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Differential effects of the phosphodiesterase type 5 inhibitors sildenafil, vardenafil, and tadalafil in rat aorta.
J Pharmacol Exp Ther. 2006 Feb; 316(2):654-61.JP

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 microM) 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(omega)-nitro-L-arginine methyl ester, 100 microM), guanylyl cyclase (1H-[1,2,4]oxadiazolo [4,3,-a]quinoxalin-1-one, 10 microM), or scavenging of NO ([carboxy-PTIO (2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide), 100 microM]) caused similar attenuation of the vasorelaxations evoked by PDE5 inhibitors. Sildenafil, tadalafil, and vardenafil significantly potentiated relaxations mediated by glyceryl trinitrate (0.0001-3 microM; 8-13-fold) and atrial natriuretic peptide (0.1-100 nM; 2-3-fold). Contractions evoked by CaCl(2) (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 Ca(2+) handling in the rat aorta in addition to increasing cGMP levels through inhibition of PDE5 to cause relaxation.

Authors+Show Affiliations

Department of Physiology, Medical College of Georgia, Augusta, 30912-3000, USA. cteixeira@mail.mcg.eduNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16204472

Citation

Teixeira, Cleber E., et al. "Differential Effects of the Phosphodiesterase Type 5 Inhibitors Sildenafil, Vardenafil, and Tadalafil in Rat Aorta." The Journal of Pharmacology and Experimental Therapeutics, vol. 316, no. 2, 2006, pp. 654-61.
Teixeira CE, Priviero FB, Webb RC. Differential effects of the phosphodiesterase type 5 inhibitors sildenafil, vardenafil, and tadalafil in rat aorta. J Pharmacol Exp Ther. 2006;316(2):654-61.
Teixeira, C. E., Priviero, F. B., & Webb, R. C. (2006). Differential effects of the phosphodiesterase type 5 inhibitors sildenafil, vardenafil, and tadalafil in rat aorta. The Journal of Pharmacology and Experimental Therapeutics, 316(2), 654-61.
Teixeira CE, Priviero FB, Webb RC. Differential Effects of the Phosphodiesterase Type 5 Inhibitors Sildenafil, Vardenafil, and Tadalafil in Rat Aorta. J Pharmacol Exp Ther. 2006;316(2):654-61. PubMed PMID: 16204472.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Differential effects of the phosphodiesterase type 5 inhibitors sildenafil, vardenafil, and tadalafil in rat aorta. AU - Teixeira,Cleber E, AU - Priviero,Fernanda B M, AU - Webb,R Clinton, Y1 - 2005/10/04/ PY - 2005/10/6/pubmed PY - 2006/4/6/medline PY - 2005/10/6/entrez SP - 654 EP - 61 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 316 IS - 2 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 microM) 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(omega)-nitro-L-arginine methyl ester, 100 microM), guanylyl cyclase (1H-[1,2,4]oxadiazolo [4,3,-a]quinoxalin-1-one, 10 microM), or scavenging of NO ([carboxy-PTIO (2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide), 100 microM]) caused similar attenuation of the vasorelaxations evoked by PDE5 inhibitors. Sildenafil, tadalafil, and vardenafil significantly potentiated relaxations mediated by glyceryl trinitrate (0.0001-3 microM; 8-13-fold) and atrial natriuretic peptide (0.1-100 nM; 2-3-fold). Contractions evoked by CaCl(2) (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 Ca(2+) handling in the rat aorta in addition to increasing cGMP levels through inhibition of PDE5 to cause relaxation. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/16204472/Differential_effects_of_the_phosphodiesterase_type_5_inhibitors_sildenafil_vardenafil_and_tadalafil_in_rat_aorta_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=16204472 DB - PRIME DP - Unbound Medicine ER -