Ischemia/Reperfusion Injury of Human Endothelium: Role of Glucose and Statins

Injury to vital organs and tissue can occur when blood flow is stopped and then
re-established. This happens in a variety of clinical situations and contributes to poor
outcomes. A newer concept of protection from this injury by an anesthetic drug might occur
because of the effect of the volatile anesthetics on the tissue that lines blood vessels.
Thus, a brief exposure to a volatile anesthetic before a harmful cessation of blood flow,
called anesthetic preconditioning (APC), can substantially reduce the resulting injury to
the lining of the blood vessels. In animal models, high levels of blood sugar block this
protection, while cholesterol lowering drugs (statins) restore the protection and may
independently protect blood vessel lining from injury. The interactions of high blood sugar
and statin drugs on the blood vessel reaction to APC and a subsequent 20-min cessation of
blood flow to the forearm will be studied in humans. In addition, the involvement of
reactive oxygen species (ROS) in the harmful effects of high blood sugar and the beneficial
effects of statins will be explored. The following four hypotheses will be studied: 1) high
blood sugar blocks the anesthetic protection of blood vessels from injury in a dose and time
dependent manner; 2) reactive oxygen species are involved in the inhibition of APC by high
blood sugar; 3) statins modulate injury in a dose related manner; and 4) statins reduce high
blood sugar inhibition of APC.

A standard model to evaluate forearm blood vessel function will be used. Thin
rubber-band-like strain gauges will be strapped around each forearm and the change in their
stretch during a variety of interventions on the experimental arm (the other arm will not
receive any interventions and will be the control arm) will be measured. These interventions
will allow the investigator to determine whether the hypotheses listed above are true.
During all studies, there will be a 20-min arrest of the forearm circulation. Additional
effects of injury, APC, high blood sugar, and statins will be determined by evaluating blood
vessel inflammatory responses from "markers" in blood samples taken before and after I/R
injury. Several studies will involve varying the forearm blood glucose concentration for
brief (30 min) to longer (2 hours) periods prior to APC and injury. The ROS scavenger
vitamin C will be used to evaluate the role of ROS in adverse effects of high blood sugar.
There are several other studies that will continue to seek the mechanism of action of this
effect via the use of other drug interactions.

Inclusion Criteria:

- Young, healthy volunteers, 18-25 yr of age;

- Females will be studied at the same phase of their estrous cycle in each protocol.

Exclusion Criteria:

- Beta-blocker therapy or any medication that might interfere with vascular responses;

- Pregnant or lactating women;

- Substance abusers;

- Smokers;

- Anyone with cardiovascular, renal, or other systemic disease including hypertension
and/or diabetes;

- Also excluded are volunteers with family history of malignant hyperthermia, or
significant gastro-esophageal reflux.