therapeutic efficacy of these drugs in the treatment of HF and progressive renal disease.     

A two-state receptor model for the interaction between angiotensin II type 1 receptors and non-peptide antagonists

The interaction between non-peptide antagonists and the human angiotensin II type 1 (AT1) receptor in CHO-K1 cells was investigated by incubating the cells with antagonist, followed by a brief exposure to angiotensin II and measurement of the resulting inositol phosphate accumulation. The experimental data, expressed either as angiotensin II concentration-response curves or as antagonist concentration-inhibition curves, were in good agreement with computer-generated data according to a single-state model for the surmountable antagonist losartan and according to a two-step, two-state receptor model for the insurmountable antagonists candesartan, EXP3174, and irbesartan. Experimental and computer-generated data concerning the simultaneous exposure of the receptors to EXP3174 and losartan indicated that losartan produced a concentration-dependent restoration of the maximal response (angiotensin II concentration-response curves) as well as a rightward shift of the insurmountable portion of the EXP3174 inhibition curves, thus counteracting the higher-affinity EXP3174 binding. In conclusion, these findings provide further support for the concept that insurmountable and surmountable AT1 antagonists are mutually competitive and that insurmountable antagonist-receptor complexes may adopt different states.     

Biased agonism of the angiotensin II type 1 receptor

G protein-coupled receptors (GPCRs) can be activated by multiple ligands and exhibit the capacity to couple to numerous intracellular signal transduction pathways. This property allows GPCRs to be modulated by biased agonists that selectively activate specific subsets of GPCR-regulated cellular signaling proteins. The angiotensin II type 1 receptor (AT1R) is a GPCR that endogenously binds to the peptide ligand angiotensin II. More recently it has been demonstrated that a modified peptide, [Sar1I-le4-Ile8]-angiotensin II (SII) acts as a biased agonist towards the AT1R. SII binds to the AT1R without promoting heterotrimeric G protein-coupling, but serves to link the receptor to the beta-arrestin-dependent activation of the mitogen activated protein kinase pathway. The present mini-review summarizes current knowledge regarding the role of biased agonists in stimulating biased AT1R signaling.     

The apelin receptor inhibits the angiotensin II type 1 receptor via allosteric trans-inhibition

Background and Purpose

The apelin receptor (APJ) is often co-expressed with the angiotensin II type-1 receptor (AT1) and acts as an endogenous counter-regulator. Apelin antagonizes Ang II signalling, but the precise molecular mechanism has not been elucidated. Understanding this interaction may lead to new therapies for the treatment of cardiovascular disease.

Experimental Approach

The physical interaction of APJ and AT1 receptors was detected by co-immunoprecipitation and bioluminescence resonance energy transfer (BRET). Functional and pharmacological interactions were measured by G-protein-dependent signalling and recruitment of β-arrestin. Allosterism and cooperativity between APJ and AT1 were measured by radioligand binding assays.

Key Results

Apelin, but not Ang II, induced APJ : AT1 heterodimerization forced AT1 into a low-affinity state, reducing Ang II binding. Likewise, apelin mediated a concentration-dependent depression in the maximal production of inositol phosphate (IP₁) and β-arrestin recruitment to AT1 in response to Ang II. The signal depression approached a limit, the magnitude of which was governed by the cooperativity indicative of a negative allosteric interaction. Fitting the data to an operational model of allosterism revealed that apelin-mediated heterodimerization significantly reduces Ang II signalling efficacy. These effects were not observed in the absence of apelin.

Conclusions and Implications

Apelin-dependent heterodimerization between APJ and AT1 causes negative allosteric regulation of AT1 function. As AT1 is significant in the pathogenesis of cardiovascular disease, these findings suggest that impaired apelin and APJ function may be a common underlying aetiology.

Linked Article

This article is commented on by Goupil et al., pp. 1101–1103 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12040     

Reversible and syntopic interaction between angiotensin receptor antagonists on Chinese hamster ovary cells expressing human angiotensin II type 1 receptors

