Cardiovascular studies of AT2 receptor in various pathophysiological settings

Sanja Bosnyak
The renin angiotensin system (RAS) plays an important role in blood pressure regulation and its importance in cardiovascular disease has been well researched. Hypertension is a major risk factor for the development of cardiovascular disease and the RAS is a chief regulator of arterial pressure. The main hormone of RAS, the octapeptide angiotensin II (Ang II), exerts its actions through stimulation of two major receptor subtypes, the angiotensin type-1 receptor (AT1R) and the angiotensin type-2
more » ... angiotensin type-2 receptor (AT2R). The focus of current literature has been on the activation of the Ang II-AT1R axis and the unfavourable effects in cardiovascular pathology. However, shorter peptide fragments of Ang II are thought to have biological activity in their own right and elicit effects that oppose those mediated by Ang II by stimulating other RAS receptors such as AT2R. Given that hypertension is well established in aged populations, it is of particular interest to determine role of the AT2R in this setting. Additionally, it has been hypothesized that females have a greater vasodilator component of the RAS than males, which may contribute to sex differences in the rates of cardiovascular disease. Therefore, aspects of this thesis explored the function of AT2R stimulation with particular attention directed towards the influence of age and sex. In Chapter 2, HEK-293 cells stably transfected with either the AT1R or the AT2R were used to perform a systematic analysis of binding affinities of all the major Ang peptides. Additionally, the novel AT2R agonist, Compound 21, as well as the MasR agonist and antagonist, AVE0991 and A779 respectively, were tested for their ability to bind to the AT1R or the AT2R. Candesartan, CGP42214 and PD123319 were used as reference compounds. Binding studies using [125I]- Sar1Ile8Ang II in AT1R transfected HEK-293 cells revealed only Ang II, Ang III and candesartan to have high affinity for AT1R. In AT2R transfected HEK-293 cells, blood pressure in adult normotensive rats via AT2R. However, in aged rats, [...]
doi:10.4225/03/589015aec33db fatcat:vb2euchhdjfhlosilhwk6nos4m