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SKA‐31, a new activator of KCa2 and KCa3.1 K+ channels, potentiates the EDHF response and lowers blood pressure
Author(s) -
Wulff Heike,
Sankaranarayanan Ananthakrishnan,
Raman Girija,
Busch Christopher,
Schultz Tim,
Zimin Pavel I.,
Hoyer Joachim,
Köhler Ralf
Publication year - 2009
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.23.1_supplement.1018.6
Subject(s) - chemistry , blood pressure , pharmacology , in vivo , medicine , biology , microbiology and biotechnology
Small‐conductance (KCa2.1‐2.3) and intermediate‐conductance (KCa3.1) Ca 2+ ‐activated K + channels are critically involved in modulating Ca 2+ ‐signaling and membrane potential in excitable and non‐excitable cells. Activators of these channels constitute useful pharmacological tools as well as potential new drugs for the treatment of ataxia, epilepsy, and hypertension. We here used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Out of a library of 55 benzothiazoles we identified SKA‐31 (naphtho[1,2‐ d ]thiazol‐2‐amine), which activated KCa2.1‐2.3 channels with EC 50 s of 2‐3 μM and KCa3.1 with an EC 50 s of 250 nM. SKA‐31 exhibited improved selectivity over Na + and Ca2 + channels and good PK properties (half‐life 12 h; plasma protein binding 40%). SKA‐31 potentiated EDHF‐mediated dilations of carotid arteries from KCa3.1 +/+ mice but not from KCa3.1 −/− mice. Administration of 10 and 30 mg/kg SKA‐31 lowered mean arterial blood pressure by 4 and 6 mmHg in normotensive mice and by 12 mmHg in angiotensin‐II‐induced hypertension. These effects were absent in KCa3.1‐deficient mice. With SKA‐31 we have designed a new pharmacological tool to study the role of KCa2/3 channel activation in vivo . The blood pressure lowering effect of SKA‐31 suggests KCa3.1 channel activation as a new therapeutic principle for the treatment of hypertension.