The renin-angiotensin system (RAS) is critical for the control of blood pressure (BP) and salt balance in mammals. Studies reveal that local RAS are present in the rat brain and renin is the first effector of the brain RAS for generating angiotensin II (Ang II) which exerts diverse physiological actions in both peripheral and central nervous system. The existence of renin within the brain has now been demonstrated by numerous studies. Previous studies suggest that renin may go through angiotensin-dependent and independent pathway to influence vascular tone, by Ang II type 1 receptor (AT1R) and renin specific (pro)renin receptor (PRR), respectively. Studies also indicate that AT1R and PRR are highly expressed in the nucleus tractus solitarii (NTS), which is important for central feedback regulation of BP. Further studies have shown that Ang II contributes to the release of NO, which plays an important role in cardiovascular regulation in the NTS. These results indicate that renin plays cardiovascular modulatory role in the NTS. However, the mechanisms how renin modulate cardiovascular functions in the NTS remained unclear. In the present study, I investigated the molecular mechanisms of renin-induced cardiovascular effects in the NTS. Unilateral microinjection of renin into the NTS of WKY rats produced prominent depressor and bradycardic effects. Pretreatment with a non-selective NOS inhibitor L-NAME, eNOS specific inhibitor L-NIO, Akt inhibitor IV, and PI3K inhibitor LY294002 significantly attenuated the cardiovascular response evoked by renin, whereas nNOS specific inhibitor Vinyl-L-NIO and MEK inhibitor PD98059 did not cause significant changes. Western blot studies showed renin increased eNOSS1177 and AktS473 phosphorylation instead of nNOSS1416 and ERK1/2T202/Y204 phosphorylation, and pretreatment with LY294002 blocked renin-induced eNOSS1177 and AktS473 phosphorylation. These results indicated that renin might go through PI3K-Akt-eNOS pathway to increase eNOS activity and ultimately result in NO release. The cardiovascular effects of renin were also attenuated by renin specific inhibitor aliskiren, angiotensin converting enzyme inhibitor lisinopril, AT1R antagonist losartan, and intracellular Ca2+ chelator, BAPTA-AM instead of G protein £]£^ subunit inhibitor gallein, PLC inhibitor U73122, calmodulin inhibitor (W-7) and (pro)renin receptor blocker, handle region peptide. These results indicated that renin mainly through AT1R to regulate BP. Therefore, my results indicated that the modulation of cardiovascular effects of renin in the NTS involves AT1R-PI3K-Akt pathway to activate eNOS activation.
| Identifer | oai:union.ndltd.org:NSYSU/oai:NSYSU:etd-0907110-165256 |
| Date | 07 September 2010 |
| Creators | Hsiao, Chun-Hui |
| Contributors | Pei-Jung Lu, Ching-Jiunn Tseng, Yow-Ling Shiue, Long-Sen Chang, Michael Hsiao |
| Publisher | NSYSU |
| Source Sets | NSYSU Electronic Thesis and Dissertation Archive |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0907110-165256 |
| Rights | not_available, Copyright information available at source archive |
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