Beta-adrenergic receptor agonists and antagonists counteract LPS-induced neuronal death in retinal cultures by different mechanisms.
Treatment with lipopolysaccharide (LPS) for 72 h was shown to dose-dependently increase nitric oxide production from 6-day-old retinal cultures. Cell death, as determined by lactate dehydrogenase (LDH) release and an increase in neuronal labelling for TUNEL, was elevated concurrently. During treatment there was an increase of both inducible nitric oxide synthase and glial fibrillary acidic protein labelling in glial cells and a reduction in the number of gamma-aminobutyric acid-positive neurones. The NOS inhibitors, N-nitro-L-arginine methyl ester, dexamethasone and indomethacin potently inhibited both nitric oxide stimulation and cell death caused by LPS. In this study, the beta(2)- (ICI-18551), beta(1)- (betaxolol) and mixed beta(1)/beta(2)- (timolol, metipranolol) adrenergic receptor antagonists were all shown to attenuate LPS-induced LDH release from these cultures, but to have no effect on LPS-stimulated nitric oxide production. This effect was mimicked by the calcium channel blocker, nifedipine. Interestingly, the beta-adrenergic receptor agonists, salbutamol, arterenol and isoproterenol were also able to attenuate cell death caused by LPS. Moreover, these compounds also inhibited LPS-stimulated nitric oxide release. These studies suggest that LPS stimulates nitric oxide release from cultured retinal glial cells and that this process leads to neurone death. beta-adrenergic receptor agonists prevent the effects of LPS by inhibiting the stimulation of nitric oxide production. The data also suggest that beta-adrenergic receptor antagonists can attenuate LPS-induced death of neurones, but that these compounds act in a manner that is neurone-dependent, is mimicked by blockade of calcium channels and is independent of the stimulation of nitric oxide release.
Arai
Kunizo
K
Nuffield Laboratory of Ophthalmology, University of Oxford, Walton Street, Oxford OX2 6AW, UK.
Wood
John P M
JP
Osborne
Neville N
NN
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D007213:Indomethacin / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D051381:Rats; D012160:Retina / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002121:Calcium Channel Blockers; C078491:Dpf1 protein, rat; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D008070:Lipopolysaccharides; D009419:Nerve Tissue Proteins; D009573:Nitrites; D014157:Transcription Factors; D009569:Nitric Oxide; D005680:gamma-Aminobutyric Acid; D003907:Dexamethasone; D007770:L-Lactate Dehydrogenase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin