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At least 19 recordsLinked to original sources
PubMed2005

Pharmacotherapy review: Angiotensin receptor antagonists.

Angiotensin receptor blockers are one of several drug classes that act by interfering with activity of the renin-angiotensin axis. Drugs in this class are as effective as angiotensin-converting enzyme inhibitors in the reduction of blood pressure in hypertensive patients. Results from a series of outcomes trials increasingly support the use of drugs in this class as cardioprotective and renoprotective agents in patients with heart failure, diabetic nephropathy, and post-myocardial infarction.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2004

Comparison of the effects of angiotensin receptor antagonist, angiotensin converting enzyme inhibitor, and their combination on regression of left ventricular hypertrophy of diabetes type 2 patients on recent onset hemodialysis therapy.

Left ventricular hypertrophy (LVH) is frequently found at the initiation of dialysis therapy of diabetic and hypertensive patients, and is highly predictive of future cardiac morbidity and mortality. In patients with hypertension and LVH, both an angiotensin converting enzyme (ACE) inhibitor and an angiotensin type 1 receptor (AT1) antagonist regress LVH. However, it remains controversial whether dual blockade of the renin-angiotensin system will regress LVH in these patients using a combination of ACE inhibitor and AT1 antagonist. Thirty-three type II diabetic patients with end-stage renal disease who had just entered into hemodialysis therapy and were diagnosed as having LVH evaluated by echocardiography were selected from three dialysis units staffed by the faculty of Saitama Medical School, Saitama, Japan between 1999 and 2001. The study was carried out for 1 year. All patients were assigned randomly to three groups with equal number: group I, an ACE inhibitor, enalapril 10 mg daily; group II, an AT1 antagonist, losartan 100 mg daily; group III, combination of enalapril 10 mg and losartan 100 mg daily. All antihypertensive drugs were given 30 min after the cessation of dialysis therapy. LVH was evaluated by echocardiography before the start of administration of drugs, at 6 months and 12 months after the start of drug therapy. Systolic blood pressure levels less than 140 mmHg were the target for the three groups. Using repeated measures analysis of variance, applied to those with four echocardiograms, there were progressive decreases over time in left ventricular mass index, posterior wall thickness and interventricular septum thickness. There were no significant differences in regression of LVH as well as blood pressure control between enalapril and losartan groups; however, dual blockade induced an additional 28% reduction in left ventricular mass index compared with any type of monotherapy. Both ACE inhibitors and AT1 antagonists benefit the regression of LVH in diabetic patients who start dialysis therapy. Moreover, combination therapy with ACE inhibitors and AT1 antagonists would provide more beneficial effects on LVH in these patients than monotherapy.

Angiotensin Receptor Antagonists↗
PubMed1996

Rationale, background, and design of the randomized angiotensin receptor antagonist--angiotensin-converting enzyme inhibitor study (RAAS).

The randomized angiotensin receptor antagonist--angiotensin converting enzyme (ACE)--Inhibitor Study (RAAS) was designed to test the hypothesis that the addition of an angiotensin II type 1 receptor blocking agent, losartan 50 mg/day, to an ACE-inhibitor, enalapril 10 mg twice a day (group 1), will be more effective than standard-dose enalapril 10 mg twice a day (group 2) or high-dose enalapril alone 20 mg twice a day (group 3), in blocking the activation of the renin angiotensin aldosterone system in patients with heart failure and left ventricular systolic dysfunction. The addition of an angiotensin II type 1 receptor blocking agent to an ACE inhibitor would theoretically block ACE as well as non-ACE-dependent angiotensin II formation while maintaining the potential beneficial effect of ACE inhibitor-induced bradykinin formation. One hundred twenty patients with left ventricular systolic dysfunction and moderate to severe heart failure despite treatment with an ACE inhibitor will be randomized to 1 of the 3 groups and followed for 6 weeks, with an optional long-term week extension to determine the safety and tolerability of the combination of losaratan and enalapril, its effectiveness in preventing rest and exercise-induced neurohumoral activation (plasma norepinephrine, N-terminal proatrial natriuretic factor, angiotensin II, and aldosterone), as well as quality of life and exercise performance (6-minute walk test).

Angiotensin Receptor Antagonists↗
PubMed2000

Angiotensin receptor antagonists.

