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Mechanisms of Cerebrovascular Control

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ClinicalTrials.gov Identifier: NCT02936687
Recruitment Status : Recruiting
First Posted : October 18, 2016
Last Update Posted : November 2, 2018
Sponsor:
Information provided by (Responsible Party):
University of Wisconsin, Madison

Brief Summary:
The objective of this study is to identify insulin-specific cerebral blood flow (CBF) control mechanisms, and establish cerebrovascular responsive baseline in younger (18-45 yrs) metabolic syndrome adults (MetSyn) who are at substantial risk of stroke and other types of cardiovascular mortality even if they never develop diabetes. The central hypothesis is that vasodilator actions of insulin are impaired in MetSyn due to loss of dilator and gain of constrictor signals. This study will focus on 2 mechanisms that likely limit CBF in MetSyn: 1) Disruption of nitric oxide (NO) vasodilation, and 2) Exaggerated endothelin (ET-1) constriction. Three specific aims will be addressed: Aim 1: To test the hypothesis that physiologic surges of insulin acutely increase CBF in young adults, but adults with MetSyn exhibit paradoxical insulin-mediated vasoconstriction. Aim 2: To test the hypotheses that key mechanisms responsible for poor CBF in MetSyn are shifts in NO and ET-1 signaling. Specifically, in healthy controls, NO mediates robust dilation, with little to no ET-1 constriction. In contrast, adults with MetSyn exhibit uncoupled NO synthase (NOS) and exaggerated ET-1 constriction. Aim 3: To test the hypothesis that insulin regulation of CBF is regionally distinct (e.g. Middle Cerebral Artery (MCA) reactive than Anterior Cerebral Artery (ACA) or basilar), and the negative effects of insulin resistance (IR) are similarly regionally specific.

Condition or disease Intervention/treatment Phase
Metabolic Syndrome X Drug: NOS Inhibition Drug: ET-1 Inhibition Drug: NOS Inhibition Placebo Device: 3 Tesla MRI Device: Intravenous Catheter Other: Oral Glucose Tolerance Test Drug: ET-1 Inhibition Placebo Phase 1

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Mechanisms of Cerebrovascular Control: Acute Insulin Surges Lead to Brain Hypoperfusion in Human Metabolic Syndrome
Actual Study Start Date : January 31, 2017
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Metabolic Syndrome NOS Inhibition
Will occur over two separate study visits after screening. Eligible subjects with MetSyn will undergo NOS Inhibition during one visit and placebo infusion in the other visit. Subjects will also undergo 3 Tesla MRI scanning and an intravenous catheter, and will complete an Oral Glucose Tolerance Test during the study visits. More details under Study Description.
Drug: NOS Inhibition
NOS inhibition: L - NMMA is a potent non-selective NOS inhibitor used to study vascular physiology. L-NMMA will be infused at 3 mg/kg body weight/hr bolus (over 10min ) followed by a maintenance infusion of 1 mg/kg/hr for the duration of the experiment. Systemic delivery of L - NMMA has been shown to elevate blood pressure ~8-15 mmHg that is within the range observed during exercise.
Other Name: L-NMMA

Drug: NOS Inhibition Placebo
Saline will be infused at the same rate and quantity as the corresponding drug visit.
Other Name: Saline

Device: 3 Tesla MRI
A 3 Tesla MRI will be used to quantify cerebral blood flow and capture cerebral vessel structure at designated time points throughout the study visits (at baseline and during treatment conditions).
Other Name: MRI

Device: Intravenous Catheter
A blood sampling IV catheter will be used to draw up to 15 mL blood samples at specific time points throughout each study visit to measure concentrations of glucose and insulin as well as for markers of inflammation and oxidative stress.
Other Name: Cath

Other: Oral Glucose Tolerance Test
The subject will drink distilled deionized water (300ml) containing 75 grams glucose within 5 minutes.
Other Name: OGTT

