Ischemia/Reperfusion Injury of Human Endothelium: Role of Glucose and Statins
Condition: Hyperglycemia
MeSH terms: Reperfusion Injury; Hyperglycemia; Ischemia
Study type: Interventional

Summary: 
      Anesthetic preconditioning (APC, a brief exposure to an anesthetic gas) has become an area of
      intense research interest because of its ability to protect tissue and organs from injury
      resulting from a cessation of blood flow and then a re-establishment of flow. The blood
      vessel lining plays a key role in this injury. This research will examine, in human
      volunteers, several important modifiers of APC in human blood vessels: high blood sugar,
      vitamin C, and statin drugs. Thus, the proposed studies will advance the investigators'
      understanding of mechanisms of this injury in humans and explore important modifiers of APC
      protection from injury.
    

Detailed description: 
      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 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.
    

Intervention name(s): 5% dextrose; Vitamin C; Simvastatin; Sevoflurane
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): Glucose is infused to prevent the anesthetic preconditioning (sevoflurane) protection against subsequent ischemia/reperfusion injury.; Vitamin C is intended to restore the impairment of the endothelium caused by the dextrose infusion.; Simvastatin will be ingested to determine the efficacy of a statin to modulate the forearm response to glucose.; Sevoflurane will be given to attenuate or prevent the I/R injury during glucose.
Other intervention name(s): Glucose; Vit C; Statin; Sevo
Intervention MeSH terms: Sevoflurane; Simvastatin
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: hyperglycemia; statin; blood vessels; ischemic preconditioning; Anesthesia, inhalational; endothelium; 5% dextrose