S-nitrosoglutathione inhibits cerebrovascular angiotensin II-dependent and -independent AT receptor responses: A possible role of S-nitrosation.

BACKGROUND AND PURPOSE

Angiotensin II (AngII) and NO regulate the cerebral circulation. AngII AT 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 AT 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 AT receptors was evaluated by obtaining concentration-response curves to AngII. Ligand-independent activation of AT 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 AT receptor inverse agonist.

KEY RESULTS

GSNO or SNP completely abolished the AngII-dependent AT 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 AT 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 AT receptor and reduces both AngII-dependent and AngII-independent activation, most likely through AT receptor S-nitrosation.