Why Is Epinephrine Preferred for Cardiac Arrest? The Answer May Lie in β₂-Adrenergic Receptor Activation

Abstract

Epinephrine (Epi, adrenaline) is routinely used during cardiopulmonary resuscitation (CPR) for cardiac arrest and is a first line treatment according to the international advanced life support (ALS) guidelines, which recommend 1 mg Epi be administered every 3–5 minutes during CPR. However, specific pharmacological factors that may distinguish Epi from other vasopressor agents used during CPR are unclear. This opinion article argues that one such factor, perhaps even the most important, is the activation of the β₂-adrenergic receptor (AR) subtype, which only Epi, among all vasopressor hormones, can induce. β₂AR activation equips Epi with more robust capabilities for pulse generation in the pacemaker cells (sinoatrial node) for the heart and of restoring contractile function in ischemic/hypoxic cardiomyocytes via sodium/potassium pump activation, compared to all other vasopressor hormones, including the closely related catecholamine norepinephrine (NE, noradrenaline). These additional actions of Epi via the β₂AR, which are probably not shared by NE or other vasopressor agents, may make it particularly useful in situations where simple blood pressure elevation is insufficient, such as cardiac arrest.

Graphical abstract

Keywords

adrenaline (epinephrine) / beta-adrenergic receptors / cardiac arrest / catecholamine / noradrenaline (norepinephrine) / return of spontaneous circulation (ROSC) / sodium-potassium pump

1. Introduction

The best choice of therapeutic agent(s) to improve outcomes of cardiopulmonary resuscitation (CPR) during cardiac arrest is still a matter of debate. Circulating hormone epinephrine (Epi, adrenaline), produced and secreted by the chromaffin cells of the adrenal medulla, with contributions from the sympathetic nervous system neurotransmitter norepinephrine (NE, noradrenaline), is responsible for generating the “fight-or-flight” response of our bodies to environmental stressful stimuli or traumatic insults [1, 2, 3]. Epi and NE exert their effects in cells via adrenergic receptors (ARs), all nine subtypes of which are class A (rhodopsin-like) G protein-coupled receptors (GPCRs) [4]: three \alpha₁-ARs (\alpha_1A, \alpha_1B, \alpha_1D), primarily exerting vasopressor actions [5]; three \alpha₂-ARs (\alpha_2A, \alpha_2B, \alpha_2C), primarily functioning as sympatho-inhibitory autoreceptors in central and peripheral nervous systems [6]; and three \betaARs (\beta₁, \beta₂, \beta₃), primarily coupling to adenylyl cyclase (AC) stimulation and cyclic adenosine monophosphate (cAMP) signaling [7]. The \betaAR subtypes share some actions, e.g., in adipocytes [7], but have very distinct functions, as well: for instance, while both \beta₁- and \beta₂ARs exert positive inotropy, chronotropy, dromotropy, and lusitropy in the myocardium, \beta₃AR exerts negative inotropy [8]. In addition, \beta₁- and \beta₃ARs are almost exclusively located at sites receiving direct sympathetic innervation, and thus, are ideally placed to respond to neuronally released NE [4]. Conversely, \beta₂AR is located at various peripheral organs and tissues that usually lack sympathetic innervation, and thus, is ideally suited to respond to the circulating hormone Epi.

NE and Epi activate all \alpha₁ARs, all \alpha₂ARs, and the \beta₁AR equipotently. Whereas Epi is more potent at \beta₁AR & \beta₂AR activation than at \alphaAR activation [9], NE is more potent at \beta₃AR activation than Epi is and, in fact, \beta₃AR is the only AR subtype for which Epi has low affinity [10]. The exact opposite is true for the \beta₂AR: NE has by far the lowest affinity for this AR subtype, much lower than that of Epi. In this opinion article, we argue that this is exactly what makes Epi much more efficacious in the treatment of cardiac arrest.

