(Verbatim from the application): Over the past three NIH grant periods we have identified numerous factors involved in the chain of events leading to the reperfusion failure of replanted tissues. Most recently, we have recognized that insufficient nitric oxide (NO) production by the endothelium as well as an excessive, toxic level of NO produced by extravasated leukocytes may contribute to the reperfusion failure of revascularized skeletal muscle. The central hypothesis of this proposal is that ischemia/reperfusion (i/r) leads to an imbalanced production of nitric oxide in skeletal muscle microdomains, and that supplementation with nitric oxide donor and/or selective pharmacological manipulation of nitric oxide synthase (NOS) isoenzymes will reduce the incidence of reperfusion failure. The proposed studies will determine the role of individual NOS isoenzyme in the pathophysiology of reperfusion failure and to assess efficacies of different NO-related agents in improving the outcome of reperfused skeletal muscle. Specifically, we will: 1) Determine the dynamic expressions and activities of NOS isoenzymes in representative rodent skeletal muscles following ischemia and reperfusion; 2) Determine the effects of NO donors and NOS inhibitors on thrombus formation at arterial and venous anastomosis sites following vessel repair; 3) Determine the effects of NO donors and NOS inhibitors on leukocyte adhesion and microcirculation of skeletal muscle after I/R injury; and 4) Determine the potential benefits of NO donors and NOS inhibitors based on the functional outcome of reperfused muscle. Our comprehensive study will include the judicial use of NOS-isoform """"""""knockout"""""""" mice to confirm the role of particular NOS isoenzyme in the pathophysiology of reperfusion failure of skeletal muscle. The results of these studies will provide a scientific basis for potential clinical applications of NO-related agents to improve the functional outcome of microvascular procedures.
Showing the most recent 10 out of 33 publications