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Research ArticleCARDIOVASCULAR

Effect of a β2-Adrenoceptor Stimulation on Hyperglycemia-Induced Endothelial Dysfunction

Armin Kabat, Klaus Pönicke, Aida Salameh, Friedrich-Wilhelm Mohr and Stefan Dhein
Journal of Pharmacology and Experimental Therapeutics February 2004, 308 (2) 564-573; DOI: https://doi.org/10.1124/jpet.103.057554
Armin Kabat
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Klaus Pönicke
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Aida Salameh
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Friedrich-Wilhelm Mohr
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Stefan Dhein
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Abstract

To investigate whether β2-adrenoceptors exist on endothelial cells and whether a β2-adrenoceptor stimulation might prevent the development of hyperglycemia-induced endothelial dysfunction, porcine aortic endothelial cells (PAECs) were cultured and chronically exposed to either 5 mM d-glucose (“normoglycemia”) or 20 mM d-glucose (“hyperglycemia”), with or without 100 nM salbutamol in absence or presence of β2-adrenoceptor antagonist ICI 118,551 [1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxyl]-3-[(1-methylethyl)-amino]-2-butanol] or β1-antagonist metoprolol. For osmotic control, PAECs were exposed to 15 mM l-glucose. We measured nitric oxide release using the met-hemoglobin assay and assessed β-adrenoceptor density and subtypes by radioligand binding. Furthermore, we determined intracellular NADH and NADPH using high-performance liquid chromatography. High d-glucose concentrations but not l-glucose led to significantly reduced basal and stimulated nitric oxide release. Chronic salbutamol treatment significantly antagonized the impairment of the nitric oxide response, which was inhibited by ICI 118,551 but not by metoprolol. The number of giant cells was significantly increased in hyperglycemia, which could be prevented by salbutamol. Binding of the radioligand (–)-[125I]iodocyanopindolol revealed a total β-adrenoceptor density of 29.8 ± 3.7 (normoglycemic) and 30.3 ± 3.6 (hyperglycemic) fmol/mg protein. Displacement by ICI 118,551 revealed β-adrenoceptor subtype distribution with 30.3 ± 4.4 (normoglycemic) and 29.1 ± 3.8% β2-adrenoceptors. NADH production increased in hyperglycemia, which was completely prevented by salbutamol. We conclude that hyperglycemia in PAEC induces endothelial dysfunction with impaired nitric oxide release and that this can be prevented by β2-adrenoceptor stimulation.

Footnotes

  • This study was supported by a grant to S.D. from the German Diabetes Foundation.

  • DOI: 10.1124/jpet.103.057554.

  • ABBREVIATIONS: PAEC, porcine aortic endothelial cell; NO, nitric oxide; PKA, protein kinase A; ROS, reactive oxygen species; eNOS, endothelial nitric-oxide synthase; Oxy-Hb, oxyhemoglobin; ICYP, (–)-[125I]iodocyanopindolol; HPLC, high-performance liquid chromatography; NBT, nitro blue tetrazolium; PKC, protein kinase C; CGP12177, 4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one; ICI 118,551, 1-[2,2-(dihydro-7-methyl-1H-inden-4-yl)oxyl]-3-[(1-methylethyl)-amino]-2-butanol.

    • Received July 24, 2003.
    • Accepted October 24, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 308 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 308, Issue 2
1 Feb 2004
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Research ArticleCARDIOVASCULAR

Effect of a β2-Adrenoceptor Stimulation on Hyperglycemia-Induced Endothelial Dysfunction

Armin Kabat, Klaus Pönicke, Aida Salameh, Friedrich-Wilhelm Mohr and Stefan Dhein
Journal of Pharmacology and Experimental Therapeutics February 1, 2004, 308 (2) 564-573; DOI: https://doi.org/10.1124/jpet.103.057554

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Research ArticleCARDIOVASCULAR

Effect of a β2-Adrenoceptor Stimulation on Hyperglycemia-Induced Endothelial Dysfunction

Armin Kabat, Klaus Pönicke, Aida Salameh, Friedrich-Wilhelm Mohr and Stefan Dhein
Journal of Pharmacology and Experimental Therapeutics February 1, 2004, 308 (2) 564-573; DOI: https://doi.org/10.1124/jpet.103.057554
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