Effect of the phosphodiesterase 5 inhibitors sildenafil, tadalafil and vardenafil on rat anococcygeus muscle: Functional and biochemical aspects

Haroldo Alfredo Flores Toque, Fernanda Priviero, Saiprasad M. Zemse, Edson Antunes, Cleber E. Teixeira, R Clinton Webb

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

The anococcygeus muscle is part of the erectile machinery in male rodents. Phosphodiesterase (PDE) 5 inhibitors enhance and prolong the effects of cGMP, which has a key role in penile erection. The aim of the present study was to provide a functional and biochemical comparison of the three PDE5 inhibitors, namely sildenafil, tadalafil and vardenafil, in the rat anococcygeus muscle. Muscle strips were mounted in 4 mL organ baths and isometric force recorded. Levels of cGMP were measured using an enzyme immunoassay kit. Western blots were used to determine PDE5 protein expression. The PDE5 inhibitors concentration-dependently relaxed carbachol-precontracted anococcygeus muscle; however, vardenafil was more potent (pEC50 = 8.11 ± 0.05) than sildenafil (7.72 ± 0.06) or tadalafil (7.69 ± 0.05). Addition of NG-nitro-l-arginine methyl ester (100 μmol/L) or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (10 μmol/L) to the organ baths caused significant rightward shifts in concentration-response curves for all PDE5 inhibitors. Sildenafil, tadalafil and vardenafil (all at 0.1 μmol/L) caused leftward shifts in the glyceryl trinitrate (GTN) concentration-response curves (by 4.0-, 3.7- and 5.5-fold, respectively). In addition, all three PDE5 inhibitors significantly potentiated relaxation responses to both GTN (0.01-10 μmol/L) and electrical field stimulation (EFS; 1-32 Hz), with vardenafil having more pronounced effects. All three PDE5 inhibitors reduced EFS-evoked contractions in a concentration-dependent manner over the concentration range 0.001-1 μmol/L. There were no significant differences between the effects of the three PDE5 inhibitors. Vardenafil (0.01-0.1 μmol/L) was more potent in preventing cGMP degradation in vitro than sildenafil (0.01-0.1 μmol/L) and tadalafil (0.01-0.1 μmol/L). Under control conditions, the expression of PDE5 was higher in the anococcygeus muscle than in the corpus cavernosum. In conclusion, PDE5 inhibitors enhance exogenous and endogenous nitric oxide-mediated relaxation in the rat anococcygeus muscle. The potency of vardenafil was greater than that of either sildenafil or tadalafil.

Original languageEnglish (US)
Pages (from-to)358-366
Number of pages9
JournalClinical and Experimental Pharmacology and Physiology
Volume36
Issue number4
DOIs
StatePublished - Apr 1 2009

Fingerprint

Phosphodiesterase 5 Inhibitors
Muscles
Nitroglycerin
Baths
Penile Erection
Sildenafil Citrate
Tadalafil
Vardenafil Dihydrochloride
Carbachol
Immunoenzyme Techniques
Electric Stimulation
Rodentia
Nitric Oxide
Western Blotting

Keywords

  • Anococcygeus muscle
  • Nitric oxide
  • Phosphodiestarase 5
  • cGMP

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Pharmacology

Cite this

@article{4ea3e5a6274445aca0dba4f9ce6c5af5,
title = "Effect of the phosphodiesterase 5 inhibitors sildenafil, tadalafil and vardenafil on rat anococcygeus muscle: Functional and biochemical aspects",
abstract = "The anococcygeus muscle is part of the erectile machinery in male rodents. Phosphodiesterase (PDE) 5 inhibitors enhance and prolong the effects of cGMP, which has a key role in penile erection. The aim of the present study was to provide a functional and biochemical comparison of the three PDE5 inhibitors, namely sildenafil, tadalafil and vardenafil, in the rat anococcygeus muscle. Muscle strips were mounted in 4 mL organ baths and isometric force recorded. Levels of cGMP were measured using an enzyme immunoassay kit. Western blots were used to determine PDE5 protein expression. The PDE5 inhibitors concentration-dependently relaxed carbachol-precontracted anococcygeus muscle; however, vardenafil was more potent (pEC50 = 8.11 ± 0.05) than sildenafil (7.72 ± 0.06) or tadalafil (7.69 ± 0.05). Addition of NG-nitro-l-arginine methyl ester (100 μmol/L) or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (10 μmol/L) to the organ baths caused significant rightward shifts in concentration-response curves for all PDE5 inhibitors. Sildenafil, tadalafil and vardenafil (all at 0.1 μmol/L) caused leftward shifts in the glyceryl trinitrate (GTN) concentration-response curves (by 4.0-, 3.7- and 5.5-fold, respectively). In addition, all three PDE5 inhibitors significantly potentiated relaxation responses to both GTN (0.01-10 μmol/L) and electrical field stimulation (EFS; 1-32 Hz), with vardenafil having more pronounced effects. All three PDE5 inhibitors reduced EFS-evoked contractions in a concentration-dependent manner over the concentration range 0.001-1 μmol/L. There were no significant differences between the effects of the three PDE5 inhibitors. Vardenafil (0.01-0.1 μmol/L) was more potent in preventing cGMP degradation in vitro than sildenafil (0.01-0.1 μmol/L) and tadalafil (0.01-0.1 μmol/L). Under control conditions, the expression of PDE5 was higher in the anococcygeus muscle than in the corpus cavernosum. In conclusion, PDE5 inhibitors enhance exogenous and endogenous nitric oxide-mediated relaxation in the rat anococcygeus muscle. The potency of vardenafil was greater than that of either sildenafil or tadalafil.",
keywords = "Anococcygeus muscle, Nitric oxide, Phosphodiestarase 5, cGMP",
author = "{Flores Toque}, {Haroldo Alfredo} and Fernanda Priviero and Zemse, {Saiprasad M.} and Edson Antunes and Teixeira, {Cleber E.} and Webb, {R Clinton}",
year = "2009",
month = "4",
day = "1",
doi = "10.1111/j.1440-1681.2008.05071.x",
language = "English (US)",
volume = "36",
pages = "358--366",
journal = "Clinical and Experimental Pharmacology and Physiology",
issn = "0305-1870",
publisher = "Wiley-Blackwell",
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TY - JOUR

