Neuroprotective effects of carvedilol, a new antihypertensive, as a Na+ channel modulator and glutamate transport inhibitor.
The potent antioxidant activity of carvedilol could explain part of its protective action in brain ischemia, and interaction as a low-affinity non-competitive (uncompetitive) antagonist of the N-methyl-D-aspartate (NMDA) receptor would provide rapid channel blockade at this subtype of glutamate receptor. We have now found carvedilol to be neuroprotective (PC50 = 306 nM) against 40 microM veratridine which kills cerebellar granule cell neurons in 60 min regardless of energy state. Carvedilol was also a potent inhibitor (IC50 = 1.7 microM) of veratridine-stimulated 3[H]aspartate release from preloaded neurons, caused by reversal of the Na(+)-dependent glutamate transporter. Veratridine caused a sustained 4.3-fold increase in intracellular Ca2+ ([Ca2+]i) up to 368 nM (n = 22). Carvedilol reversed the [Ca2+]i levels by a maximum of 73% with an IC50 of 0.9 microM. Such reversal of [Ca2+]i was facilitated by Na+/Ca2+ exchange since the stoichiometry of exchange could be disrupted by prior treatment with 1 microM ouabain to inhibit the Na+/K+ pump. These data suggest that, in addition to its antihypertensive effects, antioxidant activity and ability to act as a non-competitive inhibitor at the NMDA receptor, carvedilol has additional neuroprotective activity as a Na+ channel modulator and glutamate release inhibitor.
Lysko
P G
PG
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939.
Webb
C L
CL
Feuerstein
G
G
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001693:Biological Transport, Active / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects; D005971:Glutamates / Q000378:metabolism*; D018698:Glutamic Acid; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D014701:Veratridine / Q000037:antagonists & inhibitors / Q000633:toxicity
D000959:Antihypertensive Agents; D002227:Carbazoles; D005971:Glutamates; D011412:Propanolamines; D015222:Sodium Channels; D000077261:Carvedilol; D018698:Glutamic Acid; D014701:Veratridine; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium