Epoxyeicosatrienoic acids (EETs) are synthesized from arachidonic acid by 
cytochrome P450 epoxygenases in endothelial cells. It has previously been shown 
that EETs activate K(+) channels, which are important for the hyperpolarization 
and dilation of blood vessels. However, the effects of EETs on other ion 
channels have been less well studied. We investigated the effects of EETs on 
volume-activated Cl(-) channels (VACCs) in rat mesenteric arterial smooth muscle 
cells. Whole-cell patch clamp recording demonstrated that hypotonic solution and 
guanosine 5'-[gamma-thio]triphosphate (GTPgammaS) induced a 
5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB)- and 
4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS)-sensitive VACC current 
in the primary cultured rat mesenteric arterial smooth muscle cells. The VACC 
current was inhibited by EETs and the order of potency was 
8,9-EET>5,6-EET>11,12-EET>14,15-EET. The inhibitory effects of EETs could be 
reversed by 14,15 epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, an EET analog), 
Rp-cGMP and KT-5823 (protein kinase G inhibitors). Interestingly, the inhibitory 
effects of EETs on VACCs were not influenced by Rp-cAMP (a protein kinase A 
antagonist) but it could be abolished by NF-449 (a Gs protein inhibitor), 
indicating the involvement of cAMP but not protein kinase A. In conclusion, our 
results demonstrate that EETs inhibit VACCs in rat mesenteric arterial smooth 
muscle cells through a cGMP-dependent pathway, which is probably due to the 
cross-activation by cAMP. This mechanism may be involved in the regulation of 
cell volume and membrane potential.