BACKGROUND: Angiotensin receptor antagonists are a relatively new class of cardiovascular drugs for which the clinical application has not yet been completely defined. OBJECTIVE: This article reviews the pharmacology of the various angiotensin receptor antagonists available in Australia, including their mode of action, side effects and potential drug interactions. DISCUSSION: Angiotensin receptor antagonists are effective drugs for the treatment of mild to moderate hypertension which have a side effect profile similar to placebo. Their role in the management of hypertension remains to be defined, but they are of particular use to patients who are intolerant of ACE inhibitors because of cough. It is uncertain at the present time whether the benefits of ACE inhibition in other disorders such as congestive heart failure and following myocardial infarction will be similar for angiotensin receptor blockers.

Angiotensin II↗
PubMed1997

Angiotensin-responsive adrenal glomerulosa cell proteins: characterization by protease mapping, species comparison, and specific angiotensin receptor antagonists.

Angiotensin II (AngII)-stimulated aldosterone synthesis is mediated by the AngII type 1 (AT1) receptor and requires ongoing protein synthesis. Hormonally-stimulated turnover of a family of 28- to 30-kDa proteins (p30, or steroidogenic acute regulatory proteins) has been linked to enhanced steroid synthesis in several tissues. Our previous work showed that AngII, dibutyryl cAMP, potassium, and atrial natriuretic peptide affected labeling of a group of eight proteins (four of 28 kDa and four of 30 kDa) in bovine adrenal glomerulosa cells. This report extends our findings in three ways: 1) The eight [35S]-methionine-labeled p30 proteins in bovine cells were compared with each other by chymotryptic peptide mapping. Similarity in maps indicated that the eight proteins share a common primary structure. 2) Dibutyryl cAMP treatment of rat adrenal glomerulosa cells affected the levels of four 28-kDa proteins and one 35-kDa protein, whereas AngII affected two of the 28-kDa proteins. There were no responsive 30-kDa proteins in rats comparable with those seen in bovine cells. These results indicate a species difference in the affected proteins. 3) The AT1 receptor antagonist, losartan, inhibited the effects of AngII on aldosterone synthesis and turnover of the p30 proteins in bovine adrenal glomerulosa cells. PD123319, an antagonist specific for the AngII type 2 receptor, did not block AngII-stimulated aldosterone synthesis and had much less effect on p30 protein labeling than did losartan. These results add to the growing body of evidence that this family of p30 or steroidogenic acute regulatory proteins plays a role in the acute regulation of steroidogenesis by a wide variety of stimulatory hormones in several tissues and species. In addition, losartan's inhibition of AngII's effects on the p30 proteins is consistent with a key role for these proteins in processes linking occupation of the AT1 receptor to stimulation of aldosterone synthesis.

Aldosterone↗
PubMed2004

Angiotensin antagonism in patients with heart failure: ACE inhibitors, angiotensin receptor antagonists or both?

Chronic heart failure (CHF) is a major cause of morbidity and mortality in western society. It is now widely accepted that the renin-angiotensin-aldosterone system (RAAS) and, in particular, angiotensin II (A-II) play a key role in the pathophysiology of CHF. Large-scale clinical trials have demonstrated that inhibitors of angiotensin-converting enzyme (ACE), the principal enzyme responsible for A-II production, improve symptoms and survival in patients with CHF. This enzyme is also responsible for the breakdown of the vasodilator hormone bradykinin. Administration of ACE inhibitors is associated with increased plasma bradykinin levels and this is thought to contribute to the vascular changes associated with ACE inhibitor therapy. However, RAAS inhibition with ACE inhibitors remains incomplete because ACE inhibitors do not block the non-ACE-mediated conversion of angiotensin I to A-II. Angiotensin receptor antagonists (angiotensin receptor blockers; ARBs) antagonize the action of A-II at the A-II type 1 (AT(1)) receptor, whilst allowing the potentially beneficial actions of A-II mediated via the A-II type 2 (AT(2)) receptor. Evidence that the clinical benefit demonstrated with ACE inhibitors in patients with CHF may extend to ARBs has only emerged recently. Combination therapy with both an ACE inhibitor and an ARB has a number of potential advantages and has been investigated in several large-scale clinical trials recently. In patients with CHF, first-line therapy should include an ACE inhibitor and a beta-adrenoceptor antagonist. The addition of an ARB provides symptomatic relief but has not been shown to improve survival. Where an ACE inhibitor is not tolerated, treatment with an ARB would seem an appropriate alternative. There is insufficient data to support the routine use of ARBs as first-line therapy in the management of CHF.

