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Targeting the high‐conductance Ca2+‐activated K+ (BK) channel as vasodilator therapy for pulmonary hypertension
Author(s) -
Detweiler Neil D,
Kharade Sujay V,
Versluis Rachel J,
Rhee Sung W,
Rusch Nancy J,
Crooks Peter A
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.877.10
Subject(s) - vasodilation , bk channel , hypoxic pulmonary vasoconstriction , hypoxia (environmental) , chemistry , nitric oxide , prostacyclin , vasoconstriction , pulmonary hypertension , pharmacology , medicine , endocrinology , potassium channel , oxygen , organic chemistry
Pulmonary arterial hypertension (PAH) is characterized by a loss of nitric oxide, prostacyclin, and other vasodilator molecules resulting in pulmonary vasoconstriction. In contrast, our Western blot studies detected a 4.9‐fold increase in expression of the high‐conductance Ca 2+ ‐activated K + (BK) channel in the pulmonary arteries (PA) of rats with hypoxia‐induced PAH (n=6), suggesting the upregulation of a potent vasodilator influence. However, it is possible that BK channels are inactivated in hypoxia‐induced PAH, since RT‐PCR confirmed that the BK α‐subunit in rat PA contains a hypoxia‐sensitive STREX region known to negatively regulate channel activity. Considering these factors, we hypothesized that pharmacological activation of over‐expressed BK channels in the VSMCs of affected PA may enact vasodilation as a therapy for PAH. Patch‐clamp studies showed that NS11021 (1, 3 and 10 μmol/L), a novel pharmacological BK channel opener, increased whole‐cell K + current by 1.9‐fold in VSMCs of PA from control rats (n=3). Similar concentrations of NS11021 also partially reversed hypoxia‐induced constrictions of rat PA rings in tension‐recording studies (n=3). These results suggest that BK channel openers represent a potential vasodilator therapy for PAH, a hypothesis we plan to test using pulmonary biotelemetry in rat models of PAH. Supported by UL1RR029884 (NDD) from the NIH.