ABSTRACT
In the brief history of time since renin was fust discovered in 1898 by Tiegerstedt and Bergman we can trace the slow realization that the product of renin activity has a role in human physiology and cardiova cular disease. It took 40 years after the discovery of renin, to discover the octapeptide, angioten in II (Ang II). A flurry of paper from lab in Cleveland and Argentina independently named the same pre or ubstance ' hypertensin' (Page and Helmer, 1940) and 'angiotonin' (Munoz et al. , 1939) which became, by agreement, 'angiotensin '. It took more than a decade to work out the cascade of the renin-angiotensin system (RAS) (Elliott and Peart, 1956; Skegg et al. , 1957; Gros , 1960). By the 1960s the tory seemed to be complete, at lea t in explaining the effect on blood pres ure and sodium balance. The theory of renin-angioten in formation involving the kidney, liver and lung became a practical one for the treatment of hyperten ion. In science, however, no field i an i land. Cros -perfusion experiment in dogs showed that Ang ll could timulate the central nervou system, producing an increase in peripheral blood pre sure (Bickerton and Buckley, 1961). By the 1970 , when peptide in the gut were al o being found in the brain and receptor binding technique had become available, a coincidence of research intere t independently arrived at the arne conclu ion - that there was a RAS in the brain. Binding tudie of Ang II in the brain by Sirret et al. ( 1977) in ew Zealand, direct injection experiment in Cambridge with Ang II producing thir t (Fitzsimons, 1972), and indirect mea urements of brain renin in Montreal Address for correspondence: M. fan Phillips, Deparrmelll of Physiology, Box 100274, College of Medicine, University of Florida, Gainesville, FL 32610. Tel: (352)-392-7730. Fax: (352)-392-8340. Email: MIP @phys.med.ufl.edu
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Figure I. Tissue renin-angiotensin system (RAS). The brain RAS has a paracrine action. There are synthesizer cells and effector cells. The synthesizer cells may involve both neurons and glial cells, as in some parts of the brain, including the hypothalamus, angiotensinogen mRNA appears to be specifically located in glial cells. Angiotensin-convening enzyme (ACE) is an exoenzyme so that conversion of angiotensin Ito angiotensin II by A E must occur outside the cell. This means that either Ang U is taken up into neurons or formed internally by a non-ACE mechanism. Detectable in brain extracts are angiotensin 1-7 (Ang-1-7), Ang Ill and Ang IV [Ang-(4-8)). The effector cell, which is represented here as a neuron, has multiple AT1 receptor subtypes. These vary in density among different cells. Stimulation of these receptors produces ionic and calcium changes that lead to secretion of neurotransmjtters.
