The Effect of Dopamine on Pulmonary Diffusion and Capillary Blood Volume During Exercise

The purpose of this study is to examine the effect of dopamine infusion and dopamine-2 receptor blockade on pulmonary capillary blood volume, diffusion, and the hemodynamic variables of pulmonary artery pressure, cardiac output, and pulmonary vascular resistance during exercise. Secondarily, this study will examine the effect of dopamine infusion and dopamine-2 receptor blockade on exercise tolerance.

Study Overview

• Status: Active, not recruiting
• Conditions: Health
• Intervention / Treatment: Drug: Placebos; Drug: Dopamine; Other: Rest; Other: Exercise - 60%; Other: Exercise - 85%; Drug: Metoclopramide

Detailed Description

1. Study Objectives

   The primary objective of this study is to examine the effect of dopamine infusion and dopamine-2 receptor blockade on pulmonary capillary blood volume, diffusion, and the hemodynamic variables of pulmonary artery pressure, cardiac output, and pulmonary vascular resistance during exercise. Secondarily, this study will examine the effect of dopamine infusion and dopamine-2 receptor blockade on exercise tolerance.

2. Background

   To meet the increased oxygen demand required for exercise, pulmonary diffusing capacity (DLCO) must increase in order to avoid a drop in arterial oxygenation and early exercise termination. Enhanced DLCO during exercise is achieved by expanding pulmonary capillary blood volume (Vc) and diffusing membrane capacity (Dm) through recruitment and distention of the pulmonary capillaries, effectively increasing the surface area for diffusion. Recruitment and distention of the pulmonary capillaries decreases pulmonary vascular resistance (PVR), increasing pulmonary blood flow (Q) while limiting the rise in pulmonary artery pressure (PAP) with exercise.

   In health, pharmacological interventions are not believed to affect PAP during exercise. However, dopamine, a pulmonary vasodilator, may help to regulate PAP during exercise. Specifically, dopamine appears important for a normal cardiovascular exercise response, as Metoclopramide (pulmonary dopamine-2-receptor antagonist) decreases maximal Q and exercise tolerance (1). These results suggest that dopamine may modulate Vc during exercise via pulmonary smooth muscle regulation, subsequently affecting PVR, PAP, Q and exercise tolerance. However, how dopamine regulates DLCO, Vc, Q, and exercise tolerance is unknown.

   Purpose: The purpose of this study is to examine the effect of a dopamine agonist and a dopamine-2-receptor antagonist on DLCO, Vc, PAP, PVR, Q, and exercise tolerance.

   Hypothesis: It is hypothesized that dopamine will increase Vc, leading to a reduction in PVR and a corresponding decrease in PAP. This response will allow an increase in DLCO, Q, and exercise tolerance relative to control. Conversely, Metoclopramide (dopamine-2-receptor antagonist) will attenuate the increase in Vc as well as the reduction in PVR, leading to an increase in PAP. In this condition, DLCO, Q, and exercise tolerance will be reduced.

3. Methods

Study Overview: This study will utilize a randomized, double-blind crossover design where healthy subjects will have measurements performed at rest and 2 workloads (60% and 85% of previously determined VO2peak) with either intravenous dopamine (2µg/kg/min), dopamine receptor blockade (20mg oral Metoclopramide), or placebo (order randomized). Data will be collected across 5 different days over a 2-3 week period. Day 1: Pulmonary function and graded exercise testing to exhaustion. Day 2-4: Vc determination at rest and exercise with either intravenous dopamine, dopamine receptor blockade, or placebo (order randomized). Following a brief period of rest, time to exhaustion trials at 85% of VO2peak will be performed to characterize exercise tolerance. Day 5: Evaluation of PAP via cardiac ultrasound at rest and during exercise with either intravenous dopamine, dopamine receptor blockade, or placebo (order randomized).

Pulmonary Function & Cardiopulmonary Exercise Test: Subjects will undergo a graded exercise test to volitional exhaustion to characterize aerobic fitness (VO2peak) and a standard pulmonary function test to characterize lung function parameters.

DLCO and Vc measurement during exercise: DLCO and Vc will be measured using the multiple oxygen tension DLCO breath-hold method (2) at rest and during cycling exercise at 60% and 85% of VO2peak. Over different three days, participants will be randomized to each of the following conditions: 1) dopamine (2 μg/kg/min intravenous) and a placebo pill, 2) metoclopramide (20 mg oral) and intravenous saline, or 3) intravenous saline and a placebo pill. During each workload, subjects will perform a DLCO breath-hold maneuver for six seconds, repeated three times during exercise at differing oxygen tensions (0.21, 0.40, 0.60; workload and oxygen tension randomized) allowing for calculation of Vc and Dm. Trials will be spread over several days to ensure no CO buildup. DLCO will be corrected for hemoglobin, and we have considerable experience in performing these tests.

Pulmonary Artery Systolic Pressure (PASP), PVR, and Q: Doppler echocardiography (PASP) will be used as a non-invasive estimate of PAP in all dopamine conditions. PASP will be evaluated at rest and during exercise, and this method has been used successfully by our group and others in previous investigations(3,4). Total PVR will be evaluated by dividing PASP by Q at any given workload. Q will be evaluated using the Physioflow® Impedance Cardiography (Manatec® Biomedical). When compared to direct Fick methods, impedance cardiography provides an accurate determination of Q at rest and during exercise.

Hemoglobin: Since DLCO will be corrected for hemoglobin concentration, a small sample of blood will be collected via finger prick at rest and during exercise and analyzed for hemoglobin concentration using a hand-held Hemoglobin measurement device (HemoCue 201+, HemoCue AB, Angelholm, Sweden).

