Zhu M, Natarajan R, Nadler J L, Moore J M, Gelband C H, Sumners C
Department of Physiology, College of Medicine and University of Florida Brain Institute, University of Florida, Gainesville, Florida 32610, USA.
J Neurophysiol. 2000 Nov;84(5):2494-501. doi: 10.1152/jn.2000.84.5.2494.
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 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 A(2) (PLA(2)), 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 AT(2) 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 B(4) and C(4) do not alter neuronal I(KV). These data indicate that the AT(2) receptor-mediated stimulation of neuronal I(KV) is partially mediated through 12-LO metabolites of AA.
血管紧张素II（Ang II）可使新生大鼠下丘脑和脑干培养神经元中电压依赖性延迟整流钾电流（I(KV)）增加，这一作用由血管紧张素II 2型（AT(2)）受体介导。在以往研究中，我们已确定Ang II的这一作用是通过Gi蛋白、磷脂酶A(2)（PLA(2)）的激活以及花生四烯酸（AA）的生成来介导的。AA在细胞内可通过脂氧合酶（LO）、环氧化酶（COX）或p450单加氧酶迅速代谢，其代谢产物是已知的钾电流和通道调节因子。因此，在本研究中，我们探究了Ang II通过AT(2)受体对神经元I(KV)的作用是否需要AA代谢，若需要，涉及哪些代谢途径。此处呈现的数据表明，选择性阻断12-LO酶可减弱Ang II和AA对神经元I(KV)的刺激作用。然而，阻断5-LO或p450单加氧酶并不会改变Ang II的作用。此外，AA的一种12-LO代谢产物可模拟Ang II的作用，但5-LO代谢产物如白三烯B(4)和C(4)并不会改变神经元I(KV)。这些数据表明，AT(2)受体介导的对神经元I(KV)的刺激作用部分是通过AA的12-LO代谢产物介导的。