Adrenergic beta-Antagonists↗
PubMed1995

Effects of angiotensin receptor antagonist and angiotensin converting enzyme inhibitor on insulin sensitivity in fructose-fed hypertensive rats and essential hypertensives.

This study was designed to investigate the effects of angiotensin II (AII) receptor antagonist and angiotensin converting enzyme (ACE) inhibitor on insulin resistance, and the mechanism by which ACE inhibitor improves insulin-dependent glucose uptake (insulin sensitivity) in an insulin-resistant hypertensive rat model (fructose-fed rats, FFR) and in essential hypertensives (EHT). Male Sprague-Dawley rats were fed on fructose-rich or standard chow for 4 weeks and treated either with 10 mg/kg/day of delapril (n = 8), 1 mg/kg/day of TCV-116 (AII receptor antagonist; n = 13), or vehicle (n = 9) for the latter 2 weeks. Steady-state plasma glucose (SSPG) was measured with the subjects in the conscious state; simultaneously, we infused insulin (2.5 mU/kg/min) and glucose (8 mg/kg/min) to determine insulin sensitivity in each group. Thirteen EHT were hospitalized and the 2-h euglycemic hyperinsulinemic glucose clamp (GC) method was performed in a fasting condition before and after 2 weeks' administration of TCV-116 (8 mg/day) in 7 EHT and of delapril (120 mg/day) in 6 EHT. Insulin sensitivity was evaluated as M-value calculated from the infusion rate of glucose. Mean blood pressure (MBP) was higher in FFR (137.7 +/- 73.8 mm Hg, P < .05) compared to controls (120.8 +/- 2.7 mm Hg), and was lower in both the delapril (108.1 +/- 6.3 mm Hg, P < .05) and TCV-116 (112.8 +/- 4.3 mm Hg, P < .05) groups than in FFR.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed2000

[Comparison of angiotensin receptor antagonists and angiotensin converting enzyme inhibitors in arterial hypertension].

By blocking the renin-angiotensin system, angiotensin converting enzyme inhibitors and more recently introduced angiotensin II receptor antagonists are two important classes of antihypertensive drugs. Whether one class is superior to the other is presently unknown. Their antihypertensive efficacy is comparable. Angiotensin II receptor antagonists are particularly well tolerated but the converting enzyme inhibitors have broader indications. The results of the large studies with morbidity and mortality end-points are awaited to better define the place of the angiotensin II antagonists in monotherapy and in combination.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

Effects of AT1 and AT2 angiotensin receptor antagonists in angiotensin II-infused rats.

Angiotensin II (Ang II) appears to exert its contractile and growth-promoting effects through the AT1 receptor subtype, whereas the AT2 subtype may have growth-inhibitory and proapoptotic properties. Recently, some data have challenged this emerging concept. To clarify the role of AT1 and AT2 receptors, we treated Wistar rats that were infused with Ang II (120 ng/kg/min subcutaneously by osmotic minipump), with the AT1 antagonist losartan (10 mg/kg/d in the drinking water) and the AT2 antagonist PD123319 (30 mg/kg/d subcutaneously by osmotic minipump) for 21 days. At the end of the study, tail-cuff systolic blood pressure was 106+/-2.8 mm Hg in untreated rats and 108+/-2.0 mm Hg in rats infused with Ang II that received losartan, whereas it rose to 158+/-4.9 mm Hg in Ang II-infused rats and 158+/-3.0 mm Hg in rats infused with Ang II rats and PD123319 (the two latter groups P<.01 versus the two other groups). Heart weight, and aorta cross-section/body weight ratio were higher in Ang II-infused rats than in controls and were significantly reduced in Ang II-infused rats that received losartan (P<.05). Wire-myograph-mounted coronary, renal, mesenteric, and femoral small arteries from Ang II-infused rats and Ang II-infused rats receiving PD123319 had a greater media, media cross-section, and media/lumen ratio than vessels from untreated or Ang II-infused rats treated with losartan. These results support the concept that in Wistar normotensive rats infused for 3 weeks with angiotensin II, growth in the heart, aorta, and coronary, renal, mesenteric, and femoral small arteries is mediated by the AT1 receptor; the results show little evidence of a role of AT2 receptors in mediating angiotensin II effects in this experimental paradigm.

