Mechanisms of Cerebrovascular Control

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

Interventions

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.

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.

DRUG

NOS Inhibition Placebo

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

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).

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

Oral Glucose Tolerance Test

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

DRUG

ET-1 Inhibition Placebo

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

Sponsors & Collaborators

• American Heart Association

  collaborator OTHER

• American Diabetes Association

  collaborator OTHER

• University of Wisconsin, Madison

  lead OTHER

Principal Investigators

• William G. Schrage, Ph.D. · University of Wisconsin, Madison

Study Design

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

45 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2017-01-31

Primary Completion

2021-07-01

Completion

2021-09-30

FDA Drug

Yes

Countries

• United States

Study Locations