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: Yasutomo Hori, Chigusa Kondo, Maho Matsui, Maki Yamagishi, Shozo Okano, Seishiro Chikazawa, Kazutaka Kanai, Fumio Hoshi, Naoyuki Itoh
• Journal: Veterinary journal (London, England : 1997) (Vet J) Vol. 202 Issue 2 Pg. 334-9 (Nov 2014) ISSN: 1532-2971 [Electronic] England
• PMID: 25178687 (Publication Type: Journal Article, Randomized Controlled Trial)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Carbolines
• Phosphodiesterase 5 Inhibitors
• Vasoconstrictor Agents
• Tadalafil
• 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid

Topics

• 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid (pharmacology)
• Administration, Intravenous (veterinary)
• Administration, Oral
• Animals
• Carbolines (pharmacology, therapeutic use)
• Cross-Over Studies
• Disease Models, Animal
• Dogs
• Dose-Response Relationship, Drug
• Female
• Hemodynamics (drug effects)
• Hypertension, Pulmonary (chemically induced, drug therapy, physiopathology)
• Male
• Phosphodiesterase 5 Inhibitors (pharmacology)
• Random Allocation
• Tadalafil
• Time Factors
• Vascular Resistance (drug effects)
• Vasoconstrictor Agents (pharmacology, therapeutic use)