Administration, Oral↗
PubMed1997

HR 720, a novel angiotensin receptor antagonist inhibits the angiotensin II-induced trophic effects, fibronectin release and fibronectin-EIIIA+ expression in rat aortic vascular smooth muscle cells in vitro.

The aim of this study was to evaluate the direct trophic effects of angiotensin II (AII) on rat vascular smooth muscle cells obtained from a single cellular isolate. Cell volume, protein synthesis, fibronectin (FN) release and FN-EIIIA+ mRNA isoform expression were analyzed in parallel. The effects of HR 720, a novel AT1 angiotensin receptor antagonist with some AT2 receptor affinity, were compared with those of selective AT1 antagonist EXP 3174. Both HR 720 and EXP 3174 inhibited in a concentration-dependent manner the maximum increase in cell volume induced by 10(-9) M Sar1-All (IC50 = 0.49 x 10(-9) M and 0.79 x 10(-9) M, respectively). Maximum [3H]leucine incorporation was also achieved at 10(-9) M All. HR 720 blocked the increase in protein synthesis with potency similar to EXP 3174; the respective IC50 values were 1.04 x 10(-9) M and 1.36 x 10(-9) M. All dose-dependently increased FN release, which was also equally inhibited by about 50% with both compounds at 10(-6) M. Furthermore, All enhanced FN-EIIIA+ mRNA in rat vascular smooth muscle cells (VSMC), which indicated a modulation of FN isoform expression which was inhibited by angiotensin II antagonists. In conclusion, All induced parallel and concentration-dependent increases in cell volume, protein synthesis, FN release and FN-EIIIA+ mRNA expression in vascular smooth muscle cells. These effects appeared to be essentially mediated by AT1 receptor stimulation as indicated by the equal inhibitory effects of HR 720 and EXP 3174.

Angiotensin II↗
PubMed2001

Clinical studies of CS-866, the newest angiotensin II receptor antagonist.

Angiotensin II receptor blockers have shown widespread efficacy as antihypertensive medications. These agents bind selectively to angiotensin II type 1 (AT(1)) receptors, specifically blocking the renin-angiotensin system at the last step in its cascade. CS-866 is the most recently introduced drug in this class. This article presents integrated safety and efficacy data from 7 randomized, double-blind, placebo-controlled, parallel group studies in which once-daily CS-866 monotherapy was used in the treatment of patients with essential hypertension (sitting diastolic blood pressure > or =100 mm Hg and < or =115 mm Hg). Data from a total of 2,145 CS-866-treated patients were included in the efficacy analysis. Safety data were available from 2,540 CS-866-treated patients, with a cumulative exposure of 5,888 patient-months. The antihypertensive efficacy of the drug was assessed using both cuff blood pressure measurements and 24-hour ambulatory blood pressure monitoring. The data show that CS-866 is effective and safe for the treatment of hypertension. Dose-dependent reductions in both diastolic and systolic blood pressures occurred within 1 week of initiating treatment, and the response was almost maximal within 2 weeks. There was no difference in efficacy between younger (<65 years) and older (> or =65 years) groups of patients. Trough-to-peak ratios showed that CS-866 retains the majority of its peak effect 24 hours after treatment, and is therefore suitable for once-daily dosing. Dizziness was the only treatment-emergent adverse event with which CS-866 was associated.

Angiotensin Receptor Antagonists↗
PubMed2005

Fixed-dose combinations in the management of hypertension: defining the place of angiotensin receptor antagonists and hydrochlorothiazide.

We discuss combination therapy with angiotensin receptor antagonists (angiotensin receptor blockers; ARBs) and thiazide diuretics in light of the independent actions of both types of agents, and the adverse effects of both agents independently and in the context of the physiologic synergy achieved in using these agents together. ARBs counteract many of the adverse events associated with the use of thiazide diuretics and have been shown to reduce the occurrence of new-onset diabetes mellitus. We also review outcome trials in patients with hypertension (such as LIFE [Losartan Intervention For Endpoint reduction in hypertension], VALUE [Valsartan Antihypertensive Long-term Use Evaluation], and SCOPE [Study on COgnition and Prognosis in the Elderly]), in which losartan, valsartan, and candesartan cilexetil were used in combination with hydrochlorothiazide. Fixed combination ARB/hydrochlorothiazide agents make sense as initial therapy for patients in whom BP is >20/10 mm Hg above goal.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

Renal responses to angiotensin receptor antagonist and angiotensin-converting enzyme inhibitor in partially nephrectomized spontaneously hypertensive rats.

