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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Department of Veterans Affairs
ClinicalTrials.gov Identifier:
NCT00995670
First received: October 13, 2009
Last updated: October 23, 2013
Last verified: October 2013
  Purpose

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 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.


Condition Intervention
Hyperglycemia
Drug: 5% dextrose
Drug: vitamin C
Drug: Simvastatin
Drug: L-NMMA

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Ischemia/Reperfusion Injury of Human Endothelium: Role of Glucose and Statins

Resource links provided by NLM:


Further study details as provided by Department of Veterans Affairs:

Primary Outcome Measures:
  • endothelial function [ Time Frame: 1 hr ] [ Designated as safety issue: No ]
    endothelial responses to acetylcholine stimulation before and after ischemia/reperfusion injury.


Secondary Outcome Measures:
  • effects of glucose on endothelial function and endothelial responses to I/R injury [ Time Frame: 2 hr ] [ Designated as safety issue: No ]
    effects of glucose on endothelial function and endothelial responses to I/R injury


Enrollment: 221
Study Start Date: March 2010
Study Completion Date: September 2013
Primary Completion Date: September 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm 1
Endothelial function will be measured via invasive and noninvasive measures following ischemia, where an intervention is applied prior to the ischemia.
Drug: 5% dextrose
5% dextrose will be infused at varying dosages (150 mg/dl or 300 mg/dl) and for varying periods (20, 50 or 110 min) to determine the optimal dose and duration of dextrose to prevent the anesthetic preconditioning (sevoflurane) protection against subsequent ischemia/reperfusion injury.
Other Name: This limb is completed
Drug: vitamin C
Vitamin C is intended to restore the impairment of the endothelium by the dextrose infusion.
Drug: Simvastatin
Volunteers will be studied after 20 mg and 40 mg of simvastatin (separate days), each taken for the two evenings prior to study day and the morning of the study to determine the effect of simvastatin on modulating the I/R injury.
Other Name: statin-THis limb is completed
Drug: L-NMMA
L-NMMA will be given during several studies (dosed to effect - i.e., when forearm blood flow responses to ramps of acetylcholine are blocked) to determine the effect of a nitric oxide blocker on the effects of 5% dextrose or simvastatin on I/R injury.
Other Name: nitric oxide blocker
Placebo Comparator: Arm 2
As above with no intervention applied.
Drug: Simvastatin
Volunteers will be studied after 20 mg and 40 mg of simvastatin (separate days), each taken for the two evenings prior to study day and the morning of the study to determine the effect of simvastatin on modulating the I/R injury.
Other Name: statin-THis limb is completed
Drug: L-NMMA
L-NMMA will be given during several studies (dosed to effect - i.e., when forearm blood flow responses to ramps of acetylcholine are blocked) to determine the effect of a nitric oxide blocker on the effects of 5% dextrose or simvastatin on I/R injury.
Other Name: nitric oxide blocker

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 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.

  Eligibility

Ages Eligible for Study:   18 Years to 25 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00995670

Locations
United States, Wisconsin
Zablocki VA Medical Center, Milwaukee
Milwaukee, Wisconsin, United States, 53295-1000
Sponsors and Collaborators
Investigators
Principal Investigator: Thomas Ebert, MD PhD Zablocki VA Medical Center, Milwaukee
  More Information

No publications provided

Responsible Party: Department of Veterans Affairs
ClinicalTrials.gov Identifier: NCT00995670     History of Changes
Other Study ID Numbers: CARA-023-09S
Study First Received: October 13, 2009
Last Updated: October 23, 2013
Health Authority: United States: Federal Government

Keywords provided by Department of Veterans Affairs:
hyperglycemia
statin
blood vessels
ischemic preconditioning
Anesthesia, inhalational
endothelium
5% dextrose

Additional relevant MeSH terms:
Hyperglycemia
Ischemia
Reperfusion Injury
Wounds and Injuries
Glucose Metabolism Disorders
Metabolic Diseases
Pathologic Processes
Vascular Diseases
Cardiovascular Diseases
Postoperative Complications
Ascorbic Acid
Nitric Oxide
Vitamins
Omega-N-Methylarginine
Simvastatin
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Antioxidants
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protective Agents
Physiological Effects of Drugs
Micronutrients
Growth Substances
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Anti-Asthmatic Agents
Respiratory System Agents
Therapeutic Uses
Free Radical Scavengers

ClinicalTrials.gov processed this record on August 20, 2014