Imbalance of angiotensin receptor expression and function in the RVLM:Potential mechanism of sympathetic overactivity in CHF rat


ZUCKER Irving H;


<正>Upregulation of AT1R in the rostral ventrolateral medulla(RVLM)contributes to the sympathetic overactivity in the chronic heart failure(CHF)state.However,the role of the AT2R is not clear.In the current study,we measured both AT1R and AT2R protein expression in the RVLM and determined the effects of activating RVLM AT1R and AT2R on renal sympathetic nerve activity(RSNA),BP,and HR in anaesthetized sham and CHF rats.We found that:(1)while AT1R protein expression in the RVLM was up regulated(CHF:0.83±0.07 vs sham:0.32±0.05, P<0.05),the AT2R was significantly down regulated(CHF:0.06±0.02 vs sham:0.15±0.02,P<0.05)increasing the ratio of AT1R to AT2R in the RVLM of CHF rats(AT1R/AT2R:13.8±0.7 in CHF vs 2.1±0.4 in sham,P<0.05);(2) simultaneously stimulating AT1R and AT2R by AngⅡevoked a sympatho-excitation,hypertension,and tachycardia in both sham and CHF rats,with greater responses in CHF rats[RSNA:(235.3±11.6)%of baseline in CHF vs (146.7±9.4)%of baseline in normal,P<0.05];(3)stimulating RVLM AT1R with AngⅡplus the specific AT2R antagonist PD123319 induced a larger sympatho-excitatory response than simultaneously stimulating AT1R and AT2R in sham rats[RSNA:(193.2±6.8)%of baseline in stimulating AT1R vs(146.7±9.4)%of baseline when stimulating both AT1R and AT2R,P<0.05),but not in CHF rats;(4)activating RVLM with the AT2R agonist CGP42112 induced a sympatho-inhibition,hypotension,and bradycardia only in sham rats[RSNA:(36.4±5.1)%of baseline vs(102±3.9)%of baseline in aCSF,P<0.05),but not in CHF rats;(5)pretreatment with ETYA,a general inhibitor of AA metabolism,into the RVLM partially abolished the CGP42112 induced sympatho-inhibition.These results suggest that,in contrast to AT1R,AT2R in the RVLM exhibits an inhibitory effect on sympathetic outflow, which is partially mediated by the PLA2/AA/12-LO metabolites of the AA/PP-2A pathway.The data implicate a downregulation in the AT2R as a contributory factor in the sympatho-excitation in CHF.


rostral ventrolateral medulla;;angiotensin type 1 receptor;;renal sympathetic nerve activity;;chronic heart failure.


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