BACKGROUND AND PURPOSE: Angiotensin II (AngII) and NO regulate the cerebral circulation. AngII AT1 receptors exert ligand-dependent and ligand-independent (myogenic tone [MT]) vasoconstriction of cerebral vessels. NO induces post-translational modifications of proteins such as S-nitrosation (redox modification of cysteine residues). In cultured cells, S-nitrosation decreases AngII's affinity for the AT1 receptor. The present work evaluated the functional consequences of S-nitrosation on both AngII-dependent and AngII-independent cerebrovascular responses. EXPERIMENTAL APPROACH: S-Nitrosation was induced in rat isolated middle cerebral arteries by pretreatment with the NO donors, S-nitrosoglutathione (GSNO) or sodium nitroprusside (SNP). Agonist-dependent activation of AT1 receptors was evaluated by obtaining concentration-response curves to AngII. Ligand-independent activation of AT1 receptors was evaluated by calculating MT (active vs. passive diameter) at pressures ranging from 20 to 200 mmHg in the presence or not of a selective AT1 receptor inverse agonist. KEY RESULTS: GSNO or SNP completely abolished the AngII-dependent AT1 receptor-mediated vasoconstriction of cerebral arteries. GSNO had no impact on responses to other vasoconstrictors sharing (phenylephrine, U46619) or not (5-HT) the same signalling pathway. MT was reduced by GSNO, and the addition of losartan did not further decrease MT, suggesting that GSNO blocks AT1 receptor-dependent MT. Ascorbate (which reduces S-nitrosated compounds) restored the response to AngII but not the soluble GC inhibitor ODQ, suggesting that these effects are mediated by S-nitrosation rather than by S-nitrosylation. CONCLUSIONS AND IMPLICATIONS: In rat middle cerebral arteries, GSNO pretreatment specifically affects the AT1 receptor and reduces both AngII-dependent and AngII-independent activation, most likely through AT1 receptor S-nitrosation.
BACKGROUND AND PURPOSE:Angiotensin II (AngII) and NO regulate the cerebral circulation. AngIIAT1 receptors exert ligand-dependent and ligand-independent (myogenic tone [MT]) vasoconstriction of cerebral vessels. NO induces post-translational modifications of proteins such as S-nitrosation (redox modification of cysteine residues). In cultured cells, S-nitrosation decreases AngII's affinity for the AT1 receptor. The present work evaluated the functional consequences of S-nitrosation on both AngII-dependent and AngII-independent cerebrovascular responses. EXPERIMENTAL APPROACH: S-Nitrosation was induced in rat isolated middle cerebral arteries by pretreatment with the NO donors, S-nitrosoglutathione (GSNO) or sodium nitroprusside (SNP). Agonist-dependent activation of AT1 receptors was evaluated by obtaining concentration-response curves to AngII. Ligand-independent activation of AT1 receptors was evaluated by calculating MT (active vs. passive diameter) at pressures ranging from 20 to 200 mmHg in the presence or not of a selective AT1 receptor inverse agonist. KEY RESULTS:GSNO or SNP completely abolished the AngII-dependent AT1 receptor-mediated vasoconstriction of cerebral arteries. GSNO had no impact on responses to other vasoconstrictors sharing (phenylephrine, U46619) or not (5-HT) the same signalling pathway. MT was reduced by GSNO, and the addition of losartan did not further decrease MT, suggesting that GSNO blocks AT1 receptor-dependent MT. Ascorbate (which reduces S-nitrosated compounds) restored the response to AngII but not the soluble GC inhibitor ODQ, suggesting that these effects are mediated by S-nitrosation rather than by S-nitrosylation. CONCLUSIONS AND IMPLICATIONS: In rat middle cerebral arteries, GSNO pretreatment specifically affects the AT1 receptor and reduces both AngII-dependent and AngII-independent activation, most likely through AT1 receptor S-nitrosation.
Authors: Guido Boerrigter; David G Soergel; Jonathan D Violin; Michael W Lark; John C Burnett Journal: Circ Heart Fail Date: 2012-08-13 Impact factor: 8.790
Authors: Stephen Ph Alexander; Arthur Christopoulos; Anthony P Davenport; Eamonn Kelly; Neil V Marrion; John A Peters; Elena Faccenda; Simon D Harding; Adam J Pawson; Joanna L Sharman; Christopher Southan; Jamie A Davies Journal: Br J Pharmacol Date: 2017-12 Impact factor: 8.739