Determination of adenosine effects and adenosine receptors in murine corpus cavernosum

Rita C. Tostes, Fernanda R.C. Giachini, Fernando S. Carneiro, Romulo Leite, Edward W. Inscho, R. Clinton Webb

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Abstract

This study tested the hypothesis that adenosine, in murine corpora cavernosa, produces direct relaxation of smooth muscle cells and inhibition of contractile responses mediated by sympathetic nerve stimulation. Penes were excised from anesthetized male C57BL/6 mice, dissected, and cavernosal strips were mounted to record isometric force. Adenosine, 2-chloroadenosine (stable analog of adenosine), and 2-phenylaminoadenosine (CV1808) (A2 A/A2B agonist) produced concentration-dependent relaxations of phenylephrine-contracted tissues. Relaxation to 2-chloroadenosine was inhibited, in a concentration-dependent manner, by 2-(2-furanyl)-7-(2- phenylethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine (SCH58261; A2A antagonist; 10-9-10-6 M) and N-(4-acetylphenyl)-2-[4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8- yl)phenoxy]acetamida (MRS1706; A2B antagonist; 10-8- 10-6 M). The combination of both antagonists abrogated 2-chloroadenosine-induced relaxation. Electrical field stimulation (EFS; 1-32 Hz) of adrenergic nerves produced frequency-dependent contractions that were inhibited by compounds that increase adenosine levels, such as 5′-iodotubercidin (adenosine kinase inhibitor), erythro-9-(2-hydroxy-3- nonyl)adenine (adenosine deaminase inhibitor), and dipyridamole (inhibitor of adenosine transport). The adenosine A1 receptor agonist N6- cyclopentyladenosine (C8031) right-shifted contractile responses to EFS, with a significant inhibitory effect at 10-6 M. Blockade of adenosine A1 receptors with 8-cyclopentyl-1,3-dipropylxanthine (C101) (10-7 M) enhanced contractile responses to EFS and eliminated the inhibitory effects of 5′-iodotubercidin. Dipyridamole and 5′-iodotubercidin had no effect on adenosine-mediated relaxation. In summary, adenosine directly relaxes cavernosal smooth muscle cells, by the activation of A2A/A2 B receptor subtypes. In addition, adenosine negatively modulates sympathetic neurotransmission, by A1 receptor subtype activation, in murine corpora cavernosa. Adenosine may subserve dual roles in modulating the physiological mechanisms of erection in mice.

Original languageEnglish (US)
Pages (from-to)678-685
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume322
Issue number2
DOIs
StatePublished - Aug 1 2007

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Purinergic P1 Receptors
Adenosine
2-Chloroadenosine
Dipyridamole
adenine deaminase
varespladib methyl
Smooth Muscle Myocytes
Adenosine Deaminase Inhibitors
Adenosine A1 Receptor Agonists
Adenosine Kinase
Adenosine A1 Receptors
Phenylephrine
Inbred C57BL Mouse
Synaptic Transmission
Adrenergic Agents
Electric Stimulation
Amines

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Determination of adenosine effects and adenosine receptors in murine corpus cavernosum. / Tostes, Rita C.; Giachini, Fernanda R.C.; Carneiro, Fernando S.; Leite, Romulo; Inscho, Edward W.; Webb, R. Clinton.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 322, No. 2, 01.08.2007, p. 678-685.

Research output: Contribution to journalArticle

Tostes, Rita C. ; Giachini, Fernanda R.C. ; Carneiro, Fernando S. ; Leite, Romulo ; Inscho, Edward W. ; Webb, R. Clinton. / Determination of adenosine effects and adenosine receptors in murine corpus cavernosum. In: Journal of Pharmacology and Experimental Therapeutics. 2007 ; Vol. 322, No. 2. pp. 678-685.
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AU - Webb, R. Clinton

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N2 - This study tested the hypothesis that adenosine, in murine corpora cavernosa, produces direct relaxation of smooth muscle cells and inhibition of contractile responses mediated by sympathetic nerve stimulation. Penes were excised from anesthetized male C57BL/6 mice, dissected, and cavernosal strips were mounted to record isometric force. Adenosine, 2-chloroadenosine (stable analog of adenosine), and 2-phenylaminoadenosine (CV1808) (A2 A/A2B agonist) produced concentration-dependent relaxations of phenylephrine-contracted tissues. Relaxation to 2-chloroadenosine was inhibited, in a concentration-dependent manner, by 2-(2-furanyl)-7-(2- phenylethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine (SCH58261; A2A antagonist; 10-9-10-6 M) and N-(4-acetylphenyl)-2-[4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8- yl)phenoxy]acetamida (MRS1706; A2B antagonist; 10-8- 10-6 M). The combination of both antagonists abrogated 2-chloroadenosine-induced relaxation. Electrical field stimulation (EFS; 1-32 Hz) of adrenergic nerves produced frequency-dependent contractions that were inhibited by compounds that increase adenosine levels, such as 5′-iodotubercidin (adenosine kinase inhibitor), erythro-9-(2-hydroxy-3- nonyl)adenine (adenosine deaminase inhibitor), and dipyridamole (inhibitor of adenosine transport). The adenosine A1 receptor agonist N6- cyclopentyladenosine (C8031) right-shifted contractile responses to EFS, with a significant inhibitory effect at 10-6 M. Blockade of adenosine A1 receptors with 8-cyclopentyl-1,3-dipropylxanthine (C101) (10-7 M) enhanced contractile responses to EFS and eliminated the inhibitory effects of 5′-iodotubercidin. Dipyridamole and 5′-iodotubercidin had no effect on adenosine-mediated relaxation. In summary, adenosine directly relaxes cavernosal smooth muscle cells, by the activation of A2A/A2 B receptor subtypes. In addition, adenosine negatively modulates sympathetic neurotransmission, by A1 receptor subtype activation, in murine corpora cavernosa. Adenosine may subserve dual roles in modulating the physiological mechanisms of erection in mice.

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