Differential effects of the phosphodiesterase type 5 inhibitors sildenafil, vardenafil, and tadalafil in rat aorta

Cleber E. Teixeira, Fernanda Priviero, R Clinton Webb

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Abstract

Presumably, the vasorelaxant properties of phosphodiesterase type 5 (PDE5) inhibitors are similar in isolated blood vessels. We aimed to explore the mechanisms underlying the vasorelaxation induced by the selective PDE5 inhibitors sildenafil, vardenafil, and tadalafil in the rat aorta. Aortic rings were mounted in 5-ml organ baths, and concentration-response curves for PDE5 inhibitors (0.0001-10 μM) were constructed in phenylephrine (PE)-precontracted endothelium-intact and -denuded rings. Cyclic nucleotides were measured using enzyme immunoassay kits. Sildenafil, vardenafil, and tadalafil concentration dependently relaxed aortic rings and increased cGMP, but not cAMP, concentrations. Endothelium denudation caused marked rightward shifts in the curves to sildenafil (45-fold), tadalafil (21-fold), and vardenafil (251-fold). Maximal responses to sildenafil and tadalafil were substantially reduced (38 ± 1% and 53 ± 2%, respectively), whereas that evoked by vardenafil was not affected. Likewise, inhibition of NO synthase (N ω-nitro-L-arginine methyl ester, 100 μM), guanylyl cyclase (1H-[1,2,4]oxadiazolo [4,3,-a]quinoxalin-1-one, 10 μM), or scavenging of NO ([carboxy-PTIO (2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3- oxide), 100 μM]) caused similar attenuation of the vasorelaxations evoked by PDE5 inhibitors. Sildenafil, tadalafil, and vardenafil significantly potentiated relaxations mediated by glyceryl trinitrate (0.0001-3 μM; 8-13-fold) and atrial natriuretic peptide (0.1-100 nM; 2-3-fold). Contractions evoked by CaCl2 (0.01-5 mM) in PE-treated rings were significantly reduced (26 ± 4%) by vardenafil, but not sildenafil or tadalafil, whereas phorbol 12,13-dibutyrate-induced contractions were not affected. Ouabain, cyclopiazonic acid, and calyculin A failed to affect vasorelaxations induced by the PDE5 inhibitors. These results suggest that vardenafil, but not sildenafil or tadalafil, affects Ca2+ handling in the rat aorta in addition to increasing cGMP levels through inhibition of PDE5 to cause relaxation.

Original languageEnglish (US)
Pages (from-to)654-661
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume316
Issue number2
DOIs
StatePublished - Feb 1 2006

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Phosphodiesterase 5 Inhibitors
Aorta
Vasodilation
Phenylephrine
Endothelium
Type 5 Cyclic Nucleotide Phosphodiesterases
Phorbol 12,13-Dibutyrate
Guanylate Cyclase
Cyclic Nucleotides
Nitroglycerin
Atrial Natriuretic Factor
Ouabain
Sildenafil Citrate
Tadalafil
Vardenafil Dihydrochloride
Immunoenzyme Techniques
Vasodilator Agents
Baths
Nitric Oxide Synthase
Blood Vessels

ASJC Scopus subject areas

  • Pharmacology

Cite this

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title = "Differential effects of the phosphodiesterase type 5 inhibitors sildenafil, vardenafil, and tadalafil in rat aorta",
abstract = "Presumably, the vasorelaxant properties of phosphodiesterase type 5 (PDE5) inhibitors are similar in isolated blood vessels. We aimed to explore the mechanisms underlying the vasorelaxation induced by the selective PDE5 inhibitors sildenafil, vardenafil, and tadalafil in the rat aorta. Aortic rings were mounted in 5-ml organ baths, and concentration-response curves for PDE5 inhibitors (0.0001-10 μM) were constructed in phenylephrine (PE)-precontracted endothelium-intact and -denuded rings. Cyclic nucleotides were measured using enzyme immunoassay kits. Sildenafil, vardenafil, and tadalafil concentration dependently relaxed aortic rings and increased cGMP, but not cAMP, concentrations. Endothelium denudation caused marked rightward shifts in the curves to sildenafil (45-fold), tadalafil (21-fold), and vardenafil (251-fold). Maximal responses to sildenafil and tadalafil were substantially reduced (38 ± 1{\%} and 53 ± 2{\%}, respectively), whereas that evoked by vardenafil was not affected. Likewise, inhibition of NO synthase (N ω-nitro-L-arginine methyl ester, 100 μM), guanylyl cyclase (1H-[1,2,4]oxadiazolo [4,3,-a]quinoxalin-1-one, 10 μM), or scavenging of NO ([carboxy-PTIO (2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3- oxide), 100 μM]) caused similar attenuation of the vasorelaxations evoked by PDE5 inhibitors. Sildenafil, tadalafil, and vardenafil significantly potentiated relaxations mediated by glyceryl trinitrate (0.0001-3 μM; 8-13-fold) and atrial natriuretic peptide (0.1-100 nM; 2-3-fold). Contractions evoked by CaCl2 (0.01-5 mM) in PE-treated rings were significantly reduced (26 ± 4{\%}) by vardenafil, but not sildenafil or tadalafil, whereas phorbol 12,13-dibutyrate-induced contractions were not affected. Ouabain, cyclopiazonic acid, and calyculin A failed to affect vasorelaxations induced by the PDE5 inhibitors. These results suggest that vardenafil, but not sildenafil or tadalafil, affects Ca2+ handling in the rat aorta in addition to increasing cGMP levels through inhibition of PDE5 to cause relaxation.",
author = "Teixeira, {Cleber E.} and Fernanda Priviero and Webb, {R Clinton}",
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T1 - Differential effects of the phosphodiesterase type 5 inhibitors sildenafil, vardenafil, and tadalafil in rat aorta

AU - Teixeira, Cleber E.

