Drugs targeting the renin–angiotensin–aldosterone system

Zaman, Mohammad A.; Oparil, Suzanne; Calhoun, David A.

doi:10.1038/nrd873

Cited by 405 publications

(355 citation statements)

References 101 publications

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“…2,4 Indeed, the pharmacokinetics of ARBs in human bodies, specifically factors such as bioavailability, half-life duration and route of elimination, differ considerably between different ARBs. These different degrees of efficacy possessed by ARBs are based on differences in their chemical structures, which determine their unique pharmacological properties.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, clinical trials have indicated that ARBs provide cardiovascular protection that extends beyond blood pressure lowering. 2 Treatment with ARBs effectively prevents cardiac hypertrophy and improves cardiovascular outcomes in patients with hypertension. 2,3 Structurally, most ARBs have a common biphenyl-tetrazole ring and unique side chains, which contribute to drug-specific differences in their pharmacokinetic and pharmacodynamic properties.…”

Section: Introductionmentioning

confidence: 99%

“…2 Treatment with ARBs effectively prevents cardiac hypertrophy and improves cardiovascular outcomes in patients with hypertension. 2,3 Structurally, most ARBs have a common biphenyl-tetrazole ring and unique side chains, which contribute to drug-specific differences in their pharmacokinetic and pharmacodynamic properties. 2,4 These structural and pharmacological differences among ARBs may have an impact on long-term cardiovascular outcomes, although the clinical significance of these differences remains to be determined in large-scale trials.…”

Section: Introductionmentioning

confidence: 99%

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Multivalent ligand–receptor interactions elicit inverse agonist activity of AT1 receptor blockers against stretch-induced AT1 receptor activation

et al. 2009

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Type 1 angiotensin II (AT 1 ) receptor has a critical role in the development of load-induced cardiac hypertrophy. Recently, we showed that mechanical stretching of cells activates the AT 1 receptor without the involvement of angiotensin II (AngII) and that this AngII-independent activation is inhibited by the inverse agonistic activity of the AT 1 receptor blocker (ARB), candesartan. Although the inverse agonist activity of ARBs has been studied in terms of their action on constitutively active AT 1 receptors, the structure-function relationship of the inverse agonism they exert against stretch-induced AT 1 receptor activation has not been fully elucidated. Assays evaluating c-fos gene expression and phosphorylated extracellular signal-regulated protein kinases (ERKs) have shown that olmesartan has strong inverse agonist activities against the constitutively active AT 1 receptor and the stretch-induced activation of AT 1 receptor, respectively. Ternary drug-receptor interactions, which occur between the hydroxyl group of olmesartan and Tyr 113 and between the carboxyl group of olmesartan and Lys 199 and His 256 , were essential for the potent inverse agonist action olmesartan exerts against stretch-induced ERK activation and the constitutive activity of the AT 1 -N111G mutant receptor. Furthermore, the inverse agonist activity olmesartan exerts against stretch-induced ERK activation requires an additional drug-receptor interaction involving the tetrazole group of olmesartan and Gln 257 of the AT 1 receptor. These results suggest that multivalent interactions between an inverse agonist and the AT 1 receptor are required to stabilize the receptor in an inactive conformation in response to the distinct processes that lead to an AngII-independent activation of the Keywords: angiotensin II; cardiac hypertrophy; G protein-coupled receptor; inverse agonist; mechanical stress INTRODUCTIONThe type 1 angiotensin II (AT 1 ) receptor is a member of the G proteincoupled receptor (GPCR) family and mediates most of the actions that angiotensin II (AngII) exerts on the cardiovascular system. 1 AT 1 receptor blockers (ARBs) are non-peptide compounds that selectively bind to the AT 1 receptor and inhibit AngII-induced receptor activation. At present, several ARBs are clinically available as a highly effective and well-tolerated class of drugs for the management of hypertension. In addition, clinical trials have indicated that ARBs provide cardiovascular protection that extends beyond blood pressure lowering. 2 Treatment with ARBs effectively prevents cardiac hypertrophy and improves cardiovascular outcomes in patients with hypertension. 2,3 Structurally, most ARBs have a common biphenyl-tetrazole ring and unique side chains, which contribute to drug-specific differences in their pharmacokinetic and pharmacodynamic proper-

