Angiotensin-(1-7) inhibits neuronal activity of dorsolateral periaqueductal gray via a nitric oxide pathway

The midbrain periaqueductal gray (PAG) is a neural site for several physiological functions related to cardiovascular regulation, pain modulation and behavioral reactions. Recently, angiotensin-(1-7) [Ang-(1-7)] has been considered as an important biologically active component of the renin–angiotensin system in the CNS. The purpose of this study was to determine (1) existence of Ang-(1-7) receptor, Mas-R, within the dorsolateral PAG (dl-PAG), (2) the role for Ang-(1-7) in modulating activity of dl-PAG neurons, and (3) the mechanisms by which Ang-(1-7) plays a regulatory role. Western blot analysis showed that Mas-R appears within the dl-PAG. Whole cell patch-clamp recording demonstrated that the discharge rates of dl-PAG neurons were decreased from 4.35 ± 0.32 Hz of control to 1.06 ± 0.34 Hz (P < 0.05, vs. control) by 100 nM of Ang-(1-7). With pretreatment of A-779, a Mas-R inhibitor, the discharge rate was 4.66 ± 0.62 Hz (P > 0.05, vs. control) during infusion of Ang-(1-7). Additionally, neuronal nitric oxide synthase (nNOS) was largely localized within the dl-PAG among the three isoforms. The effects of Ang-(1-7) on neuronal activity of the PAG were attenuated in the presence of S-methyl-L-thiocitrulline (SMTC), a nNOS inhibitor. The discharge rates were 4.21 ± 0.39 Hz in control and 4.09 ± 0⋅47 Hz (P > 0.05, vs. control) when Ang-(1-7) was applied with pretreatment of SMTC. Those findings suggest that Ang-(1-7) plays an inhibitory role in the dl-PAG via a NO dependent signaling pathway. This offers the basis for the physiological role of Ang-(1-7) and Mas R in the regulation of various functions in the CNS.

► The midbrain PAG is a neural site for several physiological functions related to cardiovascular regulation.
► Ang-(1-7) is considered as an important biologically active component of the renin–angiotensin system in the CNS.
► Ang-(1-7) plays an inhibitory role in the periaqueductal gray via a NO dependent signaling pathway.