title: Activation of vascular BK channel by tempol in DOCA-salt hypertensive rats.
abstract: Large-conductance Ca2+-activated potassium (BK) channels modulate vascular smooth muscle tone. Tempol, a superoxide dismutase (SOD) mimetic, lowers blood pressure and inhibits sympathetic nerve activity in normotensive and hypertensive rats. In the present study, we tested the hypotheses depressor responses caused by tempol are partly mediated by vasodilation. It was found that tempol, but not tiron (a superoxide scavenger), dose-dependently relaxed mesenteric arteries (MA) in anesthetized sham and deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Tempol also reduced perfusion pressure in isolated, norepinephrine (NE) preconstricted MA from sham and DOCA-salt hypertensive rats. Maximal responses in DOCA-salt rats were twice as large as those in sham rats. The vasodilation caused by tempol was blocked by iberiotoxin (IBTX, BK channel antagonist, 0.1 micromol/L) and tetraethylammonium chloride (TEA) (1 mmol/L). Tempol did not relax KCl preconstricted arteries in sham or DOCA-salt rats, and Nomega-nitro-L-arginine methyl ester (L-NAME), apamin, or glibenclamide did not alter tempol-induced vasodilation. IBTX constricted MA and this response was larger in DOCA-salt compared with sham rats. Western blots and immunohistochemical analysis revealed increased expression of BK channel alpha subunit protein in DOCA-salt arteries compared with sham arteries. Whole-cell patch clamp studies revealed that tempol enhanced BK channel currents in HEK-293 cells transiently transfected with mslo, the murine BK channel a subunit. These currents were blocked by IBTX. The data indicate that tempol activates BK channels and this effect contributes to depressor responses caused by tempol. Upregulation of the BK channel alpha subunit contributes to the enhanced depressor response caused by tempol in DOCA-salt hypertension.
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA. xuhui2@msu.edu
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Bian
authors.forename: Stephanie W
authors.initials: SW
authors.lastname: Watts
authors.forename: Alexandra
authors.initials: A
authors.lastname: Hlavacova
mesh_terms: D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D003497:Cyclic N-Oxides / Q000008:administration & dosage / Q000494:pharmacology*; D003900:Desoxycorticosterone; D004305:Dose-Response Relationship, Drug; D004553:Electric Conductivity; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D006973:Hypertension / Q000139:chemically induced* / Q000503:physiopathology*; D066298:In Vitro Techniques; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D010477:Perfusion; D011312:Pressure; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D012965:Sodium Chloride; D013113:Spin Labels; D014162:Transfection; D014664:Vasodilation; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D051036:Large-Conductance Calcium-Activated Potassium Channels; D020033:Protein Isoforms; D013113:Spin Labels; D014665:Vasodilator Agents; D003900:Desoxycorticosterone; D012965:Sodium Chloride; D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; C001803:tempol