Angiotensin II Increases Neuronal Delayed Rectifier K+ Current: Role of 12-Lipoxygenase Metabolites of Arachidonic Acid

Abstract

Angiotensin II (Ang II) elicits an Ang II type 2 (AT2) receptor–mediated increase in voltage-dependent delayed rectifier K+ current ( I KV) in neurons cultured from newborn rat hypothalamus and brain stem. In previous studies, we have determined that this effect of Ang II is mediated via a Gi protein, activation of phospholipase A2(PLA2), and generation of arachidonic acid (AA). AA is rapidly metabolized within cells via lipoxygenases (LO), cyclooxygenase (COX) or p450 monooxygenase enzymes, and the metabolic products are known regulators of K+ currents and channels. Thus in the present study, we have investigated whether the AT2 receptor–mediated effects of Ang II on neuronal I KV require AA metabolism and if so, which metabolic pathways are involved. The data presented here indicate that the stimulatory actions of Ang II and AA on neuronal I KV are attenuated by selective blockade of 12-LO enzymes. However, the effects of Ang II are not altered by blockade of 5-LO or p450 monooxygenase enzymes. Furthermore, the actions of Ang II are mimicked by a 12-LO metabolite of AA, but 5-LO metabolites such as leukotriene B4 and C4 do not alter neuronal I KV. These data indicate that the AT2 receptor–mediated stimulation of neuronal I KV is partially mediated through 12-LO metabolites of AA.