Rationale for Combining a Direct Renin Inhibitor with other Renin- Angiotensin System Blockers. Focus on Aliskiren and Combinations

Siragy, Helmy M.

doi:10.1007/s10557-010-6278-0

Cited by 9 publications

(5 citation statements)

References 98 publications

(119 reference statements)

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“…Nevertheless, aliskiren does increase renin levels (Feldman, et al, 2008), suggesting activation of a feedback network to the RAS. Consistent with these findings, clinical data show that aliskiren works better when combined with other antihypertensive drugs (Azizi, et al, 2004; O’Brien, et al, 2007; Siragy, 2011). Evidence that the PRR—the newly discovered RAS component that mediates both Ang II formation and Ang II-independent intracellular signaling—plays a significant role in the development of hypertension and cardiovascular end-organ damage through prorenin (Ichihara, Itoh, & Inagami, 2008) suggests that the PRR might be a promising new target for the treatment of hypertension.…”

Section: The Development Of Prr Antagonistssupporting

confidence: 68%

The critical role of the central nervous system (pro)renin receptor in regulating systemic blood pressure

Jensen

Peng

et al. 2016

Pharmacology & Therapeutics

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The systemic renin–angiotensin system (RAS) has long been recognized as a critically important system in blood pressure (BP) regulation. However, extensive evidence has shown that a majority of RAS components are also present in many tissues and play indispensable roles in BP regulation. Here, we review evidence that RAS components, notably including the newly identified (pro)renin receptor (PRR), are present in the brain and are essential for the central regulation of BP. Binding of the PRR to its ligand, prorenin or renin, increases BP and promotes progression of cardiovascular diseases in an angiotensin II-dependent and -independent manner, establishing the PRR a promising antihypertensive drug target. We also review the existing PRR blockers, including handle region peptide and PRO20, and propose a rationale for blocking prorenin/PRR activation as a therapeutic approach that does not affect the actions of the PRR in vacuolar H+-ATPase and development. Finally, we summarize categories of currently available antihypertensive drugs and consider future perspectives.

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Section: The Development Of Prr Antagonistssupporting

confidence: 68%

The critical role of the central nervous system (pro)renin receptor in regulating systemic blood pressure

Jensen

Peng

et al. 2016

Pharmacology & Therapeutics

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“…However, it is unclear whether ALK may effectively induce regression of cardiac hypertrophy. Although the combination of ALK with an ACEI or an ARB can synergistically attenuate both 1006 www.nature.com/aps Weng LQ et al Acta Pharmacologica Sinica npg hypertrophy and dysfunction in hypertensive patients [8,9] , a systematic review of randomized, controlled clinical trials has shown that combined therapy is associated with a higher risk of hyperkalemia than monotherapy with an ACEI, an ARB or ALK [10] . In addition, some patients are intolerant of ACEI or ARB, whereas ALK is well tolerated [11] .…”

Section: Introductionmentioning

confidence: 99%

Aliskiren ameliorates pressure overload-induced heart hypertrophy and fibrosis in mice

Weng

Zhang

et al. 2014

Acta Pharmacol Sin

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Aim: Aliskiren (ALK) is a renin inhibitor that has been used in the treatment of hypertension. The aim of this study was to determine whether ALK could ameliorate pressure overload-induced heart hypertrophy and fibrosis, and to elucidate the mechanisms of action. Methods: Transverse aortic constriction (TAC) was performed in mice to induce heart pressure overload. ALK (150 mg·kg -1 ·d -1, po), the autophagy inhibitor 3-methyladenine (10 mg·kg -1 per week, ip) or the PKCβI inhibitor LY333531 (1 mg·kg, po) was administered to the mice for 4 weeks. Heart hypertrophy, fibrosis and function were evaluated based on echocardiography, histological and biochemical measurements. Mechanically stretched-cardiomyocytes of rats were used for in vitro experiments. The levels of signaling proteins were measured using Western blotting, while the expression of the relevant genes was analyzed using real-time QRT-PCR. Results: TAC induced marked heart hypertrophy and fibrosis, accompanied by high levels of Ang II in plasma and heart, and by PKCβI/α and ERK1/2 phosphorylation in heart. Meanwhile, TAC induced autophagic responses in heart, i.e. increases in autophagic structures, expression of Atg5 and Atg16 L1 mRNAs and LC3-II and Beclin-1 proteins. These pathological alterations in TAC-mice were significantly ameliorated or blocked by ALK administration. In TAC-mice, 3-methyladenine administration also ameliorated heart hypertrophy, fibrosis and dysfunction, while LY333531 administration inhibited ERK phosphorylation and autophagy in heart. In mechanically stretched-cardiomyocytes, CGP53353 (a PKCβI inhibitor) prevented ERK phosphorylation and autophagic responses, while U0126 (an ERK inhibitor) blocked autophagic responses. Conclusion: ALK ameliorates heart hypertrophy, fibrosis and dysfunction in the mouse model in setting of chronic pressure overload, via suppressing Ang II-PKCβI-ERK1/2-regulated autophagy.

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“…Angiotensinogen is the only known substrate for renin;2, 5 this renders renin of extreme importance regarding selectivity and enzyme specificity. Mature renin is a 340‐amino acid, pepsin‐like enzyme.…”

Section: Introductionmentioning

confidence: 99%

Conformational Properties and Energetic Analysis of Aliskiren in Solution and Receptor Site

Politi

Leonis

Tzoupis

et al. 2011

Molecular Informatics

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Aliskiren is the first orally active, direct renin inhibitor to be approved for the treatment of hypertension. Its structure elucidation and conformational analysis were explored using 1D and 2D NMR spectroscopy, as well as random search and molecular dynamics (MD) simulations. For the first time, MD calculations have also been performed for aliskiren at the receptor site, in order to reveal its molecular basis of action. It is suggested that aliskiren binds in an extended conformation and is involved in several stabilizing hydrogen bonding interactions with binding cavity (Asp32/255, Gly34) and other binding-cavity (Arg74, Ser76, Tyr14) residues. Of paramount importance is the finding of a loop consisting of residues around Ser76 that determines the entrapping of aliskiren into the active site of renin. The details of this mechanism will be the subject of a subsequent study. Additionally molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) free energy calculations for the aliskiren-renin complex provided insight into the binding mode of aliskiren by identifying van der Waals and nonpolar contribution to solvation as the main components of favorable binding interactions.

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Rationale for Combining a Direct Renin Inhibitor with other Renin- Angiotensin System Blockers. Focus on Aliskiren and Combinations

Cited by 9 publications

References 98 publications

The critical role of the central nervous system (pro)renin receptor in regulating systemic blood pressure

The critical role of the central nervous system (pro)renin receptor in regulating systemic blood pressure

Aliskiren ameliorates pressure overload-induced heart hypertrophy and fibrosis in mice

Conformational Properties and Energetic Analysis of Aliskiren in Solution and Receptor Site

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