Published Online
on October 10, 2005

A more recent version of this article appeared on November 1, 2005

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Submitted on July 17, 2005
Revised on July 17, 2005

Activation of Vascular BK Channel by Tempol in DOCA-Salt Hypertensive Rats

Hui Xu^*; Xiaochun Bian; Stephanie W. Watts; and Alexandra Hlavacova

From the Department of Pharmacology and Toxicology, Michigan State University, East Lansing.

^* To whom correspondence should be addressed. E-mail: xuhui2{at}msu.edu.

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 µmol/L) and tetraethylammonium chloride (TEA) (1 mmol/L). Tempol did not relax KCl preconstricted arteries in sham or DOCA-salt rats, and N-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 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 subunit contributes to the enhanced depressor response caused by tempol in DOCA-salt hypertension.

Key words: antioxidants • hypertension • vasodilation

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