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Review
. 2020;26(30):3723-3732.
doi: 10.2174/1381612826666200417150121.

The Obligatory Role of the Acetylcholine-Induced Endothelium-Dependent Contraction in Hypertension: Can Arachidonic Acid Resolve this Inflammation?

Jonnelle M Edwards  1 , Cameron G McCarthy  1 , Camilla F Wenceslau  1
Affiliations
Review

The Obligatory Role of the Acetylcholine-Induced Endothelium-Dependent Contraction in Hypertension: Can Arachidonic Acid Resolve this Inflammation?

Jonnelle M Edwards et al. Curr Pharm Des. 2020.

Abstract

The endothelium produces many substances that can regulate vascular tone. Acetylcholine is a widely used pharmacological tool to assess endothelial function. In general, acetylcholine binds to G-protein coupled muscarinic receptors that mediate a transient elevation in intracellular, free calcium. This intracellular rise in calcium is responsible for triggering several cellular responses, including the synthesis of nitric oxide, endothelium- derived hyperpolarizing factor, and eicosanoids derived from arachidonic acid. Endothelial arachidonic acid metabolism is also an important signaling pathway for mediating inflammation. Therefore, in conditions with sustained and excessive inflammation such as hypertension, arachidonic acid serves as a substrate for the synthesis of several vasoconstrictive metabolites, predominantly via the cyclooxygenase and lipoxygenase enzymes. Cyclooxygenase and lipoxygenase products can then activate G-protein coupled receptors expressed on vascular smooth muscle cells to causes contractile responses. As a result, acetylcholine-induced contraction due to arachidonic acid is a commonly observed feature of endothelial dysfunction and vascular inflammation in hypertension. In this review, we will critically analyze the literature supporting this concept, as well as address the potential underlying mechanisms, including the possibility that arachidonic acid signaling is diverted away from the synthesis of pro-resolving metabolites in conditions such as hypertension.

Keywords: Endothelium; G-protein; acetylcholine; arachidonic acid metabolites; hypertension; vascular function.

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Conflict of interest statement

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

Figures

Fig. (1).
Fig. (1).
Typical traces represent concentration response curve to acetylcholine (1nM −30 μM) in mesenteric resistance arteries from 12-weeks old spontaneously hypertensive rats (SHR) and normotensive Wistar rats. The arteries were initially contracted with phenylephrine (10 μM). Please note that at the concentration of 0.03 μM acetylcholine, arteries from SHR are completely relaxed when compared to arteries from Wistar rats. This is a representative illustration of traces observed in our laboratory. However, similar findings are quantified in multiple studies [–, –37].
Fig. (2).
Fig. (2).
Typical traces represent concentration response curve to acetycholine (1nM −30 μM) in mesenteric resistance arteries from 8-weeks old Dahl salt (S) sensitive and resistant (R) rats fed a 0.3% low-salt diet. The arteries were initially contracted with phenylephrine (10 μM). This is a representative illustration of traces observed in our laboratory. However, similar findings are quantified in multiple studies [–, –37].
Fig. (3).
Fig. (3).
Typical traces represent concentration response curve to acetylcholine (1nM −30 μM) in mesenteric resistance arteries from 15-week old Dahl salt (S) sensitive and resistant (R) rats fed a 2% high-salt diet for 8 weeks. The arteries were initially contracted with phenylephrine (10 μM). Please note that at the concentration of 0.3 μM acetylcholine, arteries from Dahl S are completely relaxed when compared to arteries from Dahl R. This is a representative illustration of traces observed in our laboratory. However, similar findings are quantified in multiple studies [–, –37].
Fig. (4).
Fig. (4).
The Janus face of acetylcholine and endothelium-dependent, arachidonic acid signaling. In physiological conditions, acetylcholine promotes the synthesis of vasodilating eicosanoids and other endothelium-derived hyperpolarizing factors (e.g., nitric oxide). However, in pathophysiological conditions such as hypertension, there is aberrant arachidonic acid signaling due to excessive inflammation. As a result, acetylcholine promotes the synthesis of vasoconstrictor metabolites, predominantly from cyclooxygenase and lipoxygenase that can act on vascular smooth muscle cells. As a result, acetylcholine causes endothelium-dependent contractile responses, as opposed to vasodilation.
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