Physiology of Local Renin-Angiotensin Systems

Abstract

Since the first identification of renin by Tigerstedt and Bergmann in 1898, the renin-angiotensin system (RAS) has been extensively studied. The current view of the system is characterized by an increased complexity, as evidenced by the discovery of new functional components and pathways of the RAS. In recent years, the pathophysiological implications of the system have been the main focus of attention, and inhibitors of the RAS such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin (ANG) II receptor blockers have become important clinical tools in the treatment of cardiovascular and renal diseases such as hypertension, heart failure, and diabetic nephropathy. Nevertheless, the tissue RAS also plays an important role in mediating diverse physiological functions. These focus not only on the classical actions of ANG on the cardiovascular system, namely, the maintenance of cardiovascular homeostasis, but also on other functions. Recently, the research efforts studying these noncardiovascular effects of the RAS have intensified, and a large body of data are now available to support the existence of numerous organ-based RAS exerting diverse physiological effects. ANG II has direct effects at the cellular level and can influence, for example, cell growth and differentiation, but also may play a role as a mediator of apoptosis. These universal paracrine and autocrine actions may be important in many organ systems and can mediate important physiological stimuli. Transgenic overexpression and knock-out strategies of RAS genes in animals have also shown a central functional role of the RAS in prenatal development. Taken together, these findings may become increasingly important in the study of organ physiology but also for a fresh look at the implications of these findings for organ pathophysiology.

Plasma and tissue concentrations of proangiotensin-12 in rats treated with inhibitors of the renin-angiotensin system

“…[1][2][3] By contrast, much less is known about the tissue RAS, and many questions about the angiotensin processing cascade and the role of the tissue RAS in regulating blood pressure and fluid balance remain unanswered. [4][5][6][7] Proangiotensin-12 (proang-12) is a 12-amino acid, C-terminal extended form of Ang I, which we recently isolated from rat small intestine. 8 In vitro, proang-12 constricts aortic strips and, when intravenously infused into rats, raises blood pressure.…”

Present and future pharmacotherapeutic agents in heart failure: an evolving paradigm

“…Despite this trend, elevations in tissue RAAS persist, indicating its critical importance in cardiovascular disease states. Components of the RAAS at a tissue level act in a paracrine or autocrine manner to produce many tissue‐specific effects, including increased vascular tone and cardiac remodelling and fibrosis (Paul et al ., 2006). Indeed, amelioration of chronic tissue RAAS activation is probably more important in the long‐term benefits of neurohormonal blockade than the haemodynamic effects of systemic RAAS blockade (Dzau and Hirsch, 1990).…”

Blood pressure and renal hemodynamic effects of angiotensin fragments

“…1, 8 The RAS was originally regarded as a circulating system; however, the existence of 'local' or 'tissue' RAS has been identified in most organs. 9 ACE is indeed also present in other vascular tissues and organs, including the heart, brain and kidney. Therefore, Ang II can be formed locally in different vascular beds and can exert biological effects independent of blood-borne Ang II.…”