Biology Reference
In-Depth Information
achieved by acute application of the PDE5 inhibitor, tadalafil. Tadalafil treatment
reversed the ischemia and reduced contraction-induced lesions and myofiber death.
Pregnant mice were administered tadalafil in their drinking water (1 mg tadalafil per
100 mL); thus, pups had received tadalafil in utero and then also received tadalafil
in their drinking water until 4 weeks of age (Asai et al.
2007
). Treated hind limb
and respiratory skeletal muscles exhibited reduced muscle necrosis and fibrosis
(Asai et al.
2007
). In addition, treated
mdx
muscles also exhibited decreased
variability in myofiber size and a reduction in regenerating centrally nucleated
myofibers, suggesting that tadalafil decreased muscle degeneration.
Taken together, these data suggest that tadalafil-mediated inhibition of PDE5A
was sufficient to restore blood supply to muscles after exercise and significantly
reduced contraction-induced damage in the dystrophin-deficient skeletal muscles.
Like the heart, PDE5A inhibition resulted in less contraction-induced damage in
mdx
muscles. The work of Asai and coworkers supports the proposition that
vascular therapy with PDE5A inhibitors may be of therapeutic benefit to DMD
patients.
Consistent with findings that
mdx
myofibers in situ experience excessive con-
traction-induced damage under ischemic conditions,
mdx
mice exhibit marked cage
inactivity after mild treadmill exercise (Kobayashi et al.
2008
). KN1 (nNOS
knockout 1) mice also exhibited the same postexercise inactivity, suggesting to
the authors that loss of skeletal muscle sarcolemmal nNOS
m
was responsible. This
postexercise decrease in cage activity is thought to be analogous to the exaggerated
fatigue response to mild exercise observed in patients with neuromuscular diseases
such as DMD.
To test the impact of improved postcontraction blood flow on postexercise cage
activity, Kobayashi and coworkers treated
mdx
and KN1 mice acutely with tadalafil
or sildenafil. Sildenafil (300 mg/kg/day) was administered in the food, while
tadalafil (300 mg/kg/day) was administered directly by gavage. Both inhibitors
were administered the day before and on the day of exercise testing. PDE5A
inhibition substantially increased perfusion of the
mdx
hind limb with blood after
exercise. Interestingly, postexercise inactivity was reduced 30-40% by PDE5A
inhibition in
mdx
mice, but was unaffected in KN1 mice, demonstrating that
nNOS expression (nNOS-2, nNOS
a
, nNOS
m
) is required for the postexercise
benefits of PDE5A inhibition. This is consistent with findings that NO is required
for both basal and maximal activation of sGC activity and for many of the
physiological effects of sildenafil (Nagayama et al.
2008
; Fernhoff et al.
2009
).
This may be an important consideration since nNOS levels may be substantially
lower or absent in DMD patients, thus lowering the potential efficacy of sildenafil
(Chang et al.
1996
). Treated
mdx
mice ran twice the distance of untreated
mdx
mice. Despite increased exercise performance, serum CK activity was significantly
reduced, suggesting reduced membrane permeability in agreement with results
reported by Asai et al. (
2007
). Together, these data suggest that in dystrophin-
deficient muscle tissues, the loss of the vasomodulatory function of nNOS
m
may be
compensated for, to some degree, by PDE5A inhibition.
