Domoic Acid Attenuates the Adenosonine-5'- Triphosphate-Induced Increase in [Ca2+] i in Adult Cardiomyocytes

Abstract

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 Ca²⁺ ([Ca²⁺]_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 [Ca²⁺]_i. ATP produced a gradual rise in [Ca²⁺]_i, reaching a peak level in 25- 30 seconds and declining thereafter. DA did not affect the [Ca²⁺]_i in cardiomyocytes; however, it diminished the ATP-induced elevation in [Ca²⁺]_i in a 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 Ca²⁺ channels, nifedipine and nicardipine, depressed the ATP- induced increase in [Ca²⁺ ]_i, but DA did not produce additive effects with either of these agents. On the other hand, DA potentiated the KCl-induced increase in [Ca²⁺]_i in quiescent cardiomyocytes and augmented the nicardipine-sensitive Ca²⁺ 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.