Evidence for a competitive type of interaction between angiotensin II type 1 (AT(1)) antagonists on Chinese hamster ovary cells expressing the human AT(1) receptor (CHO-AT(1)) was obtained by analyzing the binding of [(3)H]-2-ethoxy-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1H- ben zimidazoline-7-carboxylic acid ([(3)H]candesartan) and by measuring the AT-induced production of inositol phosphates. The AT(1) antagonists candesartan, 2-n-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]+ ++imid azole-5-carboxylic acid (EXP3174), or 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)bip hen yl- 4-yl)methyl]imidazole (losartan) produced a concentration-dependent increase in the apparent K(d) values of [(3)H]candesartan in saturation binding experiments, while the B(max) values were unchanged. Furthermore, the dissociation rate of the radioligand initiated by 1 microM unlabelled candesartan was not changed in the presence of 10 microM losartan, 10 microM EXP3174, or 10 microM irbesartan (2-n-butyl-4-spirocyclopentane-1-[(2'-(1H-tetrazol-5-yl)b iph enyl-4-yl) methyl]2-imidazolin-5-one)). Preincubation of the CHO-AT(1) cells with candesartan, EXP3174, and irbesartan caused a reduction in the maximal AT-induced inositol mono-, bis-, and trisphosphate production. This insurmountable effect was reversed in the presence of 1 microM losartan. In line with this finding, the insurmountable antagonist concentration-inhibition curves at 10 microM AT were shifted to the right in the presence of losartan. For candesartan this effect was concentration-dependent, yielding a pK(B) value for losartan of 7.7, which is similar to the pK(B) from previously obtained AT concentration-response curves. Finally, the dissociation rate of candesartan, EXP3174, irbesartan, and losartan was determined by measuring the recovery of AT responses after antagonist pretreatment and washing of the cells with medium containing 1 microM losartan to prevent re-association of the insurmountable antagonists. In addition, similar kinetic data were obtained from the slowing of the [(3)H]candesartan association rate to antagonist preincubated cells.     

Cytostatic properties of some angiotensin I converting enzyme inhibitors and of angiotensin II type I receptor antagonists

Angiotensin converting enzyme (ACE) inhibitors and angiotensin II (AII) type 1 receptor antagonists have strong cytostatic properties on in vitro cultures of many normal and neoplastic cells. They are effective, in particular, in reducing the growth of human lung fibroblasts, renal canine epithelial cells, bovine adrenal endothelial cells, simian T lymphocytes, and of neoplastic cell lines derived from human neuroblastomas, a ductal pancreatic carcinoma of the Syrian hamsters, human salivary glands adenocarcinomas, and two lines of human breast adenocarcinomas. ACE inhibitors are also effective in protecting lungs, kidneys and bladders from the development of nephropathy, pneumopathy, cystitis, and eventually fibrosis in different models of organ-induced damage such as exposure to radiation, chronic hypoxia, administration of the alkaloid monocrotaline or bladder ligation. ACE inhibitors and AII type 1 receptor antagonists are also effective in reducing excessive vascular neoformation in a model of injury to the cornea of rats and rabbits, and in controlling the excessive angiogenesis observed in the Solt-Farber model of experimentally induced hepatoma, in methylcholantrene or radiation-induced fibrosarcomas, in radiation-induced squamous cell carcinomas and in the MA-16 viral-induced mammary carcinoma of the mouse. Captopril was, in addition, effective in controlling tumor growth in a case of Kaposi's sarcoma in humans. The inhibition of AII synthesis and/or its blockade by AII receptors is likely to be an important mechanism for this cytostatic action. The mitogenic effect of AII is well established and a reduction of AII synthesis may well explain cell and neoplasm delayed growth. Moreover, AII regulates and enhances the activity of several growth factors including transforming growth factor B (TGFB) and smooth muscle actin (SMA); and many of these factors are reduced in tissues of animals treated with ACE inhibitors and AII type 1 receptor antagonists. These processes seem to be particularly relevant in the control of fibroblast growth and in the control of the ensuing fibrosis. The ACE inhibitors containing a sulphydril (SH) or thiol radical in their moiety (Captopril and CL242817) seemed to be more effective in controlling fibrosis and the growth of some neoplastic cells than those ACE inhibitors without this thiol radical in their structure, even if the second group of these drugs show in vitro a stronger inhibitory effect on converting enzyme activity. Pharmacologically it is known that ACE inhibitors containing a thiol radical also have antioxidant properties and they are efficient in controlling metalloproteinase action. However, although these additional properties are pharmacologically relevant, the blockade of AII synthesis plays an essential role in the cytostatic activity of these two categories of drugs. These observations underline that in addition to the beneficial effect of these drugs on the cardiovascular system, new potential applications are opening for their wider deployment.     

Quantitative structure activity relationship analysis of angiotensin II AT1 receptor antagonists

The quantitative structure activity relationship (QSAR) models were developed using multiple linear regression (MLR) and partial least square (PLS) for a set of 85 AT₁ receptor antagonists of hydantoin series. The MLR and PLS generated comparable models with good predictive ability and all the other statistical values, such as r, r², \textr_(\textcv)² , {\text{r}}_{{({\text{cv}})}}^{2} , and F and s values, were satisfactory. The results obtained from this study indicate the importance of steric (K-alpha3), hydrophobic (log P, and total lipole), and total energy (Cosmic total energy) in determining the activity of AT₁ receptor antagonists. The results clearly explained that optimum hydrophobicity of substituent at R₂ position is favorable for the activity and presence of a substituent of particular size and shape on phenyl ring at R₃ position is essential for the activity. This information is pertinent to the further design of new AT₁ receptor antagonist containing the hydantoin nucleus.