Tadalafil, a long-acting inhibitor of PDE5, improves pulmonary hemodynamics and survival rate of monocrotaline-induced pulmonary artery hypertension in rats.
The aim of this study was to assess the effect of tadalafil (0.5, 2.5, and 10 mg/kg per day) on the progression of pulmonary arterial hypertension (PAH) in early treatment and on the survival rate in late treatment on the monocrotaline (MCT)-induced PAH rat model. Tadalafil was administered once daily to rats for 3 weeks from the day of MCT-injection or 21 days after the injection. With early treatment, tadalafil at 10 mg/kg per day prevented the development of PAH by maintaining mean pulmonary artery pressure within the normal range and attenuated right ventricular hypertrophy. With late treatment, tadalafil tended to increase the partial pressure of oxygen in arterial blood and dose-dependently improved the survival rate by 55%, 60%, and 70% at 0.5, 2.5, and 10 mg/kg per day, respectively, versus 40% in the MCT-control group. Both early and late treatments with tadalafil were associated with elevated lung cyclic guanosine monophosphate (cGMP). These results suggest that tadalafil relaxes pulmonary arteries by elevating cGMP in lungs and extend survival time by improving pulmonary hemodynamics even when treatment occurs in the late phase of PAH. Thus, it is expected that tadalafil may be an effective, once-daily treatment option in humans with PAH.
Sawamura
Fusae
F
Lilly Research Laboratories Japan, Eli Lilly Japan K.K., Japan. sawamura_fusae@lilly.com
Kato
Masami
M
Fujita
Kazuhisa
K
Nakazawa
Takahiro
T
Beardsworth
Anthony
A
D000818:Animals; D001784:Blood Gas Analysis; D002243:Carbolines / Q000494:pharmacology / Q000627:therapeutic use*; D006152:Cyclic GMP / Q000378:metabolism; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D016686:Monocrotaline; D009929:Organ Size / Q000187:drug effects; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D011042:Poisons; D011652:Pulmonary Circulation / Q000187:drug effects*; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use; D013534:Survival; D000068581:Tadalafil
D002243:Carbolines; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011042:Poisons; D011687:Purines; D013450:Sulfones; D016686:Monocrotaline; D000068581:Tadalafil; D000068677:Sildenafil Citrate; D006152:Cyclic GMP