Reversal of Vasodilatory Shock: Current Perspectives on Conventional, Rescue, and Emerging Vasoactive Agents for the Treatment of Shock

Jonathan H. Chow, MD; Ezeldeen Abuelkasem, MBBCh, MSc; Susan Sankova, MD; Reney A. Henderson, MD; Michael A. Mazzeffi, MD, MPH; Kenichi A. Tanaka, MD, MSc

Disclosures

Anesth Analg. 2019;130(1):15-30. 

In This Article

Mechanism of Vasoconstriction and Vasodilation

The mechanisms of action of major vasoconstrictors are mediated by G-protein–coupled receptors (GPCRs), also known as 7-transmembrane receptors on vascular smooth muscle cell membranes (Figure 2). Gq proteins activate smooth muscle contraction through the inositol triphosphate (IP3) signal transduction pathway.[5,6] Vasopressin-type 1a (V1a) and angiotensin-type 1 (AT1) receptors are activated by vasopressin and angiotensin II (Ang-2), respectively. α-1 receptors are activated by vasoconstrictors such as norepinephrine (NE), Epinephrine (Epi), and phenylephrine. Receptor activation triggers a cascade of events, leading to intracellular release of Ca2+, which activates myosin light-chain kinase (MLCK) and allows the contraction to begin (vasoconstriction).[5,6]

Figure 2.

Vasoconstriction via the IP3-mediated signal transduction pathway. Gq proteins activate smooth muscle contraction through the IP3 signal transduction pathway. V1a and AT1 receptors are activated by vasopressin/terlipressin and angiotensin II, respectively, while α1 receptors are activated by NE, Epi, and phenylephrine. Receptor activation triggers stimulation of PLC, which leads to the formation of IP3 and DAG. DAG remains in the cell membrane and stimulates the influx of Ca2+ into the cell. IP3 diffuses into the cell to act on an IP3-sensitive Ca2+ channel on the surface of the endoplasmic reticulum. The release of intracellular Ca2+ stimulates the CM and JAK2 pathways. Ca2+ binds to CM and forms a Ca2+-CM complex that activates MLCK. With the addition of ATP, MLCK phosphorylates MLC and causes vasoconstriction. In the JAK2 pathway, JAK2 activates Rho kinase and prevents smooth muscle relaxation from occurring. JAK2 also leads to the release of ROS, which further increases sensitivity to Ca2+ and leads to additional stimulation of Rho kinase. Figure created with Motifolio Toolkit (Ellicott City, MD). AT1 indicates angiotensin-type 1 receptor; ATP, adenosine triphosphate; CM, calmodulin; DAG, diacylglycerol; Epi, epinephrine; IP3, inositol triphosphate; JAK2, Janus kinase 2; MLCK, myosin light-chain kinase; MLC, myosin light chain; MLCP, myosin light chain phosphatase; NE, norepinephrine; PIP2, Phosphatidylinositol 4,5-bisphosphate; PLC, phospholipase C; ROS, reactive oxygen species; V1a, vasopressin-type 1a receptor.

The mechanisms of vasodilation are summarized in Figure 3. Gs proteins are activated by Epi, adenosine, or prostacyclin, causing smooth muscle relaxation through the cyclic adenosine monophosphate (cAMP) signal transduction pathway (Figure 3A). This inhibits MLCK and causes vasodilation to occur.[5,6] Counterbalancing this pathway are Gi proteins that are activated by α2 receptors bound to NE. This inhibits cAMP and leads to further inhibition of the vasodilatory pathway.

Figure 3.

Vasodilation via the cAMP/cGMP signal transduction pathway. A, Smooth muscle cell. Activation of β2, D1, and IP receptors by epinephrine, dopamine, or prostacyclin leads to stimulation of AC. Increases in AC increase the inhibitory effect of cAMP on MLCK and leads to smooth muscle relaxation. Conversely, α2 receptors are activated by NE, which inhibits AC and decreases cAMP. This decreases the inhibition of MLCK and leads to smooth muscle contraction. B, Endothelial cell. Acetylcholine binds to M3 receptors to trigger signaling through an IP3 transduction pathway, which leads to the intracellular release of Ca2+. Vascular shear forces also increase the release of intracellular Ca2+. The resulting Ca2+-CM complex activates NOS. This leads to the production of NO which rapidly diffuses across the cell membrane into a smooth muscle cell, where GC and cGMP are activated. Inhibition of MLCK causes vasodilation to occur. Methylene blue interacts at 2 points in this pathway by inhibiting NOS and GC, thus causing the prevention of vasodilation. Figure created with Motifolio Toolkit. AC indicates adenylyl cyclase; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; CM, calmodulin; D1, dopamine-type 1 receptor; DAG, diacylglycerol; GC, guanylyl cyclase; IP, prostaglandin I2 receptor; IP3, inositol triphosphate; M3, muscarinic acetylcholine receptor; MLCK, myosin light-chain kinase; MLC, myosin light chain; MLCP, myosin light chain phosphatase; NE, norepinephrine; NEpi, norepinephrine; NOS, nitric oxide synthase; PIP2, Phosphatidylinositol 4,5-bisphosphate; PLC, phospholipase C.

Vascular shear forces can also lead to vasodilation, and this is accomplished in a receptor-independent pathway through the release of intracellular Ca2+, which upregulates nitric oxide synthase (NOS) and NO production (Figure 3B). NO rapidly diffuses across the cell membrane into a smooth muscle cell where it inhibits MLCK, leading to vasodilation.

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