Angiotensin II increases neuronal delayed rectifier K+ current: Role of 12-lipoxygenase metabolites of arachidonic acid

Angiotensin II (Ang II) elicits an Ang II type 2 (AT(2)) receptor-mediated increase in voltage-dependent delayed rectifier K+ current (I-KV) in neuron s cultured from newborn rat hypothalamus and brain stem. In previous studie s, we have determined that this effect of Ang II is mediated via a Gi prote in, activation of phospholipase A(2) (PLA(2)), and generation of arachidoni c acid (AA). AA is rapidly metabolized within cells via lipoxygenases (LO), cyclooxygenase (COX) or p450 monooxygenase enzymes, and the metabolic prod ucts are known regulators of K+ currents and channels. Thus in the present study, we have investigated whether the AT(2) receptor-mediated effects of Ang II on neuronal I-KV require AA metabolism and if so, which metabolic pa thways are involved. The data presented here indicate that the stimulatory actions of Ang II and AA on neuronal I-KV are attenuated by selective block ade of 12-LO enzymes. However, the effects of Ang II are not altered by blo ckade of 5-LO or p450 monooxygenase enzymes. Furthermore, the actions of An g II are mimicked by a 12-LO metabolite of AA, but 5-LO metabolites such as leukotriene B-4 and C-4 do not alter neuronal I-KV. These data indicate th at the AT(2) receptor-mediated stimulation of neuronal I-KV is partially me diated through 12-LO metabolites of AA.