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Change in mRNA Expression after Atenolol, a Beta-adrenergic Receptor Antagonist and Association with Pharmacological Response.

ABSTRACT: AIMS: Genetic determinants of variability in response to beta-blockers are poorly characterized. We defined changes in mRNA expression after a beta-blocker to identify novel genes that could affect response and correlated these with inhibition of exercise-induced tachycardia, a measure of beta-blocker sensitivity. METHODS: Nine subjects exercised before and after a single oral dose of 25mg atenolol and mRNA gene expression was measured using an Affymetrix GeneChip Human Gene 1.0 ST Array. The area under the heart rate-exercise intensity curve (AUC) was calculated for each subject; the difference between post- and pre-atenolol AUCs (Delta AUC), a measure of beta-blocker response, was correlated with the fold-change in mRNA expression of the genes that changed more than 1.3-fold. RESULTS: Fifty genes showed more than 1.3-fold increase in expression; 9 of these reached statistical significance (P < 0.05). Thirty-six genes had more than 1.3-fold decrease in expression after atenolol; 6 of these reached statistical significance (P < 0.05). Change in mRNA expression of FGFBP2 and Probeset ID 8118979 was significantly correlated with atenolol response (P = 0.03 and 0.02, respectively). CONCLUSION: The expression of several genes not previously identified as part of the adrenergic signaling pathway changed in response to a single oral dose of atenolol. Variation in these genes could contribute to unexplained differences in response to beta-blockers.

SUBMITTER: Kohli U

PROVIDER: S-EPMC2773526 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Change in mRNA Expression after Atenolol, a Beta-adrenergic Receptor Antagonist and Association with Pharmacological Response.

Kohli Utkarsh U Grayson Britney L BL Aune Thomas M TM Ghimire Laxmi V LV Kurnik Daniel D Stein C Michael CM

Archives of drug information 20090901 3

AIMS: Genetic determinants of variability in response to beta-blockers are poorly characterized. We defined changes in mRNA expression after a beta-blocker to identify novel genes that could affect response and correlated these with inhibition of exercise-induced tachycardia, a measure of beta-blocker sensitivity. METHODS: Nine subjects exercised before and after a single oral dose of 25mg atenolol and mRNA gene expression was measured using an Affymetrix GeneChip Human Gene 1.0 ST Array. The ar ...[more]

PMID: 19915711

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Project description:Abstract The anabolic response of aged bone to skeletal loading is typically poor. Efforts to improve mechanotransduction in aged bone have met with limited success. This study investigated whether the bone response to direct skeletal loading is improved by reducing sympathetic suppression of osteoblastic bone formation via β2AR. To test this possibility, we treated aged wild‐type C57BL/6 mice with a selective β2AR antagonist, butaxamine (Butax), before each of nine bouts of cantilever bending of the right tibia. Midshaft periosteal bone formation was assessed by dynamic histomorphometry of loaded and contralateral tibias. Butax treatment did not alter osteoblast activity of contralateral tibias. Loading alone induced a modest but significant osteogenic response. However, when loading was combined with Butax pretreatment, the anabolic response was significantly elevated compared with loading preceded by saline injection. Subsequent studies in osteoblastic cultures revealed complex negative interactions between adrenergic and mechanically induced intracellular signaling. Activation of β2AR by treatment with the β1, β2‐agonist isoproterenol (ISO) before fluid flow exposure diminished mechanically stimulated ERK1/2 phosphorylation in primary bone cell outgrowth cultures and AKT phosphorylation in MC3T3‐E1 pre‐osteoblast cultures. Expression of mechanosensitive Fos and Ptgs2 genes was enhanced with ISO treatment and reduced with flow in both MC3T3‐E1 and primary cultures. Finally, co‐treatment of MC3T3‐E1 cells with Butax reversed these ISO effects, confirming a critical role for β2AR in these responses. In combination, these results demonstrate that selective inhibition of β2AR is sufficient to enhance the anabolic response of the aged skeleton to loading, potentially via direct effects upon osteoblasts. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Dataset Information

Change in mRNA Expression after Atenolol, a Beta-adrenergic Receptor Antagonist and Association with Pharmacological Response.

Publications

Change in mRNA Expression after Atenolol, a Beta-adrenergic Receptor Antagonist and Association with Pharmacological Response.

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