• Study Type: Interventional
• Enrollment (Estimated): 35
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Desi Fuhr, MSc; Phone Number: 780-492-1121; Email: fuhr@ualberta.ca
• Study Contact Backup: Name: Wade W Michaelchuk, BSc; Phone Number: 780-632-9310; Email: wwmichae@ualberta.ca

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2J1
      • Clinical Physiology Research Laboratory

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Physically active (exercising >2 times per week)
• BMI < 30kg/m2
• No known cardiac or pulmonary disease

Exclusion Criteria:

• Known cardiac or pulmonary diseases / abnormalities
• Use of medications that could interfere with dopaminergic pathways (i.e. dopaminergic agonists / antagonists, alcohol, central nervous system depressants, and serotonergic drugs)
• BMI > 30kg/m2
• Female subjects must not be pregnant

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dopamine; Dependent variables measured with intravenous low dose dopamine infusion at rest, 60%, and 85% of VO2max	Drug: Dopamine; Other: Rest; Other: Exercise - 60%; 60% of VO2max; Other: Exercise - 85%; 85% of VO2max
Experimental: Metoclopramide; Dependent variables measured with oral metoclopramide ingestion at rest, 60%, and 85% of VO2max	Other: Rest; Other: Exercise - 60%; 60% of VO2max; Other: Exercise - 85%; 85% of VO2max; Drug: Metoclopramide
Experimental: Placebos; Dependent variables measured with orally ingested placebo pill and intravenous saline at rest, 60%, and 85% of VO2max	Drug: Placebos; Other: Rest; Other: Exercise - 60%; 60% of VO2max; Other: Exercise - 85%; 85% of VO2max

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Pulmonary Capillary Blood Volume	Roughton and Forster's Three FIO2 DLCO Method at Rest, 60% of Vo2max, and 85% of Vo2max	Dopamine (Day 1), Metoclopramide (Day 2), Placebos (Day 3) *order randomized
Diffusing Capacity for Carbon Monoxide	Roughton and Forster's Three FIO2 DLCO Method at Rest, 60% of Vo2max, and 85% of Vo2max	Dopamine (Day 1), Metoclopramide (Day 2), Placebos (Day 3) *order randomized
Pulmonary Artery Systolic Pressure	Non-invasive estimation using Doppler echocardiography at Rest & 60% of Vo2max	Dopamine (Day 1), Metoclopramide (Day 2), Placebos (Day 3) *order randomized
Cardiac Output	Non-invasive estimation using trans-thoracic impedance cardiography at rest, 60% of Vo2max, and 85% of Vo2max	Dopamine (Day 1), Metoclopramide (Day 2), Placebos (Day 3) *order randomized
Pulmonary Vascular Resistance	Calculation	Dopamine (Day 1), Metoclopramide (Day 2), Placebos (Day 3) *order randomized

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exercise Tolerance	Time-to-exhaustion at 85% of VO2max	Dopamine (Day 1), Metoclopramide (Day 2), Placebos (Day 3) *order randomized
Exertional Dyspnea	Modified Borg scale for Dyspnea	Dopamine (Day 1), Metoclopramide (Day 2), Placebos (Day 3) *order randomized

Collaborators and Investigators

• Sponsor: University of Alberta
• Collaborators: Natural Sciences and Engineering Research Council, Canada
• Investigators: Principal Investigator: Michael K Stickland, PhD, University of Alberta

Publications and helpful links

General Publications

• Tedjasaputra V, Bryan TL, van Diepen S, Moore LE, Bouwsema MM, Welsh RC, Petersen SR, Stickland MK. Dopamine receptor blockade improves pulmonary gas exchange but decreases exercise performance in healthy humans. J Physiol. 2015 Jul 15;593(14):3147-57. doi: 10.1113/JP270238. Epub 2015 Jun 8.
• ROUGHTON FJ, FORSTER RE. Relative importance of diffusion and chemical reaction rates in determining rate of exchange of gases in the human lung, with special reference to true diffusing capacity of pulmonary membrane and volume of blood in the lung capillaries. J Appl Physiol. 1957 Sep;11(2):290-302. doi: 10.1152/jappl.1957.11.2.290. No abstract available.
• Argiento P, Chesler N, Mule M, D'Alto M, Bossone E, Unger P, Naeije R. Exercise stress echocardiography for the study of the pulmonary circulation. Eur Respir J. 2010 Jun;35(6):1273-8. doi: 10.1183/09031936.00076009. Epub 2009 Nov 19.
• Bryan TL, van Diepen S, Bhutani M, Shanks M, Welsh RC, Stickland MK. The effects of dobutamine and dopamine on intrapulmonary shunt and gas exchange in healthy humans. J Appl Physiol (1985). 2012 Aug 15;113(4):541-8. doi: 10.1152/japplphysiol.00404.2012. Epub 2012 Jun 14.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2016
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: November 10, 2016
• First Submitted That Met QC Criteria: November 14, 2016
• First Posted (Estimated): November 17, 2016

Study Record Updates

• Last Update Posted (Actual): April 8, 2024
• Last Update Submitted That Met QC Criteria: April 4, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Antiemetics; Gastrointestinal Agents; Protective Agents; Cardiotonic Agents; Dopamine Agents; Dopamine D2 Receptor Antagonists; Dopamine Antagonists; Sympathomimetics; Dopamine; Metoclopramide
• Other Study ID Numbers: Pro00067664