Role of Local Renin Angiotensin Systems in Cardiac Damage

The renin angiotensin system (RAS) recently celebrated its 100th anniversary. In 1898, renin was discovered by Tigerstedt and Bergman in rabbit kidney (Tigerstedt and Bergman, 1898). Renin turned out to be the rate limiting enzyme of a proteolytic cascade leading to the formation of angiotensin (Ang) I and Ang II. In this cascade renin splits the liverderived renin substrate, angiotensinogen (AOGEN), in the plasma to form the decapeptide Ang I (Bader and Ganten, 2000). Ang I is then metabolized further into the octapeptide Ang II via the endotheliumbound angiotensin-converting enzyme (ACE). Ang II is one of the most potent vasopressor substances and releases aldosterone from the adrenal gland. The effects of the peptide are transmitted by two main G-proteincoupled receptors, AT1 and AT2, that were originally defined by the discovery of specific ligands and later confirmed by the cloning of two different genes (Murphy et al., 1991; Sasaki et al., 1991; Kambayashi et al., 1993; Mukoyama et al., 1993). This was the classic view of the RAS. However, with additional research, it became clear that it is not the whole story. The local generation of angiotensin peptides in different tissues was detected mostly even by locally produced precursors and the concept of a tissue-based RAS emerged (Bader et al., 2001). The most obvious example of such a tissue RAS was found in the brain, where AT1 and AT2 receptors have been located beyond the blood–brain barrier not