2. Why Epi Is the Sole Endogenous \beta₂AR Agonist Hormone: The Answer is Tyr308

NE has ~10–15-fold lower affinity for human \beta₂AR than Epi [11]; yet, both NE and Epi make contacts with the exact same amino acid residues in the agonist binding (orthosteric) pockets of both \beta₂AR and \beta₁AR [12, 13]. Yet, Epi displays far superior potency and efficacy at the human \beta₂AR over NE, as measured in a cAMP accumulation assay in human lymphocytes [14]. In human atrial and ventricular tissue biopsies from patients, NE displayed 20-fold lower affinity for \beta₂AR over \beta₁AR [15]. This, coupled with the fact that \beta₁AR, which both NE and Epi activate equipotently, is much (~10-fold) less efficacious at producing cAMP in human heart than \beta₂AR is [15], translates into a significantly (5-fold) higher potency for Epi over NE at stimulating cardiac contractility: 1 µM of NE produces the same degree of positive inotropy as 200 nM of Epi in human atrial myocardium [15]. It is thus clear that NE, at normal physiological concentrations, does not really activate the \beta₂AR subtype, similarly to dopamine [14], and thus, Epi is essentially the only endogenous catecholamine that activates the \beta₂AR, at least at physiological concentrations.

The only structural difference between NE and Epi is the presence of one methyl group on the positively charged (protonated)-NH₂ group, absent in NE (Fig. 1A, Ref. [16]). This methyl substitution increases the basicity (protonation) of Epi’s nitrogen atom (secondary amines like Epi are generally more basic than primary amines like NE). It also increases ligand affinity for the human \beta₂AR dramatically: when this N-methyl group is added to NE, affinity for the \beta₂AR increases ~60-fold [17]. How exactly this N-methyl group confers this dramatic difference in \beta₂AR affinity is still under investigation. However, the orientation of the catecholamine in the orthosteric pocket, a “groove” formed by Asp113 of TM3 & Asn312 of TM7 on one end, and Ser203/Ser204/Ser207 of TM5 on the other (Fig. 1A), gives some crucial hints [16]. The N-methyl group is well positioned to interact with the extracellular top of TM7 at the extracellular “lid” of the pocket. Although it does not contact the agonist in the pocket directly, Tyr308 of TM7 is in close proximity (within 8 Å) to amino acids that do contact the ligand, specifically Asn312 (Fig. 1A) [18]. Notably, all other AR subtypes, the \beta₁AR included, have phenylalanine (F^7.35) at this TM7 position (position 7.35 based on the Ballesteros-Weinstein numbering) [13]. Given that tyrosine forms both polar (hydrogen bond) interactions via its hydroxyl group and hydrophobic (Van der Waals) interactions via its phenyl group (Fig. 1A), Tyr308 is ideally placed to coordinate the entry of the N-methyl group of Epi into the pocket and to stabilize binding (prevent dissociation) to the \beta₂AR (Fig. 1A). This is because the N-methyl group also makes polar, via the protonated amino group (-⁺NH₂), and hydrophobic, via the methyl group (-CH₃), interactions. Indeed, the “on” (receptor association) rate of Epi for the \beta₂AR has been estimated to be ~14-fold faster than that of NE [11], and Tyr308 of the \beta₂AR has been documented to be the main determinant of \beta₂AR-selective affinity for \betaAR agonists via both hydrophobic (with the phenyl) and polar (with the -OH group) interactions [19]. Importantly, Tyr308 both increases the association and decreases the dissociation rates of Epi on the \beta₂AR [19]. In contrast, by lacking this N-methyl substitution, NE is probably incapable of interacting with Tyr308 (the NE molecule is not long enough to sterically reach Tyr308 for strong interaction) and thus, quickly dissociates from the \beta₂AR’s orthosteric pocket. Hence, only very high NE concentrations can activate the \beta₂AR [14]. Interestingly, Tyr308 has been reported to be essential for the Gs protein-“biased” agonism of the \beta₂AR, as well [20]. \beta₂AR’s Tyr^7.35 appears necessary for efficient activation of the Gs/AC/cAMP signaling pathway by the receptor. Since \beta₁AR has Phe instead of Tyr at this position, this could underlie, in part, the reduced efficacy, versus \beta₂AR, of \beta₁AR at producing cAMP [15]. The significantly larger (by 27 amino acids) third intracellular loop of \beta₁AR, compared to that of \beta₂AR, is another reason postulated for this reduced efficacy [15]. Taken together, Tyr308 controls both orthosteric agonist affinity (potency) and, partly, cAMP signaling efficiency (agonist efficacy) at the human \beta₂AR.