To investigate the role of the renin-angiotensin system (RAS) on nephrosclerosis in salt-loaded, partially nephrectomized spontaneously hypertensive rats (SHR), we evaluated the effects of angiotensin II (ANGII) blockade on the progression of nephrosclerosis with an angiotensin type 1 receptor (AT1rec) antagonist [TCV-116 (TCV)] and an angiotensin-converting enzyme (ACE) inhibitor (enalapril) at the doses equivalent in reducing systemic blood pressure (BP). SHR were five/sixths nephrectomized and were fed a high-salt diet. In addition to being significantly preventive against an increase in systolic BP, both TCV and enalapril significantly attenuated the increases in proteinuria and the renal histopathological alterations. Transcription of AT1rec mRNA in the remnant kidney was enhanced with the progression of nephrosclerosis, but was inhibited by TCV as well as enalapril. In these aspects, there were no apparent differences between effects of TCV and enalapril. The RAS system plays an important role in nephrosclerosis in partially nephrectomized SHR despite a high-salt diet, and direct ANGII blockade certainly protected the kidney against hypertensive injury in this model.

Angiotensin Receptor Antagonists↗
PubMed2001

Pharmacological differences among angiotensin II receptor antagonists.

Angiotensin II AT1 receptor antagonists (AIIRAs) have demonstrated efficacy similar to other classes of antihypertensive agents as well as "placebo-level" tolerability at all doses. Pharmacokinetic and pharmacodynamic studies provide a framework for understanding important intra-class dissimilarities. Disparity in antagonistic effects may be determined by in vivo responses to challenges of exogenous angiotensin II (Ang II) and by ex vivo/in vitro responses to a drug's biological activity by radioligand receptor assay (RRA). Two independent studies have been conducted in which irbesartan exhibited a more pronounced and longer-lasting antagonism to the effects of exogenous Ang II than losartan and valsartan. Comparative trials have indicated that both irbesartan and candesartan show greater clinical efficacy in lowering blood pressure than losartan. Recently, we have compared the Ang II antagonistic properties of irbesartan 150 mg/day and candesartan 8 mg/day. Both drugs block AT1 receptors with "insurmountable" antagonism and demonstrate a long duration of action. While both irbesartan and candesartan showed a similar degree of antagonistic activity in vivo, distinctly higher antagonistic activity in plasma was found for irbesartan by RRA at all time-points. Furthermore, plasma renin activity during periods with high antagonistic activity was significantly higher, and aldosterone levels following Ang II stimulation were blunted to a greater extent, following administration of irbesartan. In summary, in the doses tested, irbesartan exhibits the strongest antagonism when compared with losartan, valsartan and candesartan. This finding may have clinical implications.

Aldosterone↗
PubMed2003

Blockade of apoptosis by ACE inhibitors and angiotensin receptor antagonists.

Inhibitors of angiotensin converting enzyme (ACE-Is) and angiotensin (ANG) receptor antagonists were originally developed to aid in the management of hypertension. As the use of these agents was extended to the management of heart failure and other cardiovascular diseases, studies of tissue remodeling suggested that blockade of ANGII function might play a role in the regulation of cell death by apoptosis. Experiments with cultured cells confirmed that ANGII is an inducer of apoptosis in well differentiated cell types isolated from the heart, kidneys, lungs and other organs. More recent evidence with animal models strongly suggests that ACE-Is and ANG receptor antagonists, in addition to affecting hemodynamics, also influence disease progression through direct inhibition of ANG-induced apoptosis. This manuscript reviews the evidence supporting this view, discusses its potential relevance to disease pathogenesis and offers new hypotheses regarding novel uses of ACE-Is and ANG receptor antagonists in the control of cell death.

Angiotensin II↗
PubMed1990

Selective blockade of angiotensin responses in the rabbit isolated vas deferens by angiotensin receptor antagonists.

