Attenuated Desensitization of β-Adrenergic Receptor by Water-Soluble N-Nitrosamines That Induce S-Nitrosylation Without NO Release

Rationale:The clinical problem of loss of β-adrenergic receptor (β-AR) response, both in the pathogenesis of heart failure and during therapeutic application of β-agonists, is attributable, at least in part, to desensitization, internalization, and downregulation of the receptors. In the regulation of β-AR signaling, G protein–coupled receptor kinase 2 (GRK2) primarily phosphorylates agonist-occupied β-ARs, and this modification promotes desensitization, internalization, and downregulation of β-ARs. It has been demonstrated that GRK2 is inhibited by its S-nitrosylation. However, compounds that induce S-nitrosylation, such as S-nitrosoglutathione, simultaneously generate NO, which has been demonstrated to operate for cardiovascular protection. Objective:We examine whether S-nitrosylation without NO generation inhibits desensitization of β2-AR by GRK2. We thus aim to synthesize compounds that specifically induce S-nitrosylation. Methods and Results:We have developed water-soluble N-nitrosamines that have S-...