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Multivalent ligand–receptor interactions elicit inverse agonist activity of AT1 receptor blockers against stretch-induced AT1 receptor activation

et al. 2009

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“…Activation of AT 1 Rs promotes proliferation, vasoconstriction, antinatriuresis, and salt appetite (20). AT 2 Rs antagonize many of the biological effects of AT 1 Rs by causing vasodilation, apoptosis, and prostaglandin release (21). AT 1 and AT 2 receptors are expressed at both apical and basolateral sides in the ASDN cells, although AT 2 R expression is considerably lower (22)(23)(24).…”

Section: Whereas Regulation Of Enac By Aldosterone Is Generally Accepmentioning

confidence: 99%

Angiotensin II Increases Activity of the Epithelial Na+ Channel (ENaC) in Distal Nephron Additively to Aldosterone

Mamenko

Zaika

Ilatovskaya

et al. 2012

Journal of Biological Chemistry

132

123

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“…Excessive RAS activity is a major underlying cause of many pathological states because Ang II increases BP and exerts direct growth-promoting effects on tissues that lead to endorgan damage. [1][2][3] Indeed, RAS inhibitors, such as ACE inhibitors and angiotensin AT 1 -receptor blockers (ARBs), have proved to be highly successful treatments for hypertension, heart failure, and related cardiovascular disorders. 3 Because renin catalyzes the first and rate-limiting step of the RAS and has high specificity for its substrate, angiotensinogen, renin inhibitors offer the potential for blocking this complex hormonal system at its initial point of activation, with a low likelihood of side effects.…”

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confidence: 99%

Aliskiren, a Novel Orally Effective Renin Inhibitor, Provides Dose-Dependent Antihypertensive Efficacy and Placebo-Like Tolerability in Hypertensive Patients

et al. 2005

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Background-Stopping the detrimental effects of the renin-angiotensin system at the most upstream point of the cascade offers theoretical advantages for cardiovascular protection. This study compares the antihypertensive efficacy and safety of the novel oral renin inhibitor aliskiren with placebo and an active comparator. Methods and Results-The study was a randomized, multicenter, double-blind, placebo-controlled, active-comparator 8-week trial in patients with mild-to-moderate hypertension (mean sitting diastolic blood pressure [DBP] Ն95 and Ͻ110 mm Hg). After a 2-week, single-blind placebo run-in, 652 patients were randomized to receive double-blind treatment with once-daily oral doses of aliskiren (150, 300, or 600 mg), irbesartan 150 mg, or placebo. Aliskiren 150, 300, and 600 mg effectively lowered both trough mean sitting DBP and systolic blood pressure (SBP) (PϽ0.001 versus placebo for both variables). The least-squares mean reductions in trough DBP were 9.3Ϯ0.8, 11.8Ϯ0.8, and 11.5Ϯ0.8 mm Hg, respectively, versus 6.3Ϯ0.8 mm Hg for placebo, and the least-squares mean reductions in trough SBP were 11.4Ϯ1.3, 15.8Ϯ1.2, and 15.7Ϯ1.2 mm Hg, respectively, versus 5.3Ϯ1.2 mm Hg for placebo. The antihypertensive effect of aliskiren 150 mg was comparable to that of irbesartan 150 mg (8.9Ϯ0.7 and 12.5Ϯ1.2 mm Hg, least-squares reduction in mean sitting DBP and SBP, respectively, for irbesartan). Aliskiren 300 and 600 mg lowered mean sitting DBP significantly more than irbesartan 150 mg (PϽ0.05). Aliskiren showed safety and tolerability comparable to those of placebo and irbesartan; the incidence of adverse events and number of patients discontinuing therapy were similar in all groups. Conclusions-Once-daily oral treatment with aliskiren lowers blood pressure effectively, with a safety and tolerability profile comparable to that of irbesartan and placebo, in patients with mild-to-moderate hypertension. Aliskiren 150 mg is as effective as irbesartan 150 mg in lowering blood pressure.

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Drugs targeting the renin–angiotensin–aldosterone system

Cited by 405 publications

References 101 publications

Multivalent ligand–receptor interactions elicit inverse agonist activity of AT1 receptor blockers against stretch-induced AT1 receptor activation

Multivalent ligand–receptor interactions elicit inverse agonist activity of AT1 receptor blockers against stretch-induced AT1 receptor activation

Angiotensin II Increases Activity of the Epithelial Na+ Channel (ENaC) in Distal Nephron Additively to Aldosterone

Aliskiren, a Novel Orally Effective Renin Inhibitor, Provides Dose-Dependent Antihypertensive Efficacy and Placebo-Like Tolerability in Hypertensive Patients

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