ETA receptor and NADPH oxidase activation impairs vascular BK channel function in DOCA‐salt hypertension

Large‐conductance Ca 2+ ‐activated potassium (BK) channels and O 2 − modulate vascular tone in hypertension. We hypothesized that ET‐1 acts ET A receptors to activate NADPH oxidase to produce O 2 − which inhibits BK channels in DOCA‐salt hypertension. DOCA‐salt and sham rats were treated for 4 weeks with an ET A receptor antagonist (atrasentan) or a NADPH oxidase inhibitor (apocynin); both treatments lowered blood pressure in DOCA‐salt but not sham rats. Markers of oxidative stress were elevated in tissues from untreated DOCA‐salt rats but were reduced in rats treated with atrasentan or apocynin. BK channel function was studied in mesenteric arteries (MA) and veins (MV) using a pressure myogragh. Constriction caused by IBTX (BK channel blocker), but not norepinephrine (NE), was reduced in DOCA‐salt MV; inhibition was partly reversed in tissues from rats treated with atrasentan or apocynin. The effects of ET‐1 induced O 2 − on BK channels was also tested in MA and MV in vitro. MA or MV from sham rats were treated with ET‐1, or ET‐1/apocynin for 3 h. Then, MA and MV were maintained at 60 and 4 mmHg, respectively. Constriction caused by IBTX, but not NE, was reduced in ET‐1‐treated MA and MV; this inhibition was partly reversed by apocynin. We conclude that BK channel impairment in MV and MA contributes to DOCA‐salt hypertension. BK channel inhibition is mediated partly by activation of the ET‐1‐NADPH oxidase signaling pathway.