Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Journal of Pharmacology and Experimental Therapeutics
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Journal of Pharmacology and Experimental Therapeutics

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Visit jpet on Facebook
  • Follow jpet on Twitter
  • Follow jpet on LinkedIn
Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Role of Adenylate and Guanylate Cyclases in β1-, β2-, and β3-Adrenoceptor-Mediated Relaxation of Internal Anal Sphincter Smooth Muscle

Fangxia Li, Márcio De Godoy and Satish Rattan
Journal of Pharmacology and Experimental Therapeutics March 2004, 308 (3) 1111-1120; DOI: https://doi.org/10.1124/jpet.103.060145
Fangxia Li
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Márcio De Godoy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Satish Rattan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

Abstract

The purpose of the present study was to ascertain the role of adenylate (AC) versus guanylate cyclase (GC) signaling pathways in the internal anal sphincter (IAS) smooth muscle relaxation by β1-, β2-, and β3-adrenoceptor (AR) activation by xamoterol, procaterol, and disodium 5-[(2R)-2-(3-chlorophenyl)-2-hydroxy-ethyl]amino)propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL 316243), respectively. The above-mentioned agonists produced concentration-dependent relaxation of the smooth muscle strips. Both the selective Gi/oα and Gsα antagonists 8,8′-(carbonylbis(imino-3,1-phenylene))bis-(1,3,5-naphthalene trisulfonic acid) (NF 023) and 4,4′,4″,4‴-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakis-benzene-1,3-disulfonic acid (NF 449), respectively, inhibited the relaxation induced by procaterol. However, only NF 023 inhibited the relaxation induced by xamoterol and CL 316243. 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one, a soluble GC inhibitor, significantly inhibited the relaxation induced by different agonists. In contrast, the selective AC inhibitor [9-(tetrahydro-2′-furyl)adenine] (SQ 22536) inhibited only the relaxation induced by procaterol. (9R,10S,12S)-2,3,9,10,11,12-Hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg: 3′,2′,1′-kl]pyrrolo[3,4-l][1,6]benzodiazocine-10-carboxylic acid, hexyl ester (KT 5720), a cAMP-dependent protein kinase inhibitor, attenuated the relaxation by procaterol, whereas (9S,10R,12R)-2,3,9,10,11,12, hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9.12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-I][1,6]benzodiazocine-10-carboxylic acid methyl ester (KT 5823), a selective cGMP-dependent protein kinase (PKG) inhibitor, attenuated the relaxation induced by xamoterol and CL 316243. Xamoterol produced significant increase in cGMP levels, whereas only procaterol enhanced the cAMP levels. Western blot analysis confirmed the presence of β1, β2, and β3-AR subtypes in the IAS. In summary, β2-AR activates both Gsα and Gi/oα-protein subunits and induces relaxation in the rat IAS via both cAMP/cGMP pathways. In contrast, the β1/β3-ARs activation causes the smooth muscle relaxation via Gi/oα-protein subunit/GC/GMP/PKG pathway. These studies are important for the understanding of intracellular mechanisms underlying IAS smooth muscle relaxation and in turn the pathophysiology of certain anorectal motility disorders.

Footnotes

  • The studies were supported by National Institutes of Diabetes and Digestive and Kidney Diseases Grant DK-35385 and an institutional grant from Thomas Jefferson University (Philadelphia, PA).

  • DOI: 10.1124/jpet.103.060145.

  • ABBREVIATIONS: IAS, internal anal sphincter; β-AR, β-adrenergic receptor; CL 316243, disodium 5-[(2R)-2-(3-chlorophenyl)-2-hydroxy-ethyl] amino)propyl]-1,3-benzodioxole-2,2-dicarboxylate; AC, adenylate cyclase; GC, guanylate cyclase; CRC, concentration response curve; NF 023, 8,8′-(carbonylbis(imino-3,1-phenylene))bis-(1,3,5-naphthalene trisulfonic acid); NF 449, 4,4′,4″,4-‴(carbonylbis(imino-5,1,3-benzenetriylbis-(carbonylimino)))tetrakis-benzene-1,3-disulfonic acid; ODQ, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; SQ22536, 9-(tetrahydro-2′-furyl)adenine; KT 5720, (9R,10S,12S)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-l] [1,6]benzodiazocine-10-carboxylic acid, hexyl ester; KT 5823, (9S,10R,12R)-2,3,9,10,11,12, hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9.12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-I][1,6]benzodiazocine-10-carboxylic acid methyl ester; SNP, sodium nitroprusside; IBMX, 3-isobutyl-1-methylxanthine; BSA, bovine serum albumin; NCM, nitrocellulose membrane; IOD, integrated optical density; DMSO, dimethyl sulfoxide; ANOVA, analysis of variance; PKA, cAMP-dependent protein kinase; PKG, cGMP-dependent protein kinase; xamoterol, xamoterol hemifumarate; procaterol, (±)-erythro-8-hydroxy-5-[1-hydroxy-2-(isopropylamino) butyl]carbostyril.

    • Received September 16, 2003.
    • Accepted November 20, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
View Full Text

JPET articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Journal of Pharmacology and Experimental Therapeutics: 308 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 308, Issue 3
1 Mar 2004
  • Table of Contents
  • About the Cover
  • Index by author
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Journal of Pharmacology and Experimental Therapeutics article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Role of Adenylate and Guanylate Cyclases in β1-, β2-, and β3-Adrenoceptor-Mediated Relaxation of Internal Anal Sphincter Smooth Muscle
(Your Name) has forwarded a page to you from Journal of Pharmacology and Experimental Therapeutics
(Your Name) thought you would be interested in this article in Journal of Pharmacology and Experimental Therapeutics.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Role of Adenylate and Guanylate Cyclases in β1-, β2-, and β3-Adrenoceptor-Mediated Relaxation of Internal Anal Sphincter Smooth Muscle

Fangxia Li, Márcio De Godoy and Satish Rattan
Journal of Pharmacology and Experimental Therapeutics March 1, 2004, 308 (3) 1111-1120; DOI: https://doi.org/10.1124/jpet.103.060145

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Role of Adenylate and Guanylate Cyclases in β1-, β2-, and β3-Adrenoceptor-Mediated Relaxation of Internal Anal Sphincter Smooth Muscle

Fangxia Li, Márcio De Godoy and Satish Rattan
Journal of Pharmacology and Experimental Therapeutics March 1, 2004, 308 (3) 1111-1120; DOI: https://doi.org/10.1124/jpet.103.060145
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Materials and Methods
    • Results
    • Discussion
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • CGRP Signaling in Visceral Organ Cross-Sensitization
  • Peptide AIP Alleviates Renal Fibrosis In Vivo and In Vitro
  • 20-HETE Synthesis Inhibitor Suppresses Renal Fibrosis
Show more Gastrointestinal, Hepatic, Pulmonary, and Renal

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About JPET
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0103 (Online)

Copyright © 2023 by the American Society for Pharmacology and Experimental Therapeutics