3. Epi in Cardiac Arrest: \beta₂AR Activation is Key

3.1 Clinical Evidence for the Use of Epi in Cardiac Arrest

Their \alpha₁AR-dependent vasopressor actions form the basis for the use of catecholamines in cardiac arrest (or asystole) and during CPR [21]. In cardiac arrest, coronary artery perfusion pressure drops precipitously because the heart has stopped beating, and, since coronary perfusion pressure is defined as the difference between aortic and right atrial blood pressures, vasopressors that acutely raise arterial blood pressure are indicated to enhance coronary perfusion and restart the heart, i.e., to induce the so-called “return of spontaneous circulation” (ROSC) [22]. Thus, alongside NE and Epi, potent vasopressors, such as vasopressin and phenylephrine, are sometimes used during CPR. Epi has historically been the agent of choice for cardiac arrest/CPR with several studies/meta-analyses supporting its utility in this medical emergency setting [23, 24, 25, 26, 27], showing consistent increases in ROSC and return of pulse in CPR-receiving subjects, as well as in survival to hospital admission and even hospital discharge. Indeed, the latest American Heart Association’s guidelines recommend administering 1 mg of epinephrine intravenously (IV) or intraosseously (IO) every 3–5 minutes for adult cardiac arrest [27]. Epi can also augment the effect of vasopressin and other vasopressors on ROSC and survival rate in cardiac arrest [26]. However, a few trials have cast doubt on the actual benefit of Epi for long term cardiac arrest outcomes, particularly with respect to neurological recovery [21, 23]. Indeed, \beta₂AR activation by Epi can substantially increase myocardial oxygen consumption to meet the demands of significantly enhanced contractility, which may lead to non-favorable long term survival outcomes, especially in ischemic heart disease patients [21, 28]. In addition, \beta₂AR activation leads to vasodilation, which may affect local microcirculation negatively, particularly in the brain, due to perturbations in small vessel (arterioles/capillaries)-mediated tissue perfusion [28]. Nevertheless, other studies have failed to demonstrate any inferiority of Epi in cardiac arrest compared to NE [29] and the overall picture regarding Epi’s utility in cardiac arrest is still fuzzy. This is probably because: (a) each study’s findings may not be generalizable to all patients; (b) there are several factors, unrelated to Epi’s effects, affecting neurological outcomes in cardiac arrest survivors, as well as methodological problems in some of the studies [24]; and, perhaps most importantly, (c) since Epi increases the chances of post-cardiac arrest survival, the total number of survivors having received Epi during CPR is higher, which can skew the number of survivors that do not recover neurologically towards Epi in an unfavorable manner. In other words, the main goal of Epi administration in cardiac arrest is ROSC and return of pulse, so the patient can escape instant death and hopefully survive either to hospital admission or, if already hospitalized, to discharge.

