Abstract 170: Arginase Contributes to Delayed Constriction of Large Cerebral Arteries in a Model of Subarachnoid Hemorrhage

Abstract

Introduction: Increased arginase activity can limit nitric oxide synthase activity and contribute to age-related increase in aortic stiffness. Hypothesis: Subarachnoid hemorrhage (SAH) produces a delayed increase in arginase activity that contributes to delayed decreases in diameter of major cerebral arteries. Methods: Male rats underwent injection of blood into the cisterna magna on day 0 and again on day 2. Shams had double injection of artificial CSF. Measurements of arginase activity on vessels in the Circle of Willis and pia matter were made with an assay based on the conversion of radiolabeled arginine to urea. Measurements of diameter of basilar, posterior (PCA), middle (MCA), and anterior (ACA) cerebral arteries were made ex vivo after perfusion with paraformaldehyde and black latex casting. Results: Arginase activity (nmol of urea/min/mg of protein) increased from the control value of 13±3 (±SE; n=17) to 24±6 (n=6) at 3 days, 36±14 (n=4) at 5 days, and 48±16 (n=9) at 7 days after SAH and then recovered at 10 days (14±5; n=4) and 14 days (18±6; n=5) after SAH. Infusion of the arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) for 7 days after SAH with an ip osmotic pump blocked the increase in arginase activity (10±2; n=4). Assessment of arterial diameter at 3, 5, 7, 10, and 14 days after SAH revealed the smallest diameters occurring at 7 days (except for MCA which occurred at 5 days). Continuous ip infusion of 10 mg/kg/day ABH significantly attenuated the decrease in diameter (μm) 7 days after SAH in PCA (sham = 249±9, n=8; SAH = 209±12, n=10; SAH+ABH = 255±9, n=6) and ACA (sham = 178±11; SAH = 141±11; SAH+ABH = 198±10). Effects on basilar artery were of marginal significance (P=0.065). Conclusion: SAH produces an increase in vascular arginase activity that is temporally related to delayed decreases in diameter of cerebral arteries. Inhibition of arginase activity prevents the decrease in diameter at 7 days after SAH, thereby indicating a contribution of arginase to delayed arterial constriction/remodeling in post-fixed arteries.