Experimental: Metabolic Syndrome ET-1 Inhibition
Will occur over two separate study visits after screening. Eligible male subjects with MetSyn will complete an oral ET-1 Inhibition during one visit and an oral placebo in the other visit. Subjects will also undergo 3 Tesla MRI scanning and an intravenous catheter, and will complete an Oral Glucose Tolerance Test during the study visits. More details under Study Description.
Drug: ET-1 Inhibition
ET-1 inhibition: Ambrisentan is an antagonist of the ETA receptor. Subjects will receive 10 mg of Ambrisentan in a pill form 90-150 minutes prior to the OGTT. This class of drugs have been used to research ET-1 signaling in diabetes, obesity, and hypertension. ETA receptors are the most likely to mediate excessive constriction in MetSyn patients. Ambrisentan will be taken orally. Systemic delivery of endothelin antagonist have been shown at chronic dosing to decrease systolic blood pressure 4.5±10 mmHg and diastolic 3 ± 7.5 mmHg in hypertensives, and not alter mean arterial pressure in obesity.
Other Name: Ambrisentan

Device: 3 Tesla MRI
A 3 Tesla MRI will be used to quantify cerebral blood flow and capture cerebral vessel structure at designated time points throughout the study visits (at baseline and during treatment conditions).
Other Name: MRI

Device: Intravenous Catheter
A blood sampling IV catheter will be used to draw up to 15 mL blood samples at specific time points throughout each study visit to measure concentrations of glucose and insulin as well as for markers of inflammation and oxidative stress.
Other Name: Cath

Other: Oral Glucose Tolerance Test
The subject will drink distilled deionized water (300ml) containing 75 grams glucose within 5 minutes.
Other Name: OGTT

Drug: ET-1 Inhibition Placebo
Placebo pill similar in size and shape to Ambrisentan will be used as placebo control.
Other Name: Lactose Capsules

Experimental: Control NOS Inhibition
Will occur over two separate study visits after screening. Eligible control subjects will undergo NOS Inhibition during one visit and placebo infusion in the other visit. Subjects will also undergo 3 Tesla MRI scanning and an intravenous catheter, and will complete an Oral Glucose Tolerance Test during the study visits. More details under Study Description.
Drug: NOS Inhibition
NOS inhibition: L - NMMA is a potent non-selective NOS inhibitor used to study vascular physiology. L-NMMA will be infused at 3 mg/kg body weight/hr bolus (over 10min ) followed by a maintenance infusion of 1 mg/kg/hr for the duration of the experiment. Systemic delivery of L - NMMA has been shown to elevate blood pressure ~8-15 mmHg that is within the range observed during exercise.
Other Name: L-NMMA

Drug: NOS Inhibition Placebo
Saline will be infused at the same rate and quantity as the corresponding drug visit.
Other Name: Saline

Device: 3 Tesla MRI
A 3 Tesla MRI will be used to quantify cerebral blood flow and capture cerebral vessel structure at designated time points throughout the study visits (at baseline and during treatment conditions).
Other Name: MRI

Device: Intravenous Catheter
A blood sampling IV catheter will be used to draw up to 15 mL blood samples at specific time points throughout each study visit to measure concentrations of glucose and insulin as well as for markers of inflammation and oxidative stress.
Other Name: Cath

Other: Oral Glucose Tolerance Test
The subject will drink distilled deionized water (300ml) containing 75 grams glucose within 5 minutes.
Other Name: OGTT

Experimental: Control ET-1 Inhibition
Will occur over two separate study visits after screening. Eligible male control subjects will complete an oral ET-1 Inhibition during one visit and an oral placebo in the other visit. Subjects will also undergo 3 Tesla MRI scanning and an intravenous catheter, and will complete an Oral Glucose Tolerance Test during the study visits. More details under Study Description.
Drug: ET-1 Inhibition
ET-1 inhibition: Ambrisentan is an antagonist of the ETA receptor. Subjects will receive 10 mg of Ambrisentan in a pill form 90-150 minutes prior to the OGTT. This class of drugs have been used to research ET-1 signaling in diabetes, obesity, and hypertension. ETA receptors are the most likely to mediate excessive constriction in MetSyn patients. Ambrisentan will be taken orally. Systemic delivery of endothelin antagonist have been shown at chronic dosing to decrease systolic blood pressure 4.5±10 mmHg and diastolic 3 ± 7.5 mmHg in hypertensives, and not alter mean arterial pressure in obesity.
Other Name: Ambrisentan

