engleski

Permissive role of angiotensin II in maintaining microvascular reactivity to physiological stimuli

OBJECTIVE: A number of data suggest, rather controversial, permissive role of angiotensin II (ANGII) in maintaining vasodilator responses in microcirculation. In CSF grant: V-ELI Athero, #IP-2014-09-6380, we aimed to elucidate the effect of RAS restoration on the mechanisms of flow-induced dilation and incidence of oxidative stress in the cerebral vasculature of Sprague-Dawley rats on HS diet. DESIGN AND METHOD: Eleven-week old, male Sprague-Dawley rats were divided to control group (0.4% NaCl in rat chow) ; HS group (7 days 4% NaCl in rat chow) ; Losartan group (rats on a standard diet given AT1R blocker losartan (1 mg/mL)) ; or HS+ANGII group (7 days HS with 3 days ANGII via osmotic minipumps (100 ng/kg/min on days 4–7)). FID of MCA was determined in absence/presence of indomethacin, L-NAME, and TEMPOL. Gene and protein expression of enzymes involved in FID mechanisms and antioxidative enzymes were determined by RT-qPCR and Western blot. Direct fluorescence was used for vascular NO and superoxide/ROS levels measurements. All experimental procedures conformed to the EU Directive 2010/63/EU. RESULTS:All rats remained normotensive. HS or AT1R blockade impaired FID and increased oxidative stress. Supplementation of ANGII restored the mechanisms of FID in MCA of rats fed HS diet to the ones present in control rats by decreasing systemic oxidative stress, increasing NO bioavailability and decreasing superoxide/ROS levels in the vasculature. The AT1R blockade resulted in attenuated and altered mechanisms of FID, increased systemic and vascular oxidative stress and decreased expression/activity of antioxidative enzymes. CONCLUSION: Suppression of ANGII is a key link between HS intake and development of endothelial dysfunction. The results provide evidence for the new paradigm of crucial role of normally modulated RAS in the preservation of vascular oxidative stress-antioxidant system balance and, and in maintenance of physiological vasodilation mechanisms of MCA via AT1R.

angiotenzin II ; Sprague-Dawley rats ; FID ; high salt diet

Acknowledgements: This study was supportedby Croatian Science Fundation grant: V-ELI Athero, #IP-2014-09-6380 and by the Faculty of Medicine Osijek Institutional grant IP-1- MEFOS (2020; PI Ines Drenjančević), IP3-MEFOS (2021; PI Ines Drenjančević),