Vascular PI3K‐Akt Signaling Contributes to Peripheral NMDAR‐mediated Pressor Response in Conscious Rats

Abstract

Evidence has implicated the PI3K‐Akt‐NOS signaling pathway in neuronal responses mediated via NMDAR activation. The involvement of this pathway in the peripheral NMDAR‐mediated pressor response is unknown. We tested the hypothesis that vascular PI3K‐Akt‐NOS signaling contributes to NO and ROS generation and the subsequent pressor response mediated by peripheral NMDAR activation. Hemodynamic studies were conducted in conscious male Sprague Dawley rats that were pretreated with the selective inhibitor of: (i) eNOS, N5‐(1‐iminoethyl)‐l‐ornithine (L‐NIO), (ii) nNOS, Nw‐propyl‐l‐arginine (NPLA) or (iii) the upstream PI3K‐Akt inhibitor, Wortmannin. L‐NIO produced no change while NPLA pretreatment significantly attenuated the NMDA‐mediated pressor response. These findings are the first to implicate nNOS‐derived NO in the peripheral NMDAR signaling. Pretreatment with the PI3K inhibitor, Wortmannin significantly suppressed the NMDA mediated pressor response and the associated increases in vascular nitrate and reactive oxygen species levels. Collectively, these novel findings suggest that activation of the PI3k‐Akt‐nNOS signaling pathway serves as a molecular mechanism for the peripheral NMDAR‐mediated pressor response in conscious rats [NIH grant AA07839].