Ang II, the primary effector pleiotropic hormone of the renin-angiotensin system (RAS) cascade, mediates physiological control of blood pressure and electrolyte balance through its action on vascular tone, aldosterone secretion, renal sodium absorption, water intake, sympathetic activity and vasopressin release. It affects the function of most of the organs far beyond blood pressure control including heart, blood vessels, kidney and brain, thus, causing both beneficial and deleterious effects. However, the protective axis of the RAS composed of ACE2, Ang (1-7), alamandine, and Mas and MargD receptors might oppose some harmful effects of Ang II and might promote beneficial cardiovascular effects. Newly identified RAS family peptides, Ang A and angioprotectin, further extend the complexities in understanding the cardiovascular physiopathology of RAS. Most of the diverse actions of Ang II are mediated by AT1 receptors, which couple to classical Gq/11 protein and activate multiple downstream signals, including PKC, ERK1/2, Raf, tyrosine kinases, receptor tyrosine kinases (EGFR, PDGF, insulin receptor), nuclear factor κB and reactive oxygen species (ROS). Receptor activation via G12/13 stimulates Rho-kinase, which causes vascular contraction and hypertrophy. The AT1 receptor activation also stimulates G protein-independent signaling pathways such as β-arrestin-mediated MAPK activation and Src-JAK/STAT. AT1 receptor-mediated activation of NADPH oxidase releases ROS, resulting in the activation of pro-inflammatory transcription factors and stimulation of small G proteins such as Ras, Rac and RhoA. The components of the RAS and the major Ang II-induced signaling cascades of AT1 receptors are reviewed.
Matched MeSH terms: Receptor, Angiotensin, Type 2/metabolism
An earlier study showed that des-aspartate-angiotensin I (DAA-I) attenuated the pressor action of angiotensin III in aortic rings of the spontaneously hypertensive rat (SHR) but not the normotensive Wistar Kyoto (WKY) rat. The present study investigated similar properties of DAA-I in isolated perfused kidneys and mesenteric beds of WKY and SHR. In the renal vasculature, angiotensin III induced a dose-dependent pressor response, which was more marked in the SHR than WKY in terms of significant greater magnitude of response and lower threshold. DAA-I attenuated the pressor action of angiotensin III in both the WKY and SHR. The attenuation in SHR was much more marked, occurring at doses as low as 10(-15) M DAA-I, while effective attenuation was only seen with 10(-9) M in WKY. The effects of DAA-I was not inhibited by PD123319 and indomethacin, indicating that its action was not mediated by angiotensin AT2 receptors and prostaglandins. However, the direct pressor action of angiotensin III in the SHR but not the WKY was attenuated by indomethacin suggesting that this notable difference could be due to known decreased response of renal vasculature to vasodilator prostaglandins in the SHR. Pressor responses to angiotensin III in the mesenteric vascular bed was also dose dependent, but smaller in magnitude compared to the renal response. The responses in the SHR, though generally smaller, were not significantly different from those of the WKY. This trend is in line with the similar observations with angiotensin III and II by other investigators. In terms of the effect of DAA-I, indomethacin and PD123319 on angiotensin III action, similar patterns to those of the renal vasculature were observed. This reaffirms that in the perfused kidney and mesenteric bed, where the majority of the vessels are contractile, femtomolar concentrations of DAA-I attenuates the pressor action of angiotensin III. The attenuation is not indomethacin sensitive and does not involve the angiotensin AT2 receptor. The findings suggest that DAA-I possesses protective vascular actions and is involved in the pathophysiology of hypertension.
Matched MeSH terms: Receptor, Angiotensin, Type 2/metabolism