The Impact of Sildenafil on the Pulmonary Circulation in Healthy Trained and Untrained Humans

NCT04985929 | Completed Phase 2

• 1 other identifier: Pro000108975
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

Brief Summary

There is emerging evidence suggesting that the pulmonary vasculature and right heart may play a role in the limitation of exercise capacity in healthy individuals. It is well established that aerobic training improves cardiovascular function. While the pulmonary system is integral to the function of the cardiopulmonary system, it has been traditionally accepted that lung function does not respond to exercise training. However, recent research suggests pulmonary vascular function adaptations may occur with aerobic training, and this may contribute to enhanced exercise tolerance. Research has highlighted that increased capillary blood volume (Vc) and diffusion capacity for carbon monoxide (DLCO) are correlated with higher cardiorespiratory fitness at rest. Additionally, endurance trained participants have increased exercise DLCO concomitant to higher resting Vc when compared to untrained participants, and during exercise this difference seems to be driven by higher membrane diffusing capacity (Dm), independent of Vc or VA (alveolar volume). Of importance is also the evidence that highlights endurance trained participants having reduced pulmonary arterial pressures at rest and during exercise. Reduced pulmonary arterial pressure in endurance trained participants despite endurance trained participants consistently displaying increased diffusion capacity/pulmonary perfusion at rest and during exercise suggests a lower threshold pressure for pulmonary capillary recruitment. Together, this cross-sectional evidence suggests improvements in the pulmonary circulation due to exercise training in order to facilitate gas exchange. Whether this apparent improvement in pulmonary circulation is due to enhanced pulmonary vascular function via NO mediated vasodilation must be determined experimentally. If sildenafil administration improves DLCO, Vc, and Dm, this would provide evidence that the NO mediated vasodilatory pathway plays a role in the regulation of vascular tone, function, and perfusion across the pulmonary vasculature. Should a larger response to sildenafil be observed in untrained persons, this would suggest better baseline vascular function in trained participants compared to untrained. This would provide strong evidence that aerobic training improves pulmonary vasculature function which is contrary to the conventional understanding of aerobic training on the cardiopulmonary system.

Conditions

Healthy

Outcome Measures

Primary Outcomes (3)

• Diffusion capacity of carbon monoxide (DLCO)

  Diffusion capacity of carbon monoxide (DLCO) in selected body positions and exercise intensities. DLCO is measured with the Roughton-Forster Multiple FIO2 single-breath DLCO procedure.

  Minimum of 30 minutes post-dose.

• Capillary blood volume (Vc)

  Capillary blood volume is a component of DLCO and is measured with the Roughton-Forster Multiple FIO2 single-breath DLCO procedure.

  Minimum of 30 minutes post-dose.

• Membrane diffusing capacity (Dm)

  Membrane diffusing capacity is a component of DLCO and is measured with the Roughton-Forster Multiple FIO2 single-breath DLCO procedure.

  Minimum of 30 minutes post-dose.

Secondary Outcomes (1)

• Pulmonary artery systolic pressure (PASP)

  Minimum of 30 minutes post-dose.

Study Arms (2)

Healthy, Untrained

EXPERIMENTAL

Untrained participants will be defined as having a V̇O2peak of 30-45 ml.kg-1.min-1 and will be between 18-40 years of age.

Drug: Sildenafil 50 mg; Drug: Placebo

Healthy, Trained

EXPERIMENTAL

Trained participants will be defined as having a V̇O2peak above 55 ml.kg-1.min-1 (females) and 60 ml.kg-1.min-1 (males) and will be between 18-40 years of age.

Drug: Sildenafil 50 mg; Drug: Placebo

Interventions

Sildenafil 50 mg DRUG

Sildenafil is a phosphodiesterase type-5 inhibitor, which augments/prolongs the naturally occurring nitric oxide mediated vasodilatory pathway. Sildenafil pill is over-encapsulated to be identical in appearance to the placebo intervention.

Also known as: Accel-Sildenafil - 50 mg

Healthy, Trained; Healthy, Untrained

Placebo DRUG

Medical-grade placebo pill, over-encapsulated to be identical in appearance to the sildenafil intervention.

Healthy, Trained; Healthy, Untrained

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Untrained participants will be defined as having a V̇O2peak of 30-45 ml.kg-1.min-1.
• Trained participants will be defined as having a V̇O2peak above 55 ml.kg-1.min-1 (females) and 60 ml.kg-1.min-1 (males).
• All participants will be between the ages of 18-40 years.

You may not qualify if:

• Absolute contraindication to exercise testing or an orthopedic condition that may limit exercise testing as identified by standardized health screening tool (PAR-Q+).
• Pre-existing cardiac conditions (heart failure, congenital heart defect, valvular disease) that may limit exercise testing.
• A diagnosis of pulmonary hypertension.
• Current prescription drug use (excluding oral contraception for females).
• Pregnancy or lactation.
• Women of childbearing potential must be willing to use an acceptable method of contraception to avoid pregnancy throughout the study. Acceptable methods of contraception include tubal ligation, oral contraceptive, barrier methods (intra-uterine device, diaphragm, female condom, male condom). Abstinence is an acceptable form of contraception, only insofar as patients agree to use another acceptable method of birth control, preferably a barrier method, if they become sexually active.
• Postmenopausal female participants must be amenorrheic for ≥12 months.

Sponsors & Collaborators

• University of Alberta: lead

Study Sites (1)

Clinical Physiology Laboratory

Edmonton, Alberta, T6G2R3, Canada

Location

MeSH Terms

Interventions

Sildenafil Citrate

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Sean van Diepen, MD

  University of Alberta

  STUDY DIRECTOR

• Michael K Stickland, PhD

  University of Alberta

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Double-blind, placebo-controlled
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomized, double-blind, placebo-controlled cross-over design

Study Record Dates

• First Submitted: July 23, 2021
• First Posted: August 2, 2021
• Study Start: July 1, 2021
• Primary Completion: July 5, 2024
• Study Completion: July 5, 2024
• Last Updated: September 19, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)