Renin angiotensin aldosterone inhibition in the treatment of cardiovascular disease

Abstract

A collective century of discoveries establishes the importance of the renin angiotensin aldosterone system in maintaining blood pressure, fluid volume and electrolyte homeostasis via autocrine, paracrine and endocrine signaling. While research continues to yield new functions of angiotensin II and angiotensin-(1-7), the gap between basic research and clinical application of these new findings is widening. As data accumulates on the efficacy of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers as drugs of fundamental importance in the treatment of cardiovascular and renal disorders, it is becoming apparent that the achieved clinical benefits is suboptimal and surprisingly no different than what can be achieved with other therapeutic interventions. We discuss this issue and summarize new pathways and mechanisms effecting the synthesis and actions of angiotensin II. The presence of renin-independent non-canonical pathways for angiotensin II production are largely unaffected by agents inhibiting renin angiotensin system activity. Hence, new efforts should be directed to develop drugs that can effectively block the synthesis and/or action of intracellular angiotensin II. Improved drug penetration into cardiac or renal sites of disease, inhibiting chymase –the primary angiotensin II forming enzyme in the human heart–, and/or inhibiting angiotensinogen synthesis would all be more effective strategies to inhibit the system. Additionally, given the role of angiotensin II in the maintenance of renal homeostatic mechanisms, any new inhibitor should possess greater selectivity of targeting pathogenic angiotensin II signaling processes and thereby limit inappropriate inhibition.

Blood Pressure Lowering and Safety Improvements With Liver Angiotensinogen Inhibition in Models of Hypertension and Kidney Injury

“…It should be noted that previous reports of blood pressuring lowering with AGT inhibition using RNA-based approaches have been described 24,25 ; however, these studies have an important limitation because of their use of SHRs, a model that already displays robust antihypertensive responses to standard RAAS blockade. In addition, the early ASO studies reported only 40% to 50% maximal reductions of plasma AGT, 26 which would not have been predicted to elicit maximal BP reductions. Thus, the studies described herein are the first demonstration of the pharmacology of Plasma AGT levels are close to the Michaelis-Menten constant (K m ) of renin; thus, plasma Ang I formation is dependent on both AGT and renin.…”

Induction of LOX by TGF‐β1/Smad/AP‐1 signaling aggravates rat myocardial fibrosis and heart failure

“…RAAS activation is involved in the development of heart failure and is one of the main factors contributing to ventricular remodeling. Effective blockade of the RAAS is important for improving heart failure and ventricular remodeling in heart failure . Evidence has indicated the reciprocal interaction between LOX and RAAS in cardiovascular diseases.…”

“…In addition, CHF is characterized by overactivation of the renin‐angiotensin‐aldosterone system (RAAS), which plays an important role in the development of heart failure . Evidence indicates that the blockade of the RAAS is effective for the treatment for heart failure …”

The Second Gaddum Lecture: its origins and outcomes

“…Thus, two of the major advances in clinical medicine over the last 50 years can be traced back to the work described in Vane's Gaddum Lecture. It is worth noting that both lowdose aspirin (Bibbins-Domingo, 2016;Iacono et al, 2019;Seidu et al, 2019) and the RAS inhibitors (Ferrario & Mullick, 2017;Esser & Zraika, 2019;. Stolfo & Savarese, 2019) are still providing clinical benefit to many millions of patients worldwide.…”