TY - JOUR

T1 - Effects of Sildenafil on Cerebrovascular Reactivity in Patients with Becker Muscular Dystrophy

AU - Lindberg, Ulrich

AU - Witting, Nanna

AU - Jørgensen, Stine Lundgaard

AU - Vissing, John

AU - Rostrup, Egill

AU - Larsson, Henrik Bo Wiberg

AU - Kruuse, Christina

PY - 2017/1

Y1 - 2017/1

N2 - Patients suffering from Becker muscular dystrophy (BMD) have dysfunctional dystrophin proteins and are deficient in neuronal nitric oxide synthase (nNOS) in muscles. This causes functional ischemia and contributes to muscle wasting. Similar functional ischemia may be present in brains of patients with BMD, who often have mild cognitive impairment, and nNOS may be important for the regulation of the microvascular circulation in the brain. We hypothesized that treatment with sildenafil, a phosphodiesterase type 5 inhibitor that potentiates nitric oxide responses, would augment both the blood oxygen level-dependent (BOLD) response and cerebral blood flow (CBF) in patients with BMD. Seventeen patients (mean ± SD age 38.5 ± 10.8 years) with BMD were included in this randomized, double-blind, placebo-controlled, crossover trial. Twelve patients completed the entire study. Effects of sildenafil were assessed by 3 T magnetic resonance (MR) scanning, evoked potentials, somatosensory task-induced BOLD functional MR imaging, regional and global perfusion, and angiography before and after 4 weeks of sildenafil, 20 mg (Revatio in gelatine capsules, oral, 3 times daily), or placebo treatment. Sildenafil increased the event-related sensory and visual BOLD response compared with placebo (p < 0.01). However, sildenafil did not alter CBF, measured by MR phase contrast mapping, or the arterial diameter of the middle cerebral artery, measured by MR angiography. We conclude that nNOS may play a role in event-related neurovascular responses. Further studies in patients with BMD may help clarify the roles of dystrophin and nNOS in neurovascular coupling in general, and in patients with BMD in particular.

AB - Patients suffering from Becker muscular dystrophy (BMD) have dysfunctional dystrophin proteins and are deficient in neuronal nitric oxide synthase (nNOS) in muscles. This causes functional ischemia and contributes to muscle wasting. Similar functional ischemia may be present in brains of patients with BMD, who often have mild cognitive impairment, and nNOS may be important for the regulation of the microvascular circulation in the brain. We hypothesized that treatment with sildenafil, a phosphodiesterase type 5 inhibitor that potentiates nitric oxide responses, would augment both the blood oxygen level-dependent (BOLD) response and cerebral blood flow (CBF) in patients with BMD. Seventeen patients (mean ± SD age 38.5 ± 10.8 years) with BMD were included in this randomized, double-blind, placebo-controlled, crossover trial. Twelve patients completed the entire study. Effects of sildenafil were assessed by 3 T magnetic resonance (MR) scanning, evoked potentials, somatosensory task-induced BOLD functional MR imaging, regional and global perfusion, and angiography before and after 4 weeks of sildenafil, 20 mg (Revatio in gelatine capsules, oral, 3 times daily), or placebo treatment. Sildenafil increased the event-related sensory and visual BOLD response compared with placebo (p < 0.01). However, sildenafil did not alter CBF, measured by MR phase contrast mapping, or the arterial diameter of the middle cerebral artery, measured by MR angiography. We conclude that nNOS may play a role in event-related neurovascular responses. Further studies in patients with BMD may help clarify the roles of dystrophin and nNOS in neurovascular coupling in general, and in patients with BMD in particular.

KW - Adult

KW - Brain/blood supply

KW - Brain Mapping

KW - Double-Blind Method

KW - Humans

KW - Hypercapnia/diagnostic imaging

KW - Magnetic Resonance Imaging

KW - Middle Aged

KW - Muscular Dystrophy, Duchenne/diagnostic imaging

KW - Phosphodiesterase 5 Inhibitors/administration & dosage

KW - Physical Stimulation

KW - Psychomotor Performance

KW - Sildenafil Citrate/administration & dosage

KW - Touch Perception/physiology

KW - Treatment Outcome

U2 - 10.1007/s13311-016-0467-x

DO - 10.1007/s13311-016-0467-x

M3 - Journal article

C2 - 27485237

VL - 14

SP - 182

EP - 190

JO - Neurotherapeutics

JF - Neurotherapeutics

SN - 1933-7213

IS - 1

ER -