AU - Priviero, Fernanda

AU - Webb, R Clinton

PY - 2006/2/1

Y1 - 2006/2/1

N2 - Presumably, the vasorelaxant properties of phosphodiesterase type 5 (PDE5) inhibitors are similar in isolated blood vessels. We aimed to explore the mechanisms underlying the vasorelaxation induced by the selective PDE5 inhibitors sildenafil, vardenafil, and tadalafil in the rat aorta. Aortic rings were mounted in 5-ml organ baths, and concentration-response curves for PDE5 inhibitors (0.0001-10 μM) were constructed in phenylephrine (PE)-precontracted endothelium-intact and -denuded rings. Cyclic nucleotides were measured using enzyme immunoassay kits. Sildenafil, vardenafil, and tadalafil concentration dependently relaxed aortic rings and increased cGMP, but not cAMP, concentrations. Endothelium denudation caused marked rightward shifts in the curves to sildenafil (45-fold), tadalafil (21-fold), and vardenafil (251-fold). Maximal responses to sildenafil and tadalafil were substantially reduced (38 ± 1% and 53 ± 2%, respectively), whereas that evoked by vardenafil was not affected. Likewise, inhibition of NO synthase (N ω-nitro-L-arginine methyl ester, 100 μM), guanylyl cyclase (1H-[1,2,4]oxadiazolo [4,3,-a]quinoxalin-1-one, 10 μM), or scavenging of NO ([carboxy-PTIO (2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3- oxide), 100 μM]) caused similar attenuation of the vasorelaxations evoked by PDE5 inhibitors. Sildenafil, tadalafil, and vardenafil significantly potentiated relaxations mediated by glyceryl trinitrate (0.0001-3 μM; 8-13-fold) and atrial natriuretic peptide (0.1-100 nM; 2-3-fold). Contractions evoked by CaCl2 (0.01-5 mM) in PE-treated rings were significantly reduced (26 ± 4%) by vardenafil, but not sildenafil or tadalafil, whereas phorbol 12,13-dibutyrate-induced contractions were not affected. Ouabain, cyclopiazonic acid, and calyculin A failed to affect vasorelaxations induced by the PDE5 inhibitors. These results suggest that vardenafil, but not sildenafil or tadalafil, affects Ca2+ handling in the rat aorta in addition to increasing cGMP levels through inhibition of PDE5 to cause relaxation.

AB - Presumably, the vasorelaxant properties of phosphodiesterase type 5 (PDE5) inhibitors are similar in isolated blood vessels. We aimed to explore the mechanisms underlying the vasorelaxation induced by the selective PDE5 inhibitors sildenafil, vardenafil, and tadalafil in the rat aorta. Aortic rings were mounted in 5-ml organ baths, and concentration-response curves for PDE5 inhibitors (0.0001-10 μM) were constructed in phenylephrine (PE)-precontracted endothelium-intact and -denuded rings. Cyclic nucleotides were measured using enzyme immunoassay kits. Sildenafil, vardenafil, and tadalafil concentration dependently relaxed aortic rings and increased cGMP, but not cAMP, concentrations. Endothelium denudation caused marked rightward shifts in the curves to sildenafil (45-fold), tadalafil (21-fold), and vardenafil (251-fold). Maximal responses to sildenafil and tadalafil were substantially reduced (38 ± 1% and 53 ± 2%, respectively), whereas that evoked by vardenafil was not affected. Likewise, inhibition of NO synthase (N ω-nitro-L-arginine methyl ester, 100 μM), guanylyl cyclase (1H-[1,2,4]oxadiazolo [4,3,-a]quinoxalin-1-one, 10 μM), or scavenging of NO ([carboxy-PTIO (2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3- oxide), 100 μM]) caused similar attenuation of the vasorelaxations evoked by PDE5 inhibitors. Sildenafil, tadalafil, and vardenafil significantly potentiated relaxations mediated by glyceryl trinitrate (0.0001-3 μM; 8-13-fold) and atrial natriuretic peptide (0.1-100 nM; 2-3-fold). Contractions evoked by CaCl2 (0.01-5 mM) in PE-treated rings were significantly reduced (26 ± 4%) by vardenafil, but not sildenafil or tadalafil, whereas phorbol 12,13-dibutyrate-induced contractions were not affected. Ouabain, cyclopiazonic acid, and calyculin A failed to affect vasorelaxations induced by the PDE5 inhibitors. These results suggest that vardenafil, but not sildenafil or tadalafil, affects Ca2+ handling in the rat aorta in addition to increasing cGMP levels through inhibition of PDE5 to cause relaxation.

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