We examined the effect of two angiotensin receptor antagonists on neuromodulatory and prostaglandin-producing effects of angiotensin II in the rabbit isolated vas deferens because prior studies have established that angiotensins selectively influence the two neural events, one being adrenergic and the other nonadrenergic. Angiotensin II increased adrenergic neurotransmission and prostaglandin E synthesis in a concentration-dependent manner while depressing nonadrenergic neurotransmission. The [1-Sarcosine, 8-Alanine]-angiotensin II preferentially antagonized adrenergic neuromodulatory effects of angiotensin II. In contrast, the nonadrenergic neuromodulatory and prostaglandin E-releasing effects of angiotensin II were suppressed by [1-Sarcosine, 8-Alanine]-angiotensin II to a lesser extent. The nonpeptide angiotensin receptor antagonist, Dupont 753 (2-n-butyl-4-chloro-5-hydroxymethyl-1-[2(1)-(1-H-tetrazol-5-yl) biphenyl-4-yl)methyl] imidazole, potassium salt, exhibited the opposite selectivity. It eliminated the depression of nonadrenergic neurotransmission without significantly altering the potentiation of adrenergic neurotransmission caused by angiotensin II. The angiotensin-induced stimulation of prostaglandin E synthesis was also eliminated by this antagonist. These data suggest that angiotensin effects in the vas deferens are mediated by at least two types of angiotensin receptors.

Angiotensin II↗
PubMed1994

Effect of various angiotensin receptor antagonists on cardiovascular responses to angiotensin II in pithed rats.

The effects of four nonpeptide angiotensin receptor antagonists, i.e., losartan (AT1) PD123177 (AT2), and 4'-[(2-n-butyl-6-cyclohexylaminocarbonylamino-benzimidazole-1-yl)- methyl]biphenyl-carboxylic acid (BIBS 39; AT1 and AT2), and 2-n-butyl-1-[4-(6-carboxy-2,5-di-chlorbenzoylamino)-benzyl]-6-N- (methylaminocarbonyl)-n-pentylamino-benzimidazole (BIBS 222; AT1 and AT2) on cardiovascular responses to angiotensin II (AII) were investigated in propranolol-pretreated pithed rats. AII (0.01-10 nmol/kg intravenously, i.v.) induced a dose-dependent increase in diastolic blood pressure (DBP), the rate of increase in left ventricular pressure (LVdP/dtmax), cardiac output (CO), and total peripheral resistance (TPR) without changing LV end-diastolic pressure (LVEDP) or heart rate (HR). Losartan 3 and 10 mg/kg i.v. caused dose-dependent parallel rightward shifts of the dose-response curves (DBP and LVdP/dtmax) without altering the maximal responses to AII. PD123177 (100 mg/kg i.v.) did not influence the dose-response curves for AII significantly. BIBS 39 (1, 3, and 10 mg/kg i.v.) and BIBS 222 (1, 3, and 10 mg/kg, i.v.) shifted the dose-response curves (DBP and LVdP/dtmax) for AII to the right. Although these two compounds (BIBS 39 1, 3, and 10 mg/kg and BIBS 222 1 and 3 mg/kg) did not alter the maximal increase in DBP to angiotensin AII, they decreased the maximal increase in LVdP/dtmax by approximately 35%. BIBS 39 (3 and 10 mg/kg) significantly reduced the increase in CO caused by AII and therefore mean arterial pressure (MAP), whereas the AII-induced increase in TPR remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed2004

Therapeutic effects of angiotensin (AT1) receptor antagonists: potential contribution of mechanisms other than AT1 receptor blockade.

Blockade of the renin-angiotensin system improves morbidity and mortality of patients with cardiovascular diseases, e.g. arterial hypertension, renal failure, following myocardial infarction and in congestive heart failure. The angiotensin II type 1 (AT(1)) receptor antagonists (angiotensin receptor blockers; ARBs), i.e. losartan, eprosartan, irbesartan and valsartan were developed by computer-based molecule design. Early observations already indicate that the ARBs elicit pleiotropic effects developing anti-aggregatory, anti-inflammatory and anti-mitogenic effects independent from their actions at the AT(1) receptor. Losartan metabolism indicates a number of known active intermediates and pointed to further interactions of these derivatives with other receptors and cellular signaling systems. Here we discuss a compilation of detailed pharmacokinetic and pharmacodynamic data of active metabolites of ARBs indicating their mode of action and suggest novel therapeutic implications. The clinical observations that ARBs elicit potencies in patients with cardiovascular diseases via the regulation of inflammatory, growth and homeostatic factors lead us to focus on specific, reactive metabolites, which hold potential for future indications and possible drug interactions in cardiovascular diseases.

3',5'-Cyclic-AMP Phosphodiesterases↗