Biomedical Engineering Reference
In-Depth Information
Prostacyclin
Prostacyclin (PGi2) is another endothelium-derived vasodilator. Arachidonic acid is
a polyunsaturated fatty acid in membrane phospholipids, especially phosphatidyl-
ethanolamine, -choline, and -inositides. Synthesis of PGi2 depends on a balance
between liberation of arachidonic acid by phospholipase-A2 from membrane
phospholipids and incorporation into membrane phospholipids of arachidonate
metabolites by acyl coenzyme-A synthase.
Endothelium-Derived Hyperpolarizing Factor
Endothelium-derived hyperpolarizing factor can be a prominent vasodilator [
821
].
Endothelial-derived hyperpolarization has been attributed to K
+
ions, arachi-
donic acid metabolites, and ionic communication via gap junctions. This process
operates via calcium-sensitive, small-conductance (SK or K
Ca
2.3) and intermediate-
conductance (IK or K
Ca
3.1) potassium channels in the vascular endothelium.
Metabolites of arachidonic acid produces by cytochrome-P450 epoxygenase
such as epoxyeicosatrienoic acids can be released from endothelial cells to provoke
hyperpolarization of neighboring vascular smooth myocytes. Released epoxye-
icosatrienoic acids activate Ca
2
+
-dependent K
+
channels and Ca
2
+
-K
+
AT P a s e
(Fig.
8.4
).
In vascular endothelial and smooth muscle cells, enzymes of the cytochrome-
P450 set metabolize arachidonic acid to vasoactive substances. Epoxygenases of
the arachidonic acid metabolism in the vasculature belong to cytochrome-P450-
2B, -2C, and -2J.
-Hydroxylases are members of the cytochrome-P450-4A
and -4F classes. These enzymes produce epoxyeicosatrienoic acids (EET) and
20-hydroxyeicosatetraenoic acid (20HETE) [
822
]. Soluble epoxide hydrolase cat-
alyzes the conversion of epoxyeicosatrienoic acids into dihydroxyeicosatrienoic
acids (DHET). Cytochrome-P450 thus regulates blood pressure.
Members of the cytochrome-P450 superfamily are inhibited, i.e., EDHF produc-
tion is damped by nitric oxide. When NO synthesis is impaired, alleviation of EDHF
inhibition by NO, at least partly, maintains endothelial vasodilator function [
823
].
Epoxyeicosatrienoic and dihydroxyeicosatrienoic acids are quickly incorporated
into phospholipids in cardiomyocytes, endothelial cells, and platelets due to acyl
coenzyme-A synthase (at least in endothelial cells).
Signaling via G
ω
α
s
subunit and Src kinase operates via epoxyeicosatrienoic
acids. Epoxyeicosatrienoic acids act as auto-, juxta-, and paracrine effectors that
modulate ion transport and gene expression to regulate the vasomotor tone, hinder
inflammation, and favor fibrinolysis. Acute increase in transmural pressure in
vessels that express cytochrome P450-4A can stimulate stretch-activated Ca
2
+
channels, and subsequently enhance 20HETE formation.
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