Table 2 Mechanisms affecting the ANS that provide clinically relevant effects and may represent potential therapeutic targets during sepsis
Implicated receptors | Main endogenous and exogenous agonists | Main clinically relevant effects of receptors agonism | Potential therapeutic targets under investigation |
|---|---|---|---|
β1 | Norepinephrine, epinephrine, dobutamine, milrinone | Sinoatrial node and ectopic pacemaker acceleration Cardiac contractility increase Renin release by juxtaglomerular cells Potential pro-inflammatory action through macrophage activation | 1) Patient “decatecholaminization” from a global standpoint: - Adrenergic burden decrease by reducing both duration and intensity (i.e., dose) exposure to exogenous catecholamines - Partial exogenous catecholamine substitution by adding/shifting to alternative non-adrenergic agents (e.g., vasopressin or levosimendan) 2) Myocardial oxygen consumption reduction and ventricular filling optimization by HR control: - Cardioselective β1-receptor antagonists (e.g., esmolol or landiolol) - Selective bradycardic agent (ivabradine) 3) Attenuation of β-adrenergic induced immune cell inhibition: - Cardioselective β1-receptor antagonists as above (e.g., esmolol or landiolol) - Less cardioselective β-blockers? - Central α2-agonist agent promotion (e.g., clonidine and dexmedetomidine) to reduce peripheral α1-adrenergic receptor desensitization and restore vascular tone adrenergic control |
β2 | Norepinephrine, epinephrine, dobutamine, milrinone | Arterial and venous dilation Skeletal muscle arteriole relaxation Sinoatrial node and ectopic pacemaker acceleration Cardiac contractility increase Macrophage inhibition (anti-inflammatory and immunosuppressive effects) Neutrophil activity and endothelial adhesion inhibition NK cell activity inhibition T-lymphocyte activity and proliferation inhibition (N/A for the Th2 cells) Variable influences on B-lymphocytes and antibody production | |
β3 | Norepinephrine, epinephrine, mirabegron | Variable actions on cardiac contractility Arterial and venous vasodilation Neutrophil activity and endothelial adhesion inhibition | |
α1 | Norepinephrine, epinephrine | Arterial and venous vasoconstriction Cardiac contractility slight increase Sodium reabsorption in renal tubules Glomerular arteriole (afferent > efferent) vasoconstriction Neutrophil activity and endothelial adhesion inhibition T-lymphocyte activity and proliferation inhibition | |
α2 | Norepinephrine, epinephrine | Sympatholytic effect in the CNS by presynaptic inhibition Coronary artery and arteriole vasoconstriction Sodium reabsorption in renal tubules Pro- and anti-inflammatory action on macrophages | |
nACh | Acetylcholine | Macrophage activity reduction through the inflammatory reflex (spleen, liver, gut, heart) | External vagus nerve stimulation to reduce MOF and excessive pro-inflammatory reactions by the inflammatory reflex mechanism. |