Inhibitors of soluble epoxide hydrolase cause decreases in blood pressure as inhibition of the enzymes leads to increases in concentrations of epoxyeicosatrienoic acids. These lower blood pressure by ultimately activating large conductance Ca2+ activated K+ channels (BKCa) channels in vascular smooth muscle cells and causing hyperpolarisation and thus vasodilation.
I wanted to ask how I could investigate, in an animal model, whether blood pressure was lowered due to the activation of these channels following administration of an inhibitor of soluble epoxide hydrolase.
Typically, tetraethylammonium was used in vivo, but after the late 90s when it was realised just what an awfully nonspecific drug this is then you cannot really draw any conclusion from it. Iberiotoxin, which is selective for KCa1.1, would have too many non vascular effects.
However BKCa channels are not the only effector target for EETs. They can also activate TRP channels in the endothelium (e.g. TRPV4, TRPC3 and C6), thereby promoting Ca2+ influx and endothelial hyperpolarization. Plus they can also enhance gap junctional communication.
Hence, the problem with analyzing this in vivo is that EETs can facilitate/mediate vessel dilation via different mechanisms depending on the vessel, species, mode of endothelial stimulation, underlying disease, age etc.
I'm not saying this is approachable, but approach with caution.
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