ARACHIDONIC ACID RELAXES RAT MESENTERIC ARTERIAL BED INVOLVING BK ION CHANNEL ACTIVATION

MILESI, V; MONCADA, M; MARTÍN, P; VECCHIO, L; ENRIQUE, N

Rio de Janeiro

Congreso; 38th IUPS Congress (International Union of Physiology Sciences); 2017

International Union of Physiology Sciences

Arachidonic acid (AA) is a polyunsaturated fatty acid (PUFA-6) involved inseveral physiological processes, many times through modulation of ion channelsactivity. Previously, we reported that 10 µM AA directly activates the highconductance Ca2+ and voltage dependent K+ channel (BK).This effect was observed when the alfa subunit of BK channel was expressed togetherwith the regulatory beta1 subunit, but not in absence of beta subunits. AA increased the open probability of BK channels and shiftedthe activation voltage-dependence to the left (ΔV1/2= -55.2 ±4.4 mV, n=3, p<0.05) (Moncada et al 2014).In this work, we deeply studied several aspects of the action mechanismof AA using patch clamp technique on BK channel (alfa + beta1) heterologously expressed, and finally we analyzed therole of AA on peripheral resistance of rat mesenteric arterial bed.Considering that activation by AA requires the presence of the beta1subunit, which modulates the voltage sensor and the intrinsic opening of thechannel, we analyzed whether AA acts changing the beta1 modulation of theseprocesses. By measuring the gating currents, we evaluated if thevoltage sensor is affected by AA, observing that it produces a significant leftshift in the Q-V curve (ΔV1/2= -17.2 ±8.1 mV, n=5, p<0.05). We alsostudied the effect of AA on the intrinsic channel opening probability (NPoi).The results showed that AA increases NPoi in all tested cells (control: NPoi=0.0013 ±0.0008; AA: NPoi= 0.0245 ±0.0051; n=4; p=0.016). On the other hand, wecharacterized the dose-response dependence of activation by AA between 0.1 and30 µM.Finally, we studied AA effect on peripheral resistance of mesenteric arterial bed in Sprague Dowley rats. The results showedthat AA induces a decrease in peripheral resistance (%DPR), which is higherwhen BK is functional than when it is blocked by 500 nM paxiline (Paxi) (AA:%DPR= 54.57 ±10.76; AA+Paxi: %DPR= 26.47 ±5.99; n=5, p=0.007).These results indicated that BK activation by AA involves changes inboth voltage sensor activation and intrinsic openingof the channel. Moreover, we showed in a more physiological and complexconditions, that the BK channel activation induced by AA is able to producerelaxation in mesenteric blood vessels suggesting that AA could have a relevantrole in peripheral resistance regulation.