Age Comparisons of Exercising Muscle O2 Supply in Healthy Adults: Effects of Esmolol Infusion

Study Overview
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Brief Summary
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This study will test the central hypothesis that postmenopausal women will demonstrate increased oxygen extraction in active leg muscle during leg cycling exercise while receiving an infusion of Esmolol, a fast-acting β1 selective antagonist, when compared to premenopausal women

Detailed Description
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This study will test the central hypothesis that postmenopausal women will demonstrate increased oxygen extraction in active leg muscle during leg cycling exercise while receiving an infusion of Esmolol, a fast-acting β1 selective antagonist, when compared to premenopausal women. β1 selective antagonists (or β1 blockers) are used to lower heart rate and improve O2 supply-to-demand balance in patients with coronary artery disease. By using esmolol to attenuate the central sympathetic response to exercise (increased heart rate and cardiac output) we can examine peripheral mechanisms of O2 delivery. The current project will evaluate how older postmenopausal women adjust active muscle O2 supply to an acute reduction in systemic O2 delivery during large muscle dynamic exercise when compared to younger premenopausal women.

Official Title
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Age Comparisons of Exercising Muscle O2 Supply in Healthy Adults: Effects of Esmolol Infusion

Conditions
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Aging

Intervention / Treatment
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* Drug: Esmolol infusion
* Drug: Saline infusion
* Other: Pre exercise baseline
* Other: Isometric handgrip exercise
* Other: Semi-recumbent cycling


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with peripheral arterial disease (PAD) Capable of giving informed consent Men and women age 21-85 years Diagnosed with PAD (i.e., ankle-brachial index below 0.9) Fontaine stage II or less - no pain while resting Satisfactory history and physical exam Fluent in written and spoken English Healthy adults without PAD Capable of giving informed consent Men and women age 21-85 years Satisfactory medical history and physical exam, as determined by study physician Not currently taking medications affecting heart rate or contractility (confirmed by study physician) Fluent in written and spoken English Exclusion Criteria: Participants who will not be studied are those who: Are less than 21 years of age Are females who are pregnant or lactating Are prisoners or institutionalized individuals or unable to consent Diagnosed renal failure (Creatinine >2.0 mg/dl) Diagnosed liver disease (ALT and AST 2 times normal) Have uncontrolled diabetes Have uncontrolled hypertension Have a left ventricular ejection fraction < 40% Have a recent history of unstable angina or myocardial infarction (<6 months), unstable angina, or use of nitrate medications within past 2 weeks Severe lung disease (i.e., on supplemental oxygen or frequently use rescue inhalers) Diagnosed bleeding or clotting disorder or recent blood transfusion Have asthma, history of thyroid issues or hyperkalemia

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Esmolol Infusion<br>Drug: Esmolol Hydrochloride Dosage form: Intravenous Infusion Dosage/Frequency: 0.5 mg/(kg Fat Free Mass·min) for 3 min followed by a maintenance infusion of 0.25 mg/(kg Fat Free Mass·min) for remainder of trial, up to a maximum of 1 hour. | Drug: Esmolol infusion<br>* The Esmolol loading dose will be 0.5 mg/kg fat free mass/min administered over the first 3 minutes, followed by a maintenance dose of 0.25 mg/kg fat free mass/min for the remainder of the protocol (maximum of 60 minutes).<br>* Other names: Esmolol Hydrochloride;Other: Pre exercise baseline<br>* Subject rests quietly while drug infusion begins (3 min loading dose followed by 10 min of maintenance dose) until heart rate and blood pressure stabilize.<br>Other: Isometric handgrip exercise<br>* The subject will grip at 40% of their maximum and maintain that grip for 90 seconds. Once at rest and once during heavy intensity cycling.<br>Other: Semi-recumbent cycling<br>* Subjects will pedal for 2-4 minutes at a very light intensity (20W), followed immediately by 5 minutes at a moderate intensity (at a workload intended to elicit 85% of the oxygen consumption observed at the lactate threshold), and 5 minutes of cycling at a heavy intensity (at a workload estimated to elicit oxygen consumption half way between those observed at the lactate threshold and respiratory compensation point). Subjects will then continue cycling at the heavy intensity for 90 seconds while performing isometric handgrip exercise.<br>|
| Placebo Comparator: Saline Infusion<br>Saline infusion volume/rate matched to the calculated dose of esmolol. | Drug: Saline infusion<br>* Saline will be rate/volume matched to the calculated esmolol dose.<br>* Other names: Normal saline solution;Other: Pre exercise baseline<br>* Subject rests quietly while drug infusion begins (3 min loading dose followed by 10 min of maintenance dose) until heart rate and blood pressure stabilize.<br>Other: Isometric handgrip exercise<br>* The subject will grip at 40% of their maximum and maintain that grip for 90 seconds. Once at rest and once during heavy intensity cycling.<br>Other: Semi-recumbent cycling<br>* Subjects will pedal for 2-4 minutes at a very light intensity (20W), followed immediately by 5 minutes at a moderate intensity (at a workload intended to elicit 85% of the oxygen consumption observed at the lactate threshold), and 5 minutes of cycling at a heavy intensity (at a workload estimated to elicit oxygen consumption half way between those observed at the lactate threshold and respiratory compensation point). Subjects will then continue cycling at the heavy intensity for 90 seconds while performing isometric handgrip exercise.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tissue Saturation Index - Active leg muscle | The primary outcome variable is the difference in the change in skeletal muscle oxygenation (TSI%) in the active leg muscle from baseline during recumbent cycling exercise between saline and esmolol (∆∆TSI%) using near-infrared spectroscopy. | Recorded continuously during baseline and both exercise trials | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tissue Saturation Index - Inactive forearm muscle | Difference in the change in skeletal muscle oxygenation (TSI%) in the inactive forearm muscle from baseline during recumbent cycling exercise between saline and esmolol (∆∆TSI%) using near-infrared spectroscopy. | Recorded continuously during baseline and both exercise trials | 
| Blood Pressure | Blood Pressure recorded via an automatic sphygmomanometer (SunTech Tango) | Recorded continuously during baseline and both exercise trials. | 
| Heart Rate | Heart rate recorded via EKG | Recorded continuously during during baseline and both exercise trials | 
| Cardiac Output | Cardiac Output recorded using bioimpedance cardiography | Recorded continuously during baseline and both exercise trials | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Esmolol hydrochloride, Exercise