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.