Study: NCT02936687

Intervention type: DRUG
Group type: EXPERIMENTAL
Intervention: NOS Inhibition
Description: 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.

Intervention type: DRUG
Group type: EXPERIMENTAL
Intervention: NOS Inhibition
Description: 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.

Intervention type: DRUG
Group type: EXPERIMENTAL
Intervention: ET-1 Inhibition
Description: 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.

Intervention type: DRUG
Group type: EXPERIMENTAL
Intervention: ET-1 Inhibition
Description: 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.

Intervention type: DRUG
Group type: EXPERIMENTAL
Intervention: NOS Inhibition Placebo
Description: Saline will be infused at the same rate and quantity as the corresponding drug visit.

Intervention type: DRUG
Group type: EXPERIMENTAL
Intervention: NOS Inhibition Placebo
Description: Saline will be infused at the same rate and quantity as the corresponding drug visit.

Intervention type: DEVICE
Group type: EXPERIMENTAL
Intervention: 3 Tesla MRI
Description: 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).

Intervention type: DEVICE
Group type: EXPERIMENTAL
Intervention: 3 Tesla MRI
Description: 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).

Intervention type: DEVICE
Group type: EXPERIMENTAL
Intervention: 3 Tesla MRI
Description: 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).

Intervention type: DEVICE
Group type: EXPERIMENTAL
Intervention: 3 Tesla MRI
Description: 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).

Intervention type: DEVICE
Group type: EXPERIMENTAL
Intervention: Intravenous Catheter
Description: 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.

Intervention type: DEVICE
Group type: EXPERIMENTAL
Intervention: Intravenous Catheter
Description: 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.

Intervention type: DEVICE
Group type: EXPERIMENTAL
Intervention: Intravenous Catheter
Description: 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.

Intervention type: DEVICE
Group type: EXPERIMENTAL
Intervention: Intravenous Catheter
Description: 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.

Intervention type: OTHER
Group type: EXPERIMENTAL
Intervention: Oral Glucose Tolerance Test
Description: The subject will drink distilled deionized water (300ml) containing 75 grams glucose within 5 minutes.

Intervention type: OTHER
Group type: EXPERIMENTAL
Intervention: Oral Glucose Tolerance Test
Description: The subject will drink distilled deionized water (300ml) containing 75 grams glucose within 5 minutes.

Intervention type: OTHER
Group type: EXPERIMENTAL
Intervention: Oral Glucose Tolerance Test
Description: The subject will drink distilled deionized water (300ml) containing 75 grams glucose within 5 minutes.