Tissue angiotensin II generating system by angiotensin-converting enzyme and chymase

It had been believed that angiotensin II (Ang II) was produced by the renin-angiotensin system (RAS), which was established in the 1950's. After a while, people realized that the multiple functions of Ang II could not be explained by the conventional RAS. We have tried to determine the existence of the tissue Ang II generating system. At first, we found that vascular angiotensin-converting enzyme (ACE) was increased to generate local Ang II in the vessels of hypertension and was enhanced in lipid-loaded atherosclerosis, to respond to ACE inhibitor or Ang II antagonist (ARB). In both cases, Ang II production in vessels was independent from the systemic RAS that was estimated by the plasma renin activity. On the way to clarifying the roles of the vascular ACE, we noticed that vascular Ang II production was not completely suppressed by ACE inhibitor alone. This evidence led us to discover different types of chymase as a new Ang II producing enzyme. Now, we have obtained a strategy to distinguish the Ang II one by one, that is, circulating RAS derived, tissue ACE derived, and chymase derived. It is essential to understand not only the intracellular mechanisms of Ang II but also the process of Ang II productions in each disease to show accurate indications of the effectiveness of ACE inhibitor, ARB, and chymase inhibitor.