Neuroprotective effects of carvedilol, a new antihypertensive, at the N-methyl-D-aspartate receptor.
Carvedilol's potent antioxidant activity could explain its protective action in brain ischemia, but may not apply to glutamate-induced excitotoxicity in cultured cerebellar granule cells, since glutamate neurotoxicity was not associated with the formation of lipid peroxidative products. Rather, carvedilol diminished the N-methyl-D-aspartate (NMDA)/glycine-induced increase in intracellular calcium ([Ca2+]i), lowering [Ca2+]i by a maximum of 66 +/- 5% (n = 8) with a 50% inhibitory concentration of 0.8 microM. Prior addition of 5 microM dihydropyridines did not shift the dose-response of carvedilol, but did significantly lower the NMDA/glycine-stimulated response to 64% of untreated (n = 8, P = 0.014). Inclusion of 5 microM carvedilol before the additions of NMDA/glycine prevented 85% of the increase in [Ca2+]i. Furthermore, carvedilol displaced 3[H]MK-801 binding to rat brain cortical membranes with a Kd of 29.4 +/- 2.2 microM (n = 6) and no selectively for the glutamate or glycine binding sites. These data therefore suggest that, in addition to its antihypertensive and anti-lipid peroxidative functions, carvedilol has neuroprotective activity as a calcium channel blocker and as a non-competitive inhibitor at the NMDA receptor.
Lysko
P G
PG
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406.
Lysko
K A
KA
Webb
C L
CL
Feuerstein
G
G
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005998:Glycine / Q000494:pharmacology; D007700:Kinetics; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011412:Propanolamines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D014316:Tritium
D000959:Antihypertensive Agents; D002227:Carbazoles; D011412:Propanolamines; D016194:Receptors, N-Methyl-D-Aspartate; D000077261:Carvedilol; D014316:Tritium; D016291:Dizocilpine Maleate; D002118:Calcium; D005998:Glycine