Device: 3 Tesla MRI
A 3 Tesla MRI will be used to quantify cerebral blood flow and capture cerebral vessel structure at designated time points throughout the study visits (at baseline and during treatment conditions).
Other Name: MRI

Device: Intravenous Catheter
A blood sampling IV catheter will be used to draw up to 15 mL blood samples at specific time points throughout each study visit to measure concentrations of glucose and insulin as well as for markers of inflammation and oxidative stress.
Other Name: Cath

Other: Oral Glucose Tolerance Test
The subject will drink distilled deionized water (300ml) containing 75 grams glucose within 5 minutes.
Other Name: OGTT

Drug: ET-1 Inhibition Placebo
Placebo pill similar in size and shape to Ambrisentan will be used as placebo control.
Other Name: Lactose Capsules




Primary Outcome Measures :
  1. Change in cerebrovascular blood flow in response to NOS inhibition. [ Time Frame: Through study completion (an average of 2 years) ]
    A 3 Tesla MRI will be used to quantify cerebral blood flow and capture cerebral vessel structure at designated time points throughout the study visits.

  2. Change in cerebrovascular blood flow in response to ET-1 inhibition. [ Time Frame: Through study completion (an average of 2 years) ]
    A 3 Tesla MRI will be used to quantify cerebral blood flow and capture cerebral vessel structure at designated time points throughout the study visits.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Controls: Subjects will be healthy, sedentary individuals. They will be normotensive, and without any cardiovascular co-morbidities.
  • Metabolic Syndrome: Subjects must qualify under the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) definition of metabolic syndrome as modified by the American Heart Association and International Diabetes Federation. Subjects must meet 3 or more of the following 5 criteria:

    1. fasting glucose ≥ 100 mg/dL,
    2. fasting triglycerides ≥ 150 mg/dL,
    3. HDL-cholesterol < 40 mg/dL (men) or < 50 mg/dL (women),
    4. elevated blood pressure (≥ 130 systolic and/or ≥ 85 diastolic mmHg),
    5. waist circumference at the iliac crest > 102 cm (men) or ≥ 88 cm (women).

Exclusion Criteria:

  • Subjects with ≥126 mg * dL-1 fasting glucose and having 1-2 of the above criteria for MetSyn
  • A personal medical history of coronary artery disease, stroke, heart attack, heart valve disease, congestive heart failure, previous heart surgery, history of lung disease or peripheral artery disease, or history of renal/kidney and liver/hepatic disease
  • Subjects that take insulin or any medications for cardiovascular-related issues
  • Subjects who report sleep apnea
  • Subjects who report current or past tobacco use (> 1 year in duration). Tobacco use will include smoking and all forms of smoke-less tobacco (e-cigarettes and chewing tobacco).
  • Females that are pregnant, lactating, or postmenopausal
  • Contraindications of having an MRI (such as claustrophobia, metallic implant, etc.)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02936687


Contacts
Contact: William G. Schrage, Ph.D. (608) 263-6308 william.schrage@wisc.edu
Contact: Shawn E. Bolin, M.S. (608) 263-6308 sbolin@wisc.edu

Locations
United States, Wisconsin
University of Wisconsin, Madison Recruiting
Madison, Wisconsin, United States, 53706
Contact: William G. Schrage, Ph.D.    608-263-6308    william.schrage@wisc.edu   
Sponsors and Collaborators
University of Wisconsin, Madison
Investigators
Principal Investigator: William G. Schrage, Ph.D. University of Wisconsin, Madison

Responsible Party: University of Wisconsin, Madison
ClinicalTrials.gov Identifier: NCT02936687     History of Changes
Other Study ID Numbers: 2015-0197
First Posted: October 18, 2016    Key Record Dates
Last Update Posted: November 2, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Wisconsin, Madison:
blood flow
magnetic resonance imaging
insulin
vasodilation

Additional relevant MeSH terms:
Syndrome
Metabolic Syndrome X
Disease
Pathologic Processes
Insulin Resistance
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Insulin
Ambrisentan
Hypoglycemic Agents
Physiological Effects of Drugs
Antihypertensive Agents