Activation of PI3K/Akt signaling, leading to upregulation of
nitric oxide synthase II (
NOS II)/
peroxynitrite cascade in the rostral ventrolateral medulla (RVLM), the brain stem site that maintains blood pressure and sympathetic vasomotor tone, underpins cardiovascular depression induced by the
organophosphate pesticide mevinphos. By exhibiting dual-specificity
protein- and
lipid-
phosphatase activity,
phosphatase and
tensin homolog (PTEN) directly antagonizes the PI3K/Akt signaling by dephosphorylation of phosphatidylinositol-3,4,5-trisphosphate, the
lipid product of PI3K. Based on the guiding hypothesis that PTEN may sustain brain stem cardiovascular regulation during
mevinphos intoxication as a negative regulator of PI3K/Akt signaling in the RVLM, we aimed in this study to clarify the mechanistic role of PTEN in
mevinphos-induced circulatory depression. Microinjection bilaterally of
mevinphos (10 nmol) into the RVLM of anesthetized Sprague-Dawley rats induced a progressive
hypotension and a decrease in baroreflex-mediated sympathetic vasomotor tone. There was progressive augmentation in PTEN activity as reflected by a decrease in the oxidized form of PTEN in the RVLM during mevinhpos intoxication, without significant changes in the
mRNA or
protein level of PTEN. Loss-of-function manipulations of PTEN in the RVLM by immunoneutralization, pharmacological blockade or
siRNA pretreatment significantly potentiated the increase in Akt activity or
NOS II/
peroxynitrite cascade in the RVLM, enhanced the elicited
hypotension and exacerbated the already reduced baroreflex-mediated sympathetic vasomotor tone. We conclude that augmented PTEN activity via a decrease of its oxidized form in the RVLM sustains brain stem cardiovascular regulation during
mevinphos intoxication via downregulation of the
NOS II/
peroxynitrite cascade as a negative regulator of PI3K/Akt signaling.