The Effect of Sildenafil and Tadalafil on Skeletal Muscle and Perceptual Fatigue
| Status: | Completed |
|---|---|
| Conditions: | Other Indications |
| Therapuetic Areas: | Other |
| Healthy: | No |
| Age Range: | 50 - 60 |
| Updated: | 7/19/2018 |
| Start Date: | November 2012 |
| End Date: | June 2015 |
The Effect of Sildenafil and Tadalafil on Skeletal Muscle and Perceptual Fatigue.
This study is funded by the Moody Endowment. In this project, we will investigate the
potential effect of skeletal muscle nitric oxide (NO) production on skeletal muscle
anabolism, muscle strength, physical function, and body composition in older individuals.
Further, we will determine whether augmentation of NO-mediated signaling reduces fatigue and
fatigability.
potential effect of skeletal muscle nitric oxide (NO) production on skeletal muscle
anabolism, muscle strength, physical function, and body composition in older individuals.
Further, we will determine whether augmentation of NO-mediated signaling reduces fatigue and
fatigability.
The Investigators hypothesize that upregulation of skeletal muscle NO-cGMP mediated responses
through phosphodiesterase (PDE) inhibition by sildenafil or tadalafil causes an acute
anabolic response of skeletal muscle protein synthesis. NO is well-known to elicit
vasodilation through stimulation of cGMP signaling, and NO-mediated changes in muscle
perfusion may influence both skeletal muscle anabolism and perceptual fatigue. To measure
skeletal muscle protein synthesis, we will infuse a stable isotope tracer of phenylalanine
and measure its incorporation into skeletal muscle proteins following a dose of sildenafil,
tadalafil, or placebo. The Investigators will also determine whether differences exist
between men and women in response to PDE inhibition. As skeletal muscle NO-cGMP signaling has
been implicated in fatigue responses, we will assess the acute effect of sildenafil and
tadalafil on fatigue. Fatigue can be manifested both as a performance deficit at a local
level (e.g., a reduced ability of skeletal muscle to produce power or force) as well as a
subjective experience of lacking physical or mental energy. Accordingly, we will use more
than one means (skeletal muscle performance, fatigue questionnaires, accelerometers) to study
fatigue. The Investigators hypothesize that sildenafil or tadalafil will acutely reduce
exercise-associated fatigability and skeletal muscle fatigue development
through phosphodiesterase (PDE) inhibition by sildenafil or tadalafil causes an acute
anabolic response of skeletal muscle protein synthesis. NO is well-known to elicit
vasodilation through stimulation of cGMP signaling, and NO-mediated changes in muscle
perfusion may influence both skeletal muscle anabolism and perceptual fatigue. To measure
skeletal muscle protein synthesis, we will infuse a stable isotope tracer of phenylalanine
and measure its incorporation into skeletal muscle proteins following a dose of sildenafil,
tadalafil, or placebo. The Investigators will also determine whether differences exist
between men and women in response to PDE inhibition. As skeletal muscle NO-cGMP signaling has
been implicated in fatigue responses, we will assess the acute effect of sildenafil and
tadalafil on fatigue. Fatigue can be manifested both as a performance deficit at a local
level (e.g., a reduced ability of skeletal muscle to produce power or force) as well as a
subjective experience of lacking physical or mental energy. Accordingly, we will use more
than one means (skeletal muscle performance, fatigue questionnaires, accelerometers) to study
fatigue. The Investigators hypothesize that sildenafil or tadalafil will acutely reduce
exercise-associated fatigability and skeletal muscle fatigue development
Inclusion Criteria:
1. Age 50-60 years of age
2. Ability to sign consent form (score>23 on the 30-item Mini Mental Status examination,
MMSE)
3. Stable body weight for at least three months.
Exclusion Criteria:
1. Physical dependence or frailty (impairment in any of the Activities of Daily Living
(ADL), history of falls (>2/year) or significant weight loss in the past year).
2. Pregnancy
3. Significant heart, liver, kidney, blood or respiratory disease.
4. Peripheral vascular disease.
5. Diabetes mellitus or other untreated endocrine disease.
6. Active cancer
7. Use of nitrates.
8. Recent (within 6 months) treatment with anabolic steroids, or corticosteroids.
9. Alcohol or drug abuse.
10. Severe depression (>5 on the 15-item Geriatric Depression Scale, GDS).
11. Cardiac abnormalities such as cardiac shunt or previously diagnosed pulmonary
hypertension.
12. Systolic blood pressure <100 or>150, diastolic blood pressure <60 or 90>. This range
is smaller than the acceptable range stated in the prescribing information for
sildenafil/tadalafil (90/50 and <170/110).
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