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.

β₁ beta-1 adrenergic receptors, β₂ beta-2 adrenergic receptors, β₃ beta-3 adrenergic receptors, α₁ alpha-1 adrenergic receptors, α₂ alpha-2 adrenergic receptors, nACh nicotinic acetylcholine receptors, CNS central nervous system