Adrenergic Downregulation in Critical Care: Molecular Mechanisms and Therapeutic Evidence

The autonomic nervous system in septic shock and its role as a future therapeutic target: a narrative review

“…Adrenergic receptors are characteristic only of the SNS, and can be divided into two types, α-receptors and β-receptors, which can be further divided into subtypes and subclasses [ 19 , 20 ]. From the cardiovascular standpoint, α1-receptors are mostly located on the blood vessels and when activated are responsible for vasoconstriction; β1 (and β2) receptors are mostly present on the heart (the β1/β2 ratio in the myocardium is around 3:1 to 4:1) where their stimulation mediates positive chronotropic, dromotropic and inotropic effects.…”

“…From the cardiovascular standpoint, α1-receptors are mostly located on the blood vessels and when activated are responsible for vasoconstriction; β1 (and β2) receptors are mostly present on the heart (the β1/β2 ratio in the myocardium is around 3:1 to 4:1) where their stimulation mediates positive chronotropic, dromotropic and inotropic effects. At the vessel level, β2-receptor stimulation causes vasodilation [ 20 ]. Of note, in the CNS, presynaptic α2-receptor activation inhibits the release of norepinephrine and thus produces a global sympatholytic action.…”

“…The entity of damage depends on the vulnerability of the different organs to adrenergic overstimulation and to the presence of coexisting chronic diseases. For example, the heart, which has abundant β-adrenergic receptors, seems to be most susceptible to sympathetic overstimulation, with detrimental consequences such as impaired diastolic function, tachyarrhythmia, myocardial ischemia, vasospasm, impaired coronary microcirculation, stunning, and apoptosis [ 20 ]. Other organs are also affected by adrenergic stress, with associated consequences such as pulmonary edema (with subsequent right ventricular dysfunction/failure), increased thrombosis formation, gastrointestinal hypoperfusion, immunosuppression, increased cell energy expenditure and microvascular dysfunction [ 42 , 43 , 46 ].…”

Beta-Adrenergic Blockade in Critical Illness

“…However, at high concentrations of catecholamines, the lusitropic effect is overwhelmed by tachycardia and increased contractility (Dunser and Hasibeder, 2009;Wachter and Gilbert, 2012). β2 produces similar cardiac effects to β1 (Belletti et al, 2020), but sustained β2 activation leads to a counteracting of β1 effects (Lucia et al, 2018). Moreover, the cardiac-mediated epinephrine response appears independent of functional β2 and is mediated primarily by β1relies on β1 activation (Chruscinski et al, 1999).…”

“…The αand β-adrenergic receptors form the response mechanism for endogenous catecholamines and exogenously administered catecholamine vasoactive agents (e.g., dobutamine, dopamine, norepinephrine, and epinephrine) (Preiser et al, 2014). These receptors elicit responses in nearly every major organ system and change their expression levels during the body's stress response to critical illness (Belletti et al, 2020). Prolonged exposure to high levels of catecholamines in these altered states may evoke detrimental metabolic and hemodynamic effects.…”