title: Effect of the phosphodiesterase type 5 inhibitor tadalafil on pulmonary hemodynamics in a canine model of pulmonary hypertension.
abstract: 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.
authors.affiliation: Laboratory of Small Animal Internal Medicine, School of Veterinary Medicine, Kitasato University, 23-35-1 Higashi, Towada, Aomori 034-8628, Japan. Electronic address: hori@vmas.kitasato-u.ac.jp.
authors.forename: Yasutomo
authors.initials: Y
authors.lastname: Hori
authors.affiliation: Laboratory of Small Animal Internal Medicine, School of Veterinary Medicine, Kitasato University, 23-35-1 Higashi, Towada, Aomori 034-8628, Japan.
authors.forename: Chigusa
authors.initials: C
authors.lastname: Kondo
authors.affiliation: Laboratory of Small Animal Internal Medicine, School of Veterinary Medicine, Kitasato University, 23-35-1 Higashi, Towada, Aomori 034-8628, Japan.
authors.forename: Maho
authors.initials: M
authors.lastname: Matsui
authors.affiliation: Laboratory of Small Animal Internal Medicine, School of Veterinary Medicine, Kitasato University, 23-35-1 Higashi, Towada, Aomori 034-8628, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Yamagishi
authors.affiliation: Laboratory of Small Animal Surgery 2, School of Veterinary Medicine, Kitasato University, 23-35-1 Higashi, Towada, Aomori 034-8628, Japan.
authors.forename: Shozo
authors.initials: S
authors.lastname: Okano
authors.affiliation: Laboratory of Small Animal Internal Medicine, School of Veterinary Medicine, Kitasato University, 23-35-1 Higashi, Towada, Aomori 034-8628, Japan.
authors.forename: Seishiro
authors.initials: S
authors.lastname: Chikazawa
authors.affiliation: Laboratory of Small Animal Internal Medicine, School of Veterinary Medicine, Kitasato University, 23-35-1 Higashi, Towada, Aomori 034-8628, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Kanai
authors.affiliation: Laboratory of Small Animal Internal Medicine, School of Veterinary Medicine, Kitasato University, 23-35-1 Higashi, Towada, Aomori 034-8628, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Hoshi
authors.affiliation: Laboratory of Small Animal Internal Medicine, School of Veterinary Medicine, Kitasato University, 23-35-1 Higashi, Towada, Aomori 034-8628, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Itoh
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D061605:Administration, Intravenous / Q000662:veterinary; D000284:Administration, Oral; D000818:Animals; D002243:Carbolines / Q000494:pharmacology* / Q000627:therapeutic use; D018592:Cross-Over Studies; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D008297:Male; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D011897:Random Allocation; D000068581:Tadalafil; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D002243:Carbolines; D058986:Phosphodiesterase 5 Inhibitors; D014662:Vasoconstrictor Agents; D000068581:Tadalafil; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
keywords: Dog; Hemodynamic; Phosphodiesterase type 5 (PDE5) inhibitor; Pulmonary arterial hypertension; Tadalafil