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Exp Physiol. 2007 Nov;92(6):1067-76. Epub 2007 Aug 3.

The vasodilator 17,18-epoxyeicosatetraenoic acid targets the pore-forming BK alpha channel subunit in rodents.

Author information

1
Nephrology/Hypertension Division, Franz Volhard Clinic, HELIOS Klinikum-Berlin, Campus Buch, Berlin, Germany.

Abstract

17,18-Epoxyeicosatetraenoic acid (17,18-EETeTr) stimulates vascular large-conductance K(+) (BK) channels. BK channels are composed of the pore-forming BK alpha and auxiliary BK beta1 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 beta1 gene-deficient (-/-), BK alpha (-/-), RyR3 (-/-) and wild-type mice. The 17,18-EETeTr (100 nm) increased tetraethylammonium (1 mm)-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 mum). BK channel currents were increased 3.5-fold in VSMC from BK beta1 (-/-) 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 nm), nor by external calcium influx. The 17,18-EETeTr did not induce outward currents in VSMC BK alpha (-/-) cells. We next tested the vasodilator effects of 17,18-EETeTr on isolated arteries of BK alpha-deficient mice. Vasodilatation was largely inhibited in cerebral and mesenteric arteries isolated from BK alpha (-/-) mice compared with that observed in wild-type and BK beta1 (-/-) 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 beta1, the data further suggest that BK alpha 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.

PMID:
17675416
DOI:
10.1113/expphysiol.2007.038166
[Indexed for MEDLINE]
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