Activation of potassium channels by tempol in arterial smooth muscle cells from normotensive and deoxycorticosterone acetate-salt hypertensive rats.
Large-conductance Ca(2+)-activated potassium (BK) channels modulate vascular tone. Tempol, an O(2)(-) dismutase mimetic, causes vasodilation via activation of vascular BK channels. In this study, we investigated the mechanisms underlying tempol-induced activation of BK channels in mesenteric arterial (MA) myocytes from sham and deoxycorticosterone acetate (DOCA)-salt hypertensive rats. In sham myocytes, whole-cell patch clamp studies showed that tempol enhanced peak outward currents (I(o)). This effect was larger in DOCA-salt myocytes. Tempol caused a leftward shift in the activation curve for I(o) in sham and DOCA-salt myocytes. In DOCA-salt myocytes, the peak I(o) at +80 mV did not differ from sham myocytes, but iberiotoxin (BK channel blocker) caused a larger reduction of I(o) in DOCA-salt compared with sham myocytes. Iberiotoxin but not 4-aminopyridine blocked the I(o) activated by tempol. Tiron, another O(2)(-) scavenger, had no effect on I(o). Using inside-out patches, we found that tempol caused a 4-fold increase in open probability (P(o)) of BK channels but did not change the mean channel open time in sham and DOCA-salt myocytes. Tempol did not change single channel conductance in sham or DOCA-salt myocytes. Western blot and immunocytochemical studies revealed that BK channel alpha-subunit expression was increased in DOCA-salt MA compared with sham MA. The data indicate that tempol directly activates BK channels by increasing channel P(o). We conclude that upregulation of the BK channel alpha-subunit protein and tempol-induced increases in BK channel P(o) contribute to the enhanced depressor response caused by tempol in DOCA-salt hypertensive rats.
Xu
Hui
H
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA. xuhui2@msu.edu
Jackson
William F
WF
Fink
Gregory D
GD
Galligan
James J
JJ
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002478:Cells, Cultured; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D003900:Desoxycorticosterone; D004195:Disease Models, Animal; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D024681:Potassium Channels, Calcium-Activated / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013113:Spin Labels; D015854:Up-Regulation
D000975:Antioxidants; D003497:Cyclic N-Oxides; D024681:Potassium Channels, Calcium-Activated; D013113:Spin Labels; D003900:Desoxycorticosterone; C001803:tempol