Figure 1.

Schematic presentation of the molecular and blood pressure responses elicited by peripheral NMDAR activation. This model is based on our reported findings in male conscious Sprague-Dawley rats.^42,59,118 The peripheral NMDAR can be activated by its ligands, glutamate or NMDA. NMDAR blockade with antagonists, AP-5 or ethanol attenuates peripheral NMDAR-mediated cardiovascular responses. Following activation, Ca²⁺ influx occurs and multiple signaling cascades are triggered: 1) PI3K-Akt signaling, 2) NOX activation and 3) PKC activation. PI3K-Akt signaling increased nNOS phosphorylation leading to NO generation, which in turn contributes to ROS generation within the vasculature and vasoconstriction. This signaling is inhibited at multiple points within the pathway by either PI3K inhibitor, wortmannin or nitric oxide synthase (NOS) inhibitors, N (ω)-propyl-L-arginine (NPLA) or N(ω)-nitro-L-arginine methyl ester (L-NAME). Peripheral NMDAR activation also activates NOX leading to ROS generation and vasoconstriction; nonspecific NOX inhibitor, apocynin attenuates these responses. Activation of PKC mediates the phosphorylation of NOS leading to NO generation, which contribute to downstream ROS generation and vasoconstriction. Inhibition of PKC with chelerythrine reduces vascular NO and ROS generation and NOX activation as well as the pressor response elicited by peripheral NMDAR activation.