In:
Experimental Physiology, Wiley, Vol. 92, No. 6 ( 2007-11), p. 1067-1076
Abstract:
17,18‐Epoxyeicosatetraenoic acid (17,18‐EETeTr) stimulates vascular large‐conductance K + (BK) channels. BK channels are composed of the pore‐forming BK α and auxiliary BK β1 subunits that confer an increased sensitivity for changes in membrane potential and calcium to BK channels. Ryanodine‐sensitive calcium‐release channels (RyR3) in the sarcoplasmic reticulum (SR) control the process. To elucidate the mechanism of BK channel activation, we performed whole‐cell and perforated‐patch clamp experiments in freshly isolated cerebral and mesenteric artery vascular smooth muscle cells (VSMC) from Sprague–Dawley rats, BK β1 gene‐deficient (−/−), BK α (−/−), RyR3 (−/−) and wild‐type mice. The 17,18‐EETeTr (100 n m ) increased tetraethylammonium (1 m m )‐sensitive outward K + currents in VSMC from wild‐type rats and wild‐type mice. The effects were not inhibited by the epoxyeicosatrienoic acid (EET) antagonist 14,15‐epoxyeicosa‐5( Z )‐enoic acid (10 μ m ). BK channel currents were increased 3.5‐fold in VSMC from BK β1 (−/−) mice, whereas a 2.9‐fold stimulation was observed in VSMC from RyR3 (−/−) mice (at membrane voltage 60 mV). The effects were similar compared with those observed in cells from wild‐type mice. The BK current increase was neither influenced by strong internal calcium buffering (Ca 2 + , 100 n m ), nor by external calcium influx. The 17,18‐EETeTr did not induce outward currents in VSMC BK α (−/−) cells. We next tested the vasodilator effects of 17,18‐EETeTr on isolated arteries of BK α‐deficient mice. Vasodilatation was largely inhibited in cerebral and mesenteric arteries isolated from BK α (−/−) mice compared with that observed in wild‐type and BK β1 (−/−) arteries. We conclude that 17,18‐EETeTr represents an endogenous BK channel agonist and vasodilator. Since 17,18‐EETeTr is active in small arteries lacking BK β1, the data further suggest that BK α represents the molecular target for the principal action of 17,18‐EETeTr. Finally, the action of 17,18‐EETeTr is not mediated by changes of the internal global calcium concentration or local SR calcium release events.
Type of Medium:
Online Resource
ISSN:
0958-0670
,
1469-445X
DOI:
10.1113/eph.2007.92.issue-6
DOI:
10.1113/expphysiol.2007.038166
Language:
English
Publisher:
Wiley
Publication Date:
2007
detail.hit.zdb_id:
1493802-9
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