Mechanisms of Cerebrovascular Control

NCT02936687 | Completed Phase 1 DMC FDA Drug

• 6 other identifiers: 2015-0197A176000EDUC\KINESIOLOGY\KINESIO1-16-ICTS-09915POST23100020Protocol Version 9/3/2020
• Study Type: interventional
• Target: 59
• Locations: 1 country
• Sites: 1

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.

Conditions

Metabolic Syndrome X

Keywords

blood flow; magnetic resonance imaging; insulin; vasodilation

Outcome Measures

Primary Outcomes (2)

• Change in cerebrovascular blood flow in response to NOS inhibition.

  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.

  Through study completion (an average of 2 years)

• Change in cerebrovascular blood flow in response to ET-1 inhibition.

  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.

  Through study completion (an average of 2 years)

Study Arms (4)

Metabolic Syndrome NOS Inhibition

EXPERIMENTAL

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; Drug: NOS Inhibition Placebo; Device: 3 Tesla MRI; Device: Intravenous Catheter; Other: Oral Glucose Tolerance Test

Metabolic Syndrome ET-1 Inhibition

EXPERIMENTAL

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; Device: 3 Tesla MRI; Device: Intravenous Catheter; Other: Oral Glucose Tolerance Test; Drug: ET-1 Inhibition Placebo

Control NOS Inhibition

EXPERIMENTAL

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; Drug: NOS Inhibition Placebo; Device: 3 Tesla MRI; Device: Intravenous Catheter; Other: Oral Glucose Tolerance Test

Control ET-1 Inhibition

EXPERIMENTAL

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; Device: 3 Tesla MRI; Device: Intravenous Catheter; Other: Oral Glucose Tolerance Test; Drug: ET-1 Inhibition Placebo

Interventions

NOS Inhibition DRUG

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.

Also known as: L-NMMA

Control NOS Inhibition; Metabolic Syndrome NOS Inhibition

ET-1 Inhibition DRUG

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.

Also known as: Ambrisentan

Control ET-1 Inhibition; Metabolic Syndrome ET-1 Inhibition

NOS Inhibition Placebo DRUG

Saline will be infused at the same rate and quantity as the corresponding drug visit.

Also known as: Saline

Control NOS Inhibition; Metabolic Syndrome NOS Inhibition

3 Tesla MRI DEVICE

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).

Also known as: MRI

Control ET-1 Inhibition; Control NOS Inhibition; Metabolic Syndrome ET-1 Inhibition; Metabolic Syndrome NOS Inhibition

Intravenous Catheter DEVICE

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.

Also known as: Cath

Control ET-1 Inhibition; Control NOS Inhibition; Metabolic Syndrome ET-1 Inhibition; Metabolic Syndrome NOS Inhibition

Oral Glucose Tolerance Test OTHER

The subject will drink distilled deionized water (300ml) containing 75 grams glucose within 5 minutes.

Also known as: OGTT

Control ET-1 Inhibition; Control NOS Inhibition; Metabolic Syndrome ET-1 Inhibition; Metabolic Syndrome NOS Inhibition

ET-1 Inhibition Placebo DRUG

Placebo pill similar in size and shape to Ambrisentan will be used as placebo control.

Also known as: Lactose Capsules

Control ET-1 Inhibition; Metabolic Syndrome ET-1 Inhibition

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Sedentary (≤ 90 minutes of vigorous physical activity per week)
• Women must be premenopausal with a regular menstrual cycle
• For the Ambrisentan trial, participants must be male, due to potential harmful effects of drug on fetus
• Participants will be lean (BMI ≥19 - ≤25 kg/m2)
• Sedentary (≤ 90 minutes of vigorous physical activity per week)
• Without any cardiovascular co-morbidities
• Participants 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. Participants must meet 3 or more of the following 5 criteria:
• fasting glucose ≥ 100 mg/dL,
• fasting triglycerides ≥ 150 mg/dL,
• elevated blood pressure (≥ 130 systolic and/or ≥ 85 diastolic mmHg),
• waist circumference at the iliac crest \> 102 cm (men) or ≥ 88 cm (women).

You may not qualify if:

• Fasting glucose ≥ 126 mg/dL
• Having ≥1- ≤ 2 of the above criteria for MetSyn.
• Taking metabolic medications (insulin-sensitizing, lipid-lowering medications, etc.) or any medications for cardiovascular-related issues will be excluded.
• Current use of tobacco (i.e. smoke, smokeless, and vapor). If participant has used tobacco products ≤10 in the last year and ≤1 time in the last month, he or she will still be considered eligible.
• Females will be excluded if pregnant, lactating, or postmenopausal.
• Participants having any contraindications of having an MRI (such as claustrophobia, metallic implant, etc.).
• Participant has an abnormality or contraindication to study participation, which is not covered in the eligibility criteria.

Sponsors & Collaborators

• University of Wisconsin, Madison: lead
• American Heart Association: collaborator
• American Diabetes Association: collaborator

Study Sites (1)

University of Wisconsin, Madison

Madison, Wisconsin, 53706, United States

Location

MeSH Terms

Conditions

Metabolic Syndrome; Insulin Resistance; Aneurysm

Interventions

omega-N-Methylarginine; ambrisentan; Sodium Chloride; Vascular Access Devices; Glucose Tolerance Test; Lactose

Condition Hierarchy (Ancestors)

Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Arginine; Amino Acids, Basic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Diamino; Amino Acids, Essential; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Catheters; Equipment and Supplies; Blood Chemical Analysis; Clinical Chemistry Tests; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Endocrine; Investigative Techniques; Disaccharides; Oligosaccharides; Polysaccharides; Carbohydrates; Sugars

Study Officials

• William G. Schrage, Ph.D.

  University of Wisconsin, Madison

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 28, 2016
• First Posted: October 18, 2016
• Study Start: January 31, 2017
• Primary Completion: July 1, 2021
• Study Completion: September 30, 2021
• Last Updated: October 18, 2021

Record last verified: 2021-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)