The results of present study show that AA inhibits L-type channel currents. Similar findings have been reported for smooth muscle cells from the vas deferens of the guinea pig
46 and rabbit intestine,
47 and in cardiac myocytes from frog ventricle.
48 There is no consensus on the mechanism responsible. Khurana and Bennett
49 suggested that in ciliary ganglion cells leukotrienes synthesized from AA by lipoxygenase act as second messengers responsible for AA-induced block of voltage-dependent Ca
2+ channels. Other studies, meanwhile, have reported that the inhibition of voltage-gated Ca
2+ channels by AA may, at least in part, be due to superoxide radicals derived from AA oxidation.
46 Regardless of the mode of action at the ion channel level, our results are consistent with the idea that the effects of AA on subcellular Ca
2+ signaling, and hence vascular tone in retinal arterioles are most likely due to the inhibition of voltage-dependent Ca
2+ entry. Indeed in previous work, we have shown that blockade of L-type Ca
2+ channels suppresses Ca
2+ sparks and oscillations in retinal arterioles, and causes vasodilation through a pathway associated with a reduction in the sarcoplasmic reticulum (SR) Ca
2+ content.
27 It is worth stressing, however, that at this stage other possible contributory mechanisms cannot be fully discounted. For example, possible effects of AA on sarcoplasmic/endoplasmic reticulum Ca
2+-ATPase (SERCA) activity and store-operated Ca
2+ entry could also contribute to the inhibition of subcellular Ca
2+-signaling activity by modifying SR Ca
2+ content. It is also possible that AA may act to block the function of ryanodine receptors on the SR, which are known to underlie Ca
2+ spark and oscillation activity in retinal arteriolar myocytes.
27 Previous biophysical studies using lipid-bilayer systems, however, have suggested that AA is not a direct inhibitor of these channels.
20