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

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

Study Overview

• Status: Completed
• Conditions: Aging
• Intervention / Treatment: Other: Pre exercise baseline; Drug: Esmolol infusion; Other: Isometric handgrip exercise; Other: Semi-recumbent cycling; Drug: Saline infusion

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • University Park, Pennsylvania, United States, 16803
      • Noll Laboratory

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

3.1 Inclusion Criteria

1. Capable of giving informed consent
2. Premenopausal women ages 18-35 years OR post-menopausal women ages 55-70 years
3. Satisfactory medical history and physical exam, as determined by a CRC clinician
4. Not currently taking medications affecting heart rate or contractility
5. Fluent in written and spoken English

3.2 Exclusion Criteria

Participants who will not be studied are those who:

1. Are less than 19 years of age or more than 70 years of age
2. Are pregnant or lactating
3. Are prisoners or institutionalized individuals or unable to consent
4. Diagnosed renal failure (Creatinine >2.0 mg/dl)
5. Diagnosed liver disease (ALT and AST 2 times normal)
6. Diagnosed Reynaud's disease
7. Have uncontrolled diabetes
8. Have uncontrolled hypertension
9. Have a left ventricular ejection fraction < 40%
10. Have a recent history of unstable angina or myocardial infarction (<6 months), unstable angina, or use of nitrate medications within past 2 weeks

10. Severe lung disease (i.e., on supplemental oxygen or frequently use rescue inhalers) 11. Diagnosed bleeding or clotting disorder or recent blood transfusion 12. Have asthma, history of thyroid issues or hyperkalemia 13. Known use of recreational drugs 14. Methylphenidate use

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Esmolol Infusion; 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.	Other: Pre exercise baseline; 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.; Drug: Esmolol infusion; 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).; Other Names: Esmolol Hydrochloride; Other: Isometric handgrip exercise; 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.; Other: Semi-recumbent cycling; 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.
Placebo Comparator: Saline Infusion; Saline infusion volume/rate matched to the calculated dose of esmolol.	Other: Pre exercise baseline; 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.; Other: Isometric handgrip exercise; 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.; Other: Semi-recumbent cycling; 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.; Drug: Saline infusion; Saline will be rate/volume matched to the calculated esmolol dose.; Other Names: Normal saline solution

What is the study measuring?

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.	Last 60 seconds of Rest, Moderate exercise, and Heavy Exercise.

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.	Last 60 seconds of Rest, Moderate exercise, and Heavy Exercise.
Blood Pressure	Blood Pressure recorded via an automatic sphygmomanometer (SunTech Tango)	At rest and 3 minutes into moderate exercise and heavy exercise.
Heart Rate	Heart rate recorded via EKG	Last 60 seconds of Rest, Moderate exercise, and Heavy Exercise.
Cardiac Output	Cardiac Output recorded using bioimpedance cardiography	Last 60 seconds of Rest, Moderate exercise, and Heavy Exercise.

Collaborators and Investigators

• Sponsor: David N. Proctor, PhD

Study record dates

Study Major Dates

• Study Start (Actual): February 2, 2022
• Primary Completion (Actual): April 12, 2023
• Study Completion (Actual): April 12, 2023

Study Registration Dates

• First Submitted: November 26, 2019
• First Submitted That Met QC Criteria: November 26, 2019
• First Posted (Actual): November 29, 2019

Study Record Updates

• Last Update Posted (Estimated): February 15, 2024
• Last Update Submitted That Met QC Criteria: February 13, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Exercise; Esmolol hydrochloride
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis; Peripheral Arterial Disease; Peripheral Vascular Diseases; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Adrenergic beta-1 Receptor Antagonists; Esmolol
• Other Study ID Numbers: 10736

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No