Domoic Acid Attenuates the Adenosine-5'-Triphosphate-Induced Increase in

BACKGROUND: Although domoic acid (DA), a shellfish neurotoxin, carries a negative surface charge at physiological pH like that of adenosine-5'-triphosphate (ATP), very little is known about its cellular effects. In view of the potentially significant role of extracellular ATP as a signaling molecule for increasing the intracellular concentration of Ca(2+) ([Ca(2+)](i)), we examined the possibility that DA may interfere with this signal transduction mechanism in the myocardium. METHODS AND RESULTS: Cardiomyocytes were isolated from rat heart and loaded with Fura-2 to measure the [Ca(2+)](i). ATP produced a gradual rise in [Ca(2+)](i), reaching a peak level in 25-30 seconds and declining thereafter. DA did not affect the [Ca(2+)](i) in cardiomyocytes; however, it diminished the ATP-induced elevation in [Ca(2+)](i) in the concentration-dependent manner. Kainic acid, an analogue of DA, had a similar effect but at a 25-fold higher concentration, whereas glutamate and aspartate did not modify the action of ATP. Well-known inhibitors of L-type voltage-sensitive Ca(2+) channels, nifedipine and nicardipine, depressed the ATP-induced increase in [Ca(2+)](i), but DA did not produce additive effects with either of these agents. On the other hand, DA potentiated the KCl-induced increase in [Ca(2+)](i) in quiescent cardiomyocytes and augmented the nicardipine-sensitive Ca(2+) transients in electrically stimulated cardiomyocytes. CONCLUSIONS: These results suggest that DA may diminish the ATP-induced increase in [Ca(2+)](i) by inhibiting the ATP interaction with cardiomyocytes in a specific manner.