Abstract TMP113: Oxidative stress and Extracellular Signal-regulated Kinase (ERK) Play a Key Role in Impairment of Receptor Desensitization and Prolongation of Vascular Reactivity in the Cerebral Artery after Subarachnoid Hemorrhage

Abstract

Cerebral vasospasm is a critical determinant in the prognosis of subarachnoid hemorrhage (SAH). The vasospasm is characterized by not only enhanced but also prolonged contraction. The enhanced response is attributable to an increased receptor expression, while a prolonged response is attributable to impaired receptor desensitization. This study addressed this hypothesis and investigated the mechanism underlying a prolonged contraction, using a rabbit SAH model and A7r5 smooth muscle cells. A thrombin receptor (PAR 1 )-activating peptide (PAR 1 AP) induced a transient contraction in the basilar arteries of the control rabbits. The subsequent second stimulation produced 8% of the first response. PAR 1 AP induced an enhanced and prolonged contraction in SAH, and the second stimulation produced a 75% response. Thrombin induced an enhanced and prolonged contraction in SAH. This contraction irreversibly persisted even after terminating thrombin stimulation. The enhancement and prolongation of the contractile response after SAH was further observed with angiotensin II, vasopressin and PGF 2 α. The heparinization of autologous blood or the intrathecal application of a thrombin inhibitor, argatroban, prevented the enhancement of contraction, while they had no effect on the prolongation of the contraction. The addition of vitamin C or tempol to argatroban restored the transient response, tachyphylactic attenuation of the second response and reversibility of thrombin contraction. The amount of malondialdehyde, an indicator of oxidative stress, in the brain tissues increased after SAH, and this increase was prevented by either argatroban or vitamin C. The Ca 2+ responses to thrombin and PAR 1 AP in A7r5 cells exhibited a phenomenon similar to those seen with the contractile response in an SAH model. ERK inhibitors restored the transient response, tachyphylactic attenuation and reversibility of thrombin response, while the inhibitors of JNK, p38 kinase or Rho kinase had no effect. In conclusion, oxidative stress and ERK activation play a key role in the impaired receptor desensitization and prolonged vascular reactivity after SAH. Targeting oxidative stress and ERK could provide a novel strategy to normalize vascular reactivity after SAH.