Combined argatroban and anti-oxidative agents prevents increased vascular contractility to thrombin and other ligands after subarachnoid haemorrhage.

BACKGROUND AND
PURPOSE: Increased vascular contractility plays a fundamental role in cerebral vasospasm in subarachnoid haemorrhage (SAH). We investigated the role of thrombin and its receptor, proteinase-activated receptor 1 (PAR1), and other G protein-coupled receptors in the increased contractility, and examined the preventive effects of the thrombin inhibitor, argatroban, and anti-oxidative agents, vitamin C and tempol. EXPERIMENTAL APPROACH: A rabbit model of SAH was utilized. Contractile responses of the isolated basilar artery and the level of oxidative stress of brain tissues were evaluated. KEY
RESULTS: Contractile responses to thrombin and PAR1-activating peptide (PAR1-AP) were enhanced and prolonged after SAH. The thrombin-induced contraction persisted even after terminating thrombin stimulation. When sequentially stimulated with PAR1-AP, the second response was maintained in SAH, while it was substantially attenuated in the control. Only a combination of argatroban with vitamin C or tempol prevented both the enhancement and prolongation of the contractile response to PAR1-AP and restored the reversibility of the thrombin-induced contraction. The responses to angiotensin II, vasopressin and PGF(2α) were enhanced and prolonged after SAH to varying degrees, and responded differently to the treatment. The response to vasopressin exhibited a similar phenomenon to that seen with PAR1-AP. Oxidative stress was increased in SAH, and normalized by the treatment with argatroban, vitamin C or their combination. CONCLUSIONS AND IMPLICATIONS: Increased vascular reactivity to agonists in SAH was attributable to the enhancement and prolongation of the contractile response. A combination of argatroban and anti-oxidative agents was required to prevent both the enhancement and prolongation of the contractile response.