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 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.
Zhu
M
M
Department of Physiology, College of Medicine and University of Florida Brain Institute, University of Florida, Gainesville, Florida 32610, USA.
Natarajan
R
R
Nadler
J L
JL
Moore
J M
JM
Gelband
C H
CH
Sumners
C
C
D015117:5,8,11,14-Eicosatetraynoic Acid / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001092:Arachidonate 12-Lipoxygenase / Q000276:immunology / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism*; D001933:Brain Stem / Q000166:cytology; D002478:Cells, Cultured; D051668:Delayed Rectifier Potassium Channels; D044950:Flavanones; D005419:Flavonoids / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D007031:Hypothalamus / Q000166:cytology; D007211:Indoles / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D002722:Chlorobenzenes
D015117:5,8,11,14-Eicosatetraynoic Acid; D000804:Angiotensin II; D000906:Antibodies; D001092:Arachidonate 12-Lipoxygenase; D016718:Arachidonic Acid; D051668:Delayed Rectifier Potassium Channels; D044950:Flavanones; D005419:Flavonoids; D016166:Free Radical Scavengers; D007211:Indoles; D016859:Lipoxygenase Inhibitors; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D014662:Vasoconstrictor Agents; C060893:MK-886; D002722:Chlorobenzenes; C006680:baicalein