Abstract 15076: Phosphodiesterase 5A Inhibition Prevents Functional Muscle Ischemia in the Mdx Mouse Model of Duchenne/Becker Muscular Dystrophy
Background: The fatal muscle-wasting diseases Duchenne and Becker muscular dystrophy (DMD, BMD) are caused by mutations in the gene encoding dystrophin, a cytoskeletal protein that provides mechanical support and targets other proteins to the sarcolemma including the muscle-specific variant of neuronal nitric oxide synthase (nNOS). Loss of sarcolemmal nNOS impairs the normal paracrine effect of muscle-derived NO to attenuate α-adrenergic vasoconstriction in exercising muscle and renders the dystrophin-deficient muscles of boys with DMD and mdx mice susceptible to ischemia. We hypothesized that treatment with a phosphodiesterase 5A (PDE5A) inhibitor to reduce cGMP breakdown and enhance the NO signal from residual cytosolic nNOS would prevent functional muscle ischemia in mdx mice.
Methods: Male C57BL6 or mdx mice (10-14 wks old) were anesthetized and instrumented to measure arterial pressure and femoral artery blood flow responses to intra-arterial delivery of norepinephrine (NE) into the resting and contracting hindlimbs. Mdx mice were studied after acute treatment with vehicle or one of two chemically distinct PDE5A inhibitors: the first generation, short-acting inhibitor zaprinast (4, 8 mg/kg, ip) or the more potent, long-acting inhibitor tadalafil (2, 4, 8, 16 mg/kg, po).
Results: Compared to responses in the resting hindlimbs, NE-mediated vasoconstriction was appropriately attenuated by 64 ± 6% in the contracting hindlimbs of C57BL6 mice (n = 8), but was reduced only by 7 ± 10% in the contracting hindlimbs of vehicle-treated mdx mice (n = 10; P<0.05 vs BL6), indicating functional ischemia. This NE-induced ischemia in the mdx mice was prevented by PDE5A inhibition: vasoconstrictor responses in the contracting hindlimbs were attenuated by 76 ± 5% with zaprinast (8 mg/kg; n = 10; P<0.05 vs vehicle) and by 69 ± 9% with tadalafil (4 mg/kg; n = 6; P<0.05 vs vehicle).
Conclusion: These data indicate that PDE5A inhibition prevents NE-induced ischemia in the contracting muscles of mdx mice. A tadalafil dose of 4 mg/kg in the mdx mouse is equivalent to 20 mg in humans, which is the highest FDA-approved dose used to treat erectile dysfunction. These findings suggest a novel potential use for tadalafil to ameliorate functional muscle ischemia in DMD and BMD patients.
- © 2012 by American Heart Association, Inc.