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Molecular Pharmacology

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Research ArticleArticle

Selective Inhibition of α1B-Adrenergic Receptor Expression and Function Using a Phosphorothioate Antisense Oligodeoxynucleotide

Pedro J. Gonzalez-Cabrera, Patrick L. Iversen, Marvin F. Liu, Margaret A. Scofield and William B. Jeffries
Molecular Pharmacology June 1998, 53 (6) 1034-1039;
Pedro J. Gonzalez-Cabrera
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Patrick L. Iversen
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Marvin F. Liu
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Margaret A. Scofield
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William B. Jeffries
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Abstract

To investigate α1B-adrenoceptor function, we developed a phosphorothioate antisense oligodeoxynucleotide (AO) to inhibit the expression of the α1B-adrenoceptor subtype in DDT1 MF2 cells. We measured the cellular uptake of the AO and its effect on α1B-adrenoceptor mRNA expression, protein density, and coupling to phospholipase C. Cells treated with either a control oligodeoxynucleotide (CO) or medium alone served as control groups. Confocal microscopy demonstrated that DDT1MF2 cells internalized carboxyfluorescein-labeled (FAM) AO within 30 min. Analysis of cellular lysates showed that approximately 50% of the intracellular FAM-AO was present as an intact 18-mer for up to 48 hr. Incubation of cells with AO for 48 hr decreased α1B-adrenoceptor density ([3H]prazosinBmax) versus control groups by 12% (1 μm AO) and 72% (10 μm AO). In time course experiments, AO (10 μm) reduced α1B-adrenoceptor density by 28, 64, and 68% versus controls after 24, 48, and 72 hr of exposure, respectively. α1B-Adrenoceptor mRNA concentration (measured by RT-PCR) was reduced by 25% in cells treated for 48 hr with 10 μmAO versus controls. AO pretreatment (10 μm, 48 hr) reduced the maximum response to agonist-stimulated [3H]inositol phosphate accumulation. The maximal response of the full agonist norepinephrine was reduced by 30% after AO treatment, and by 73% for the partial agonist naphazoline. In contrast, AO did not affect histamine-stimulated total [3H]inositol phosphate accumulation. Thus, AO effectively reduced α1B-adrenoceptor subtype expression and functionin vitro, suggesting a potential to selectively inhibit α1B-adrenoceptor function in vivo.

Footnotes

  • Send reprint requests to: Dr. William B. Jeffries, Department of Pharmacology, Creighton University School of Medicine, 2500 California Plaza, Omaha, NE 68178. E-mail: wbjeff{at}creighton.edu

  • ↵1 Current affiliation: Research and Development, AVI BioPharma Inc., Corvallis, OR 97333.

  • This work was supported by grants from the American Heart Association, Nebraska Affiliate, and the Paul Teschan Research Fund of Dialysis Clinic, Inc., Nashville, TN.

  • Abbreviations:
    AO
    antisense oligodeoxynucleotide
    CO
    control oligodeoxynucleotide
    FAM
    carboxyfluorescein
    DMEM
    Dulbecco’s modified Eagle’s medium
    RT
    reverse transcription
    PCR
    polymerase chain reaction
    PBS
    phosphate-buffered saline
    HEPES
    4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
    • Received November 10, 1997.
    • Accepted February 18, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 53 (6)
Molecular Pharmacology
Vol. 53, Issue 6
1 Jun 1998
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Research ArticleArticle

Selective Inhibition of α1B-Adrenergic Receptor Expression and Function Using a Phosphorothioate Antisense Oligodeoxynucleotide

Pedro J. Gonzalez-Cabrera, Patrick L. Iversen, Marvin F. Liu, Margaret A. Scofield and William B. Jeffries
Molecular Pharmacology June 1, 1998, 53 (6) 1034-1039;

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Research ArticleArticle

Selective Inhibition of α1B-Adrenergic Receptor Expression and Function Using a Phosphorothioate Antisense Oligodeoxynucleotide

Pedro J. Gonzalez-Cabrera, Patrick L. Iversen, Marvin F. Liu, Margaret A. Scofield and William B. Jeffries
Molecular Pharmacology June 1, 1998, 53 (6) 1034-1039;
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