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

Haroldo Alfredo Flores Toque, C. E. Teixeira, Fernanda Priviero, R. P. Morganti, E. Antunes, G. De Nucci

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

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 Ca 2+ 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. Ca 2+ 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 N ω-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 CaCl 2. Vardenafil, but neither sildenafil nor tadalafil, significantly reduced the Ca 2+ mobilization and Ca 2+ influx in thrombin-stimulated washed platelets. Conclusions and implications: Our results indicate that vardenafil, in contrast to sildenafil or tadalafil, also blocked Ca 2+ fluxes, thus enhancing its vasorelaxation of the pulmonary artery.

Original languageEnglish (US)
Pages (from-to)787-796
Number of pages10
JournalBritish Journal of Pharmacology
Volume154
Issue number4
DOIs
StatePublished - Jun 21 2008

Fingerprint

Calcium Channels
Pulmonary Artery
Blood Platelets
Rabbits
Endothelium
Phosphodiesterase 5 Inhibitors
Phenylephrine
Vasodilation
Thrombin
Type 5 Cyclic Nucleotide Phosphodiesterases
Quinoxalines
Sildenafil Citrate
Tadalafil
Vardenafil Dihydrochloride
Transducers
Baths
Pulmonary Hypertension
Therapeutics

Keywords

  • Calcium blockade
  • Endothelium
  • NO
  • PDE5 inhibitors
  • Pulmonary artery
  • Relaxation
  • cGMP

ASJC Scopus subject areas

  • Pharmacology

Cite this

Vardenafil, but not sildenafil or tadalafil, has calcium-channel blocking activity in rabbit isolated pulmonary artery and human washed platelets. / Flores Toque, Haroldo Alfredo; Teixeira, C. E.; Priviero, Fernanda; Morganti, R. P.; Antunes, E.; De Nucci, G.

In: British Journal of Pharmacology, Vol. 154, No. 4, 21.06.2008, p. 787-796.

Research output: Contribution to journalArticle

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abstract = "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 Ca 2+ 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. Ca 2+ 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 N ω-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 CaCl 2. Vardenafil, but neither sildenafil nor tadalafil, significantly reduced the Ca 2+ mobilization and Ca 2+ influx in thrombin-stimulated washed platelets. Conclusions and implications: Our results indicate that vardenafil, in contrast to sildenafil or tadalafil, also blocked Ca 2+ fluxes, thus enhancing its vasorelaxation of the pulmonary artery.",
keywords = "Calcium blockade, Endothelium, NO, PDE5 inhibitors, Pulmonary artery, Relaxation, cGMP",
author = "{Flores Toque}, {Haroldo Alfredo} and Teixeira, {C. E.} and Fernanda Priviero and Morganti, {R. P.} and E. Antunes and {De Nucci}, G.",
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T1 - Vardenafil, but not sildenafil or tadalafil, has calcium-channel blocking activity in rabbit isolated pulmonary artery and human washed platelets

AU - Flores Toque, Haroldo Alfredo

AU - Teixeira, C. E.

AU - Priviero, Fernanda

AU - Morganti, R. P.

AU - Antunes, E.

AU - De Nucci, G.

PY - 2008/6/21

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N2 - 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 Ca 2+ 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. Ca 2+ 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 N ω-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 CaCl 2. Vardenafil, but neither sildenafil nor tadalafil, significantly reduced the Ca 2+ mobilization and Ca 2+ influx in thrombin-stimulated washed platelets. Conclusions and implications: Our results indicate that vardenafil, in contrast to sildenafil or tadalafil, also blocked Ca 2+ fluxes, thus enhancing its vasorelaxation of the pulmonary artery.

AB - 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 Ca 2+ 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. Ca 2+ 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 N ω-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 CaCl 2. Vardenafil, but neither sildenafil nor tadalafil, significantly reduced the Ca 2+ mobilization and Ca 2+ influx in thrombin-stimulated washed platelets. Conclusions and implications: Our results indicate that vardenafil, in contrast to sildenafil or tadalafil, also blocked Ca 2+ fluxes, thus enhancing its vasorelaxation of the pulmonary artery.

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KW - cGMP

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