Abstract
The Ca2+/voltage-gated K+ large conductance (BK) channel β1 subunit is particularly abundant in vascular smooth muscle. By determining their phenotype, BK β1 allows the BK channels to reduce myogenic tone, facilitating vasodilation. The endogenous steroid lithocholic acid (LCA) dilates cerebral arteries via BK channel activation, which requires recognition by a BK β1 site that includes Thr169. Whether exogenous nonsteroidal agents can access this site to selectively activate β1-containing BK channels and evoke vasodilation remain unknown. We performed a chemical structure database similarity search using LCA as a template, along with a two-step reaction to generate sodium 3-hydroxyolean-12-en-30-oate (HENA). HENA activated the BK (cbv1 + β1) channels cloned from rat cerebral artery myocytes with a potency (EC50 = 53 μM) similar to and an efficacy (×2.5 potentiation) significantly greater than that of LCA. This HENA action was replicated on native channels in rat cerebral artery myocytes. HENA failed to activate the channels made of cbv1 + β2, β3, β4, or β1T169A, indicating that this drug selectively targets β1-containing BK channels via the BK β1 steroid-sensing site. HENA (3–45 μM) dilated the rat and C57BL/6 mouse pressurized cerebral arteries. Consistent with the electrophysiologic results, this effect was larger than that of LCA. HENA failed to dilate the arteries from the KCNMB1 knockout mouse, underscoring BK β1’s role in HENA action. Finally, carotid artery-infusion of HENA (45 μM) dilated the pial cerebral arterioles via selective BK-channel targeting. In conclusion, we have identified for the first time a nonsteroidal agent that selectively activates β1-containing BK channels by targeting the steroid-sensing site in BK β1, rendering vasodilation.
Footnotes
- Received November 7, 2012.
- Accepted March 1, 2013.
This work was supported by the National Institutes of Health National Heart, Lung and Blood Institute [Grants AA011560, HL104631, HL34059, and HL042851].
Preliminary data were previously presented as a poster presentation: Bukiya A, McMillan J, Fedinec A, Leffler C, Parrill A, Dopico A (2012) Sodium 3-hydroxyolean-12-en-30-oate is a novel and selective activator of b1 subunit-containing BK channel and thus cerebral artery dilator. 2012 Annual Meeting of the Biophysical Society; 2012 Feb 25–29; San Diego, CA.
↵This article has supplemental material available at molpharm.aspetjournals.org.
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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