Role of ion channels and subcellular Ca2+ signaling in arachidonic acid-induced dilation of pressurized retinal arterioles

• Published in: Investigative ophthalmology & visual science 2014-05, Vol.55 (5), p.2893-2902
• Main Authors: Kur, Joanna, McGahon, Mary K, Fernández, Jose A, Scholfield, C Norman, McGeown, J Graham, Curtis, Tim M
• Format: Article
• Language: English
• Subjects: 5,8,11,14-Eicosatetraynoic Acid - pharmacology; Animals; Arachidonic Acid - pharmacology; Arachidonic Acid - physiology; Arterioles - physiology; Calcium - physiology; Electrophysiology; Models, Animal; Myocytes, Smooth Muscle - drug effects; Potassium Channels - drug effects; Potassium Channels - physiology; Rats; Rats, Sprague-Dawley; Retinal Artery - drug effects; Retinal Artery - physiology; Signal Transduction - drug effects; Signal Transduction - physiology; Vasodilation - drug effects
• ISSN: 1552-5783
• DOI: 10.1167/iovs.13-13511

To investigate the mechanisms responsible for the dilatation of rat retinal arterioles in response to arachidonic acid (AA). Changes in the diameter of isolated, pressurized rat retinal arterioles were measured in the presence of AA alone and following pre-incubation with pharmacologic agents inhibiting Ca(2+) sparks and oscillations and K(+) channels. Subcellular Ca(2+) signals were recorded in arteriolar myocytes using Fluo-4-based confocal imaging. The effects of AA on membrane currents of retinal arteriolar myocytes were studied using whole-cell perforated patch clamp recording. Arachidonic acid dilated pressurized retinal arterioles under conditions of myogenic tone. Eicosatetraynoic acid (ETYA) exerted a similar effect, but unlike AA, its effects were rapidly reversible. Arachidonic acid-induced dilation was associated with an inhibition of subcellular Ca(2+) signals. Interventions known to block Ca(2+) sparks and oscillations in retinal arterioles caused dilatation and inhibited AA-induced vasodilator responses. Arachidonic acid accelerated the rate of inactivation of the A-type Kv current and the voltage dependence of inactivation was shifted to more negative membrane potentials. It also enhanced voltage-activated and spontaneous large-conductance calcium-activated K(+) (BK) currents, but only at positive membrane potentials. Pharmacologic inhibition of A-type Kv and BK currents failed to block AA-induced vasodilator responses. Arachidonic acid suppressed L-type Ca(2+) currents. These results suggest that AA induces retinal arteriolar vasodilation by inhibiting subcellular Ca(2+)-signaling activity in retinal arteriolar myocytes, most likely through a mechanism involving the inhibition of L-type Ca(2+)-channel activity. Arachidonic acid actions on K(+) currents are inconsistent with a model in which K(+) channels contribute to the vasodilator effects of AA.