Vardenafil, but not sildenafil or tadalafil, has calcium‐channel blocking activity in rabbit isolated pulmonary artery and human washed platelets

• Published in: British journal of pharmacology 2008-06, Vol.154 (4), p.787-796
• Main Authors: Toque, H A, Teixeira, C E, Priviero, F B M, Morganti, R P, Antunes, E, De Nucci, G
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Blood Platelets - drug effects; Blood Platelets - metabolism; Calcium - metabolism; calcium blockade; Calcium Channel Blockers - administration & dosage; Calcium Channel Blockers - pharmacology; Calcium Channels - drug effects; Calcium Channels - metabolism; Carbolines - administration & dosage; Carbolines - pharmacology; cGMP; Dose-Response Relationship, Drug; endothelium; Endothelium, Vascular - metabolism; Humans; Imidazoles - administration & dosage; Imidazoles - pharmacology; In Vitro Techniques; Male; Medical sciences; PDE5 inhibitors; Pharmacology. Drug treatments; Phosphodiesterase Inhibitors - administration & dosage; Phosphodiesterase Inhibitors - pharmacology; Piperazines - administration & dosage; Piperazines - pharmacology; pulmonary artery; Pulmonary Artery - drug effects; Pulmonary Artery - metabolism; Purines - administration & dosage; Purines - pharmacology; Rabbits; relaxation; Research Papers; Sildenafil Citrate; Sulfones - administration & dosage; Sulfones - pharmacology; Tadalafil; Triazines - administration & dosage; Triazines - pharmacology; Vardenafil Dihydrochloride; Vasodilation - drug effects
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/bjp.2008.141

Background and purpose: Phosphodiesterase type‐5 (PDE5) inhibitors constitute a novel and important therapeutic option for the treatment of pulmonary hypertension. The effects of the PDE5 inhibitors sildenafil, tadalafil and vardenafil on rabbit isolated pulmonary artery ring preparations and on intracellular Ca2+ concentration of thrombin‐stimulated human platelets were investigated. Experimental approach: Rabbit pulmonary artery rings were mounted in 10 mL organ bath containing Krebs solution. Tissues were connected to force‐displacement transducers, and changes in isometric force were recorded. Ca2+ flux in human washed platelets was measured. Key results: Sildenafil, tadalafil and vardenafil (0.0001–10 μM) concentration‐dependently relaxed endothelium‐intact and endothelium‐denuded pulmonary artery rings. Endothelium denudation caused rightward shifts in the concentration–response curves to sildenafil, tadalafil and vardenafil (9‐, 12‐ and 123‐fold, respectively). Incubation with Nω‐nitro‐L‐arginine methyl ester (100 μM) or ODQ (1H‐[1,2,4] oxadiazolo [4,3,‐a]quinoxalin‐1‐one) (10 μM) caused similar reductions of PDE5‐induced vasorelaxations in intact rings. Sildenafil and tadalafil did not affect the phenylephrine‐induced contractions, whereas vardenafil reduced the maximal responses, and shifted the phenylephrine‐induced contraction curves to the right in endothelium‐denuded rings (5‐ and 19‐fold for 1 and 10 μM, respectively). Vardenafil (but neither sildenafil nor tadalafil) caused a marked rightward shift and a decrease of maximal contractile response to CaCl2. Vardenafil, but neither sildenafil nor tadalafil, significantly reduced the Ca2+ mobilization and Ca2+ influx in thrombin‐stimulated washed platelets. Conclusions and implications: Our results indicate that vardenafil, in contrast to sildenafil or tadalafil, also blocked Ca2+ fluxes, thus enhancing its vasorelaxation of the pulmonary artery. British Journal of Pharmacology (2008) 154, 787–796; doi:10.1038/bjp.2008.141; published online 21 April 2008