Therapeutic Strategies to Reduce Endothelial Ischemia-reperfusion Injury

The objective of this Intervention is to show that ischemic preconditioning (IPC) protects against endothelial ischemia/reperfusion injury. Baseline endothelium-dependent vasodilation to reactive hyperemia will be performed on the nondominant arm, followed by 3 × 5-minute cycles of IPC in the opposite arm. IPC will be induced using a blood pressure cuff placed on the opposite upper arm and inflated to 220 mmHg for 5 min, followed by 5 min of deflation. This procedure will be repeated two additional times taking about 30 minutest to complete. Following a 10-minute rest phase, endothelial injury will be induced using a blood pressure cuff that will be inflated to stop blood flow through the nondominant arm for 20 minutes, followed by 15 minutes of cuff deflation. Endothelium-dependent vasodilation measurements will be repeated immediately after the 15-minute cuff deflation phase.

The objective of this Intervention is to show that an intravenous infusion of lactate protects against endothelial ischemia/reperfusion injury. Baseline endothelium-dependent vasodilation to reactive hyperemia will be performed on the nondominant arm. Thereafter, a continuous intravenous infusion of lactate will be delivered in the contralateral arm. After systemic lactate reaches \~3 mmol/L, endothelial injury will be induced using a blood pressure cuff that will be inflated to stop blood flow through the nondominant arm for 20 minutes, followed by 15 minutes of cuff deflation. Endothelium-dependent vasodilation measurements will be repeated immediately after the 15-minute cuff deflation phase.

The objective of this Intervention is to show that a control experiment without ischemic preconditioning does not provide protection against endothelial ischemia/reperfusion injury. Baseline endothelium-dependent vasodilation to reactive hyperemia will be performed on the nondominant arm, followed by 3 × 5-minute cycles of no upper arm occlusion in the opposite arm. To avoid upper arm occlusion, a blood pressure cuff will be placed on the upper arm and inflated to a low pressure of 20 mmHg pressure to not influence blood flow through the arm. This control procedure will be repeated two additional times taking about 30 minutes to complete. Following a 10-minute rest phase, endothelial injury will be induced using a blood pressure cuff that will be inflated to stop blood flow through the nondominant arm for 20 minutes, followed by 15 minutes of cuff deflation. Endothelium-dependent vasodilation measurements will be repeated immediately after the 15-minute cuff deflation phase.

The objective of this Intervention is to show that a placebo intravenous infusion does not protect against endothelial ischemia/reperfusion injury. Baseline endothelium-dependent vasodilation to reactive hyperemia will be performed on the nondominant arm. Thereafter, a continuous infusion of normal saline that does not contain lactate will be delivered in the contralateral arm. After 20 minutes of the placebo infusion, endothelial injury will be induced using a blood pressure cuff that will be inflated to stop blood flow through the nondominant arm for 20 minutes, followed by 15 minutes of cuff deflation. Endothelium-dependent vasodilation measurements will be repeated immediately after the 15-minute cuff deflation phase.

The objective of this Intervention is to show that combining ischemic preconditioning (IPC) with an intravenous infusion of lactate provides the best protection against endothelial injury. First, baseline endothelial function to reactive hyperemia will be performed on the nondominant arm. Thereafter, a continuous intravenous infusion of lactate will be delivered in the contralateral arm. After that investigators will administer IPC using a blood pressure cuff placed on the same upper arm and inflated to 220 mmHg for 5 min, followed by 5 min of deflation. This procedure will be repeated two more times taking about 30 minutes to complete. The intravenous lactate infusion will be maintained. After a 10-minute rest phase and while lactate is still being infused, endothelial injury will be induced using a blood pressure cuff inflated to stop blood flow through the opposite arm (nondominant arm) for 20 minutes, followed by 15 minutes of cuff deflation. Endothelial function will be repeated.