T1 - Effect of the phosphodiesterase 5 inhibitors sildenafil, tadalafil and vardenafil on rat anococcygeus muscle

T2 - Functional and biochemical aspects

AU - Flores Toque, Haroldo Alfredo

AU - Priviero, Fernanda

AU - Zemse, Saiprasad M.

AU - Antunes, Edson

AU - Teixeira, Cleber E.

AU - Webb, R Clinton

PY - 2009/4/1

Y1 - 2009/4/1

N2 - The anococcygeus muscle is part of the erectile machinery in male rodents. Phosphodiesterase (PDE) 5 inhibitors enhance and prolong the effects of cGMP, which has a key role in penile erection. The aim of the present study was to provide a functional and biochemical comparison of the three PDE5 inhibitors, namely sildenafil, tadalafil and vardenafil, in the rat anococcygeus muscle. Muscle strips were mounted in 4 mL organ baths and isometric force recorded. Levels of cGMP were measured using an enzyme immunoassay kit. Western blots were used to determine PDE5 protein expression. The PDE5 inhibitors concentration-dependently relaxed carbachol-precontracted anococcygeus muscle; however, vardenafil was more potent (pEC50 = 8.11 ± 0.05) than sildenafil (7.72 ± 0.06) or tadalafil (7.69 ± 0.05). Addition of NG-nitro-l-arginine methyl ester (100 μmol/L) or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (10 μmol/L) to the organ baths caused significant rightward shifts in concentration-response curves for all PDE5 inhibitors. Sildenafil, tadalafil and vardenafil (all at 0.1 μmol/L) caused leftward shifts in the glyceryl trinitrate (GTN) concentration-response curves (by 4.0-, 3.7- and 5.5-fold, respectively). In addition, all three PDE5 inhibitors significantly potentiated relaxation responses to both GTN (0.01-10 μmol/L) and electrical field stimulation (EFS; 1-32 Hz), with vardenafil having more pronounced effects. All three PDE5 inhibitors reduced EFS-evoked contractions in a concentration-dependent manner over the concentration range 0.001-1 μmol/L. There were no significant differences between the effects of the three PDE5 inhibitors. Vardenafil (0.01-0.1 μmol/L) was more potent in preventing cGMP degradation in vitro than sildenafil (0.01-0.1 μmol/L) and tadalafil (0.01-0.1 μmol/L). Under control conditions, the expression of PDE5 was higher in the anococcygeus muscle than in the corpus cavernosum. In conclusion, PDE5 inhibitors enhance exogenous and endogenous nitric oxide-mediated relaxation in the rat anococcygeus muscle. The potency of vardenafil was greater than that of either sildenafil or tadalafil.

AB - The anococcygeus muscle is part of the erectile machinery in male rodents. Phosphodiesterase (PDE) 5 inhibitors enhance and prolong the effects of cGMP, which has a key role in penile erection. The aim of the present study was to provide a functional and biochemical comparison of the three PDE5 inhibitors, namely sildenafil, tadalafil and vardenafil, in the rat anococcygeus muscle. Muscle strips were mounted in 4 mL organ baths and isometric force recorded. Levels of cGMP were measured using an enzyme immunoassay kit. Western blots were used to determine PDE5 protein expression. The PDE5 inhibitors concentration-dependently relaxed carbachol-precontracted anococcygeus muscle; however, vardenafil was more potent (pEC50 = 8.11 ± 0.05) than sildenafil (7.72 ± 0.06) or tadalafil (7.69 ± 0.05). Addition of NG-nitro-l-arginine methyl ester (100 μmol/L) or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (10 μmol/L) to the organ baths caused significant rightward shifts in concentration-response curves for all PDE5 inhibitors. Sildenafil, tadalafil and vardenafil (all at 0.1 μmol/L) caused leftward shifts in the glyceryl trinitrate (GTN) concentration-response curves (by 4.0-, 3.7- and 5.5-fold, respectively). In addition, all three PDE5 inhibitors significantly potentiated relaxation responses to both GTN (0.01-10 μmol/L) and electrical field stimulation (EFS; 1-32 Hz), with vardenafil having more pronounced effects. All three PDE5 inhibitors reduced EFS-evoked contractions in a concentration-dependent manner over the concentration range 0.001-1 μmol/L. There were no significant differences between the effects of the three PDE5 inhibitors. Vardenafil (0.01-0.1 μmol/L) was more potent in preventing cGMP degradation in vitro than sildenafil (0.01-0.1 μmol/L) and tadalafil (0.01-0.1 μmol/L). Under control conditions, the expression of PDE5 was higher in the anococcygeus muscle than in the corpus cavernosum. In conclusion, PDE5 inhibitors enhance exogenous and endogenous nitric oxide-mediated relaxation in the rat anococcygeus muscle. The potency of vardenafil was greater than that of either sildenafil or tadalafil.

KW - Anococcygeus muscle

KW - Nitric oxide

KW - Phosphodiestarase 5

KW - cGMP

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