Effect of the phosphodiesterase type 5 inhibitor tadalafil on pulmonary hemodynamics in a canine model of pulmonary hypertension

• A dog model of pulmonary arterial hypertension was used to evaluate the pharmacology of tadalafil in dogs.
• Intravenous infusion of tadalafil decreased U46619-elevated pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) in dogs without changes in systemic arterial pressure (SAP) and systemic vascular resistance (SVR).
• Oral administration of tadalafil alone did not change PAP, but decreased U46619-elevated PAP. The effect occurred 1 h after oral administration and was maintained for 6 h.
• These results suggest that tadalafil improved U46619-induced pulmonary arterial constriction, leading to pulmonary arterial relaxation.

Phosphodiesterase type 5 (PDE5) inhibitors are used for treating pulmonary arterial hypertension (PAH) in dogs. The long-acting PDE5 inhibitor tadalafil was recently approved for treatment of PAH in humans. Basic information related to the pharmacological and hemodynamic effects of tadalafil in dogs is scarce. In this study, the hemodynamic effects of tadalafil after intravenous (IV) and oral administration were investigated in a healthy vasoconstrictive PAH Beagle dog model induced by U46619, a thromboxane A2 mimetic. Six healthy Beagle dogs were anesthetized with propofol and maintained with isoflurane. Fluid-filled catheters were placed into the descending aorta to measure systemic arterial pressure and in the pulmonary artery to measure pulmonary arterial pressure (PAP). U46619 was infused via the cephalic vein to induce PAH.IV infusion of U46619 significantly elevated PAP from baseline in a dose-dependent manner. U46619-elevated PAP and pulmonary vascular resistance was significantly attenuated by the simultaneous infusion of tadalafil at 100 and 200 µg/kg/h. Likewise, oral administration of tadalafil at 1.0, 2.0, and 4.0 mg/kg significantly attenuated U46619-elevated PAP in a dose-dependent manner. U46619-elevated systolic and mean PAP decreased significantly 1 h after oral tadalafil administration at 4.0 mg/kg, and this effect was maintained for 6 h. In conclusion, tadalafil had a pharmacological effect in dogs and IV infusion of tadalafil induced pulmonary arterial relaxation, while oral administration of tadalafil decreased PAP. These results suggest that tadalafil may offer a new therapeutic option for treating dogs with PAH.