Abstract 9395: Oxidative Stress Impairs Desensitization of the G-Protein Coupled Receptors (GPCRs) and Increases Vascular Reactivity by Prolonging the Contractile Responses in the Cerebral Arteries After Subarachnoid Hemorrhage
Cerebral vasospasm is a critical determinant in the prognosis of subarachnoid hemorrhage (SAH). Increased vascular reactivity plays a key role in cerebral vasospasm. Not only enhanced contraction, but also prolonged contraction are characteristic of cerebral vasospasm. The up-regulation of GPCRs, including thrombin receptor PAR1, contributes to enhanced contraction. The present study addressed the hypothesis that changes in the mechanisms regulating the activity of GPCRs contribute to a prolonged vascular reactivity. This study used a rabbit double SAH model. PAR1-activating peptide (PAR1AP) induced a transient contraction in the control basilar arteries, while it induced an enhanced and sustained contraction in SAH. When sequentially applied, the second stimulation of PAR1AP induced 75% of the first response, while it induced an 8% response in the controls. Thrombin induced an enhanced and sustained contraction in SAH. Notably, the thrombin-induced contraction persisted irreversibly even after terminating thrombin stimulation. The responses to angiotensin II, vasopressin, and PGF2α were also enhanced and prolonged to varying degrees after SAH. These observations suggested that, in addition to receptor up-regulation, the mechanism for the desensitization of GPCRs was impaired during SAH. Intrathecal treatment with argatroban, a thrombin inhibitor, prevented the enhancement of the response to PAR1 agonists in SAH. However, PAR1AP still induced a sustained response, the reactivity to the second stimulation was maintained, and thrombin induced an irreversible contraction. Addition of vitamin C or tempol to argatroban restored a transient response, tachyphylactic attenuation, and reversibility of thrombin response. The level of oxidative stress in the brain tissues increased after SAH, and it was normalized by either argatroban or vitamin C. The results suggest that oxidative stress impairs the desensitization of GPCRs, thus prolonging vascular reactivity after SAH. The impaired desensitization significantly influenced the activity of PAR1, thereby causing irreversible contraction. Combined thrombin inhibition and anti-oxidative agents is therefore considered to be a novel strategy to normalize vascular reactivity.
- © 2011 by American Heart Association, Inc.