The renin‐angiotensin system – a functional ‘jack‐of‐all‐trades’

It is now more than two and a half century that blood pressure was measured for the first time by Stephen Hales in a dramatic experiment on a horse. About 150 years later, in 1897, the discovery of a pressor principle by Robert Tigerstedt and Per Bergman gave the first insight into the regulation of blood pressure when they described a substance from rabbit kidney extracts that increased blood pressure when injected into rabbits. They named this unknown pressor agent renin (de Gasparo et al. 2000). This pioneering work was published in the Scandinavian Archives of Physiology and, today, the 49-page article is considered as possibly Tigerstedts most important scientific contribution (Hirvonen & Timijorn 1990). The next three decades were characterized by stagnation until the 1930s when Harry Goldblatt reported his now classic experiments on renal hypertension (Laragh & Brenner 1995). In 1934, his first article was published in which he referred to an artificial production of persistent hypertension by uniand bilateral constriction of the renal arteries in dogs. On the one hand, Goldblatts experiments lead to the first description of secondary renovascular hypertension in animals and in humans, and on the other hand, this extensive work stimulated the international research in hypertension (Goldblatt et al. 1934). However, the next major step came in the 1940s when similar findings were made from the groups of Irvine Page and Eduardo Braun-Menendez (Braun-Menendez et al. 1940). Both groups independently showed that renin is an enzyme that forms a pressor polypeptide from a plasma globulin when released to the blood stream (Laragh & Brenner 1995). The pressor substance was named ‘hypertensin’ in Argentina and ‘angiotonin’ in the United States. First, there were a lot of differences between laboratories concerning interpretations and nomenclature, but in the end, both groups agreed that hypertensin and angiotonin were the same substance and ‘angiotensin’ was born. After this important discovery, the several components of the classical renin-angiotensin system (RAS) cascade leading to the generation of angiotensin II were characterized, including angiotensinogen, angiotensin-converting enzyme (ACE) and angiotensins I, II and III (de Gasparo et al. 2000). The RAS is a coordinated endocrine system that plays a key role in blood pressure control and fluid volume homoeostasis. Moreover, the systemic RAS and many local renin-angiotensin systems contribute to a variety of physiological and pathophysiological processes, including vascular hypertrophy, cardiac remodelling and renal fibrosis (de Gasparo et al. 2000). If you have a look at PubMed results when you are searching for ‘renin-angiotensin system’ or ‘angiotensin’, the overwhelming majority will consist of cardiovascular-related research or angiotensin II, the main effector peptide of the RAS, related experimental work. The publications in Acta Physiologica (Oxf) concerning the RAS show a similar picture as shown by the following examples: in 2011, Rajapakse NW and colleagues showed that an intact renal l-arginine transport attenuates the vasoconstrictor effects of circulating angiotensin II in the renal cortex in SpragueDawley rats. They also found that l-arginine plays an important role in protecting the renal medullary circulation from the ischaemic effects of angiotensin II in Dahl salt-sensitive rats (Rajapakse & Mattson 2011). Investigations of several groups demonstrated synergistic interactions between adenosine and angiotensin II in the control of renal perfusion (Weihprecht et al. 1994). In this context, studies also showed that adenosine is able to accelerate re-sensitization of isolated rat afferent arterioles, which may contribute to renal autoregulation via tubuloglomerular feedback (Lai et al. 2006). However, a recent study in Acta Physiologica (Oxf) demonstrated that adenosine did not enhance angiotensin II-induced contractions in afferent arterioles from two-kidney, one-clip (2K1C) hypertensive rats (Dahl et al. 2011). The finding indicates that the adenosine–angiotensin II interaction is modified in this model of hypertension. With regard to the endothelium, another strong point of our journal (Bidwell et al. 2010, Malmstrom et al. 2010, Whyte & Laughlin 2010, Xu et al. 2012), Martini et al. focused on the endothelial functional role of T-type calcium channel-dependent calcium under angiotensin II stimulation. Their data clearly showed that angiotensin II, via the AT1 receptor, modulates calcium concentration involving T-type calcium channel, but only the calcium influx via T-type calcium channels regulates endothelial cell migration, which is essential for angiogenesis (Martini et al. 2010). Among the impressive studies investigating physiological and pathological cardiac remodelling (Daniels et al. 2010), one studied the induction by pregnancy and angiotensin II, respectively, and showed that pregnancy