Mechanisms of BKCa channel agonist NS-1619-elicited protection against oxidative stress from venules to arterioles

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Tissue ischemia occurs in patients with myocardial infarction, stroke and other vascular occlusive diseases. While restitution of blood supply is necessary to prevent the progression of tissue injury, it also initiates a complex series of microvascular inflammatory changes which paradoxically induce additional cellular damage beyond ischemia alone. Pharmacological preconditioning is a powerful protective intervention against ischemia and reperfusion (I/R) injury. Previous work from our laboratory demonstrated that treatment with the calcium activated, large conductance potassium (BKCa) channel opener NS-1619 24 hours prior to the induction of I/R in mice confers protection against intestinal I/R injury. The aims of the studies outlined in this dissertation thus were to examine the mechanisms underlying NS-1619-induced protection against oxidative injury in mice, rats and human microvascular endothelial cells (HMECs). Evidence presented in this dissertation supported the notions that: 1) NS-1619 elicits preconditioning against mice intestinal I/R injury in a reactive oxygen species (ROS) and heme oxygenase (HO)-1 dependent pathway; 2) the preconditioning induced by NS-1619 against oxidative injury in HMECs is independent of BKCa channel activation, but dependent upon ROS and HO-1; 3) connective tissue mast cells and proteases, especially matrix metalloproteinase-9 (MMP-9), contribute to the pathogenesis of arteriolar endothelium-dependent vasodilation dysfunction during intestinal I/R in rat mesentery.