3.2 Physiological Mechanisms of Epi in Cardiac Arrest

Apart from Epi-activated \alpha₁AR-mediated vasoconstriction that enhances coronary perfusion, Epi-activated \beta₂ARs in the airways dilate the bronchi and lungs, an action crucial not only in treatment of anaphylactic shock but also during CPR to improve blood oxygenation [30]. In addition, cAMP elevation inside cardiomyocytes by Epi-activated \beta₁ARs and \beta₂ARs affords two additional important benefits in cardiac arrest. One of these benefits is stimulation of the sinoatrial (SA) node, the natural pacemaker of the myocardium, to increase the If current via enhanced opening of hyperpolarization-activated cyclic nucleotide-gated (HCN)-4 channels [31, 32]. These channels are directly bound and operated by cAMP and their opening results in increased beating frequency, i.e., elevated heart rate (Fig. 1B). It is well established that \beta₂ARs are abundant in the SA node (in fact, more abundant than in the rest of the atria) and mediate HCN4 channel activation and positive chronotropy alongside \beta₁ARs [33, 34, 35]. Given that cardiac \beta₂ARs are 10 times more potent at cAMP synthesis than their \beta₁AR counterparts [15] and that Epi activates both subtypes equipotently, unlike NE that activates the \beta₁AR but not the \beta₂AR subtype at normal concentrations, it follows that Epi can stimulate the pacemaker activity of the SA nodal cardiomyocytes much more robustly than NE (Fig. 1B). This would be consistent with the long-reported greater potency of Epi over NE at stimulating contractility, as well (higher heart rate normally leads to increased contractility) [15]. Being able to stimulate pacemaker activity more robustly via greater cAMP production driven by both \beta₁- and \beta₂ARs gives Epi a unique ability to generate heartbeats (pulse), and thus, a significant advantage over NE (and other vasopressors) in treatment of cardiac arrest.

Finally, the other cAMP-dependent benefit that is therapeutically exploited by using Epi in cardiac arrest is stimulation of the sodium-potassium pump (Na⁺/K⁺-ATPase, NKA) (Fig. 1B). Protein kinase A (PKA), the main effector of cAMP, activates NKA via phosphorylation of FXYD1 (also known as phospholemman, PLM), a protein that physically interacts with NKA reducing its affinity for intracellular Na⁺ and thus, its activity [36, 37]. PKA-dependent phosphorylation releases PLM inhibition of NKA, robustly increasing NKA activity [37, 38]. Since NKA-dependent Na⁺ efflux and K⁺ influx are essential for restoration of the resting membrane potential and gradients of these two cations, NKA activation is an integral part of the adrenergic “fight-or-flight” response [37] (Fig. 1B). It is also essential for reduction of intracellular [Ca²⁺] (via the Na⁺/Ca²⁺ exchanger) [38] (Fig. 1B). High intracellular [Na⁺] suppresses excitability of working cardiomyocytes due to perturbation (suppression) of normal Na⁺ currents, on which fast depolarization (Phase 0 of the action potential) depends [39]. Therefore, NKA stimulation by cAMP is crucial for maintaining cardiac function, particularly in ischemic (hypoxic) cardiomyocytes, where NKA activity is low due to energy (ATP) depletion. \beta₂AR, probably again due to its greater potency at increasing cAMP, stimulates NKA activity more robustly than \beta₁AR does: the \beta₂AR-selective agonist salbutamol is equipotent to Epi but 100-fold more potent than a \beta₁AR-selective agonist at stimulating NKA in rat soleus muscle [40]. Together with activation of both \beta₁- and \beta₂ARs, this means that Epi stimulates cardiomyocyte NKA more robustly than NE does (Fig. 1B), which is also consistent with the well-documented, clinically, Epi-induced hypokalemia (due to high NKA activity) [41]. In conclusion, Epi stimulates cardiac NKA more robustly than NE and other vasopressors used in cardiac arrest, which is another crucial beneficial mechanism by which Epi can restore cardiac pulse and contraction, i.e., increase ROSC.

4. Conclusions & Future Perspectives

Epi is a particularly useful drug (the agent of choice) in cardiac arrest thanks to its unique, among vasopressor hormones/agents, activation of cardiac \beta₂ARs. \beta₂AR activation results in profound increases in potency and efficacy of Epi, compared to NE and other non-catecholamine vasopressors, towards pulse generation in the SA node and contractility restoration in the working myocardium via NKA activation. Of course, other important mechanisms for cardiomyocyte homeostasis, such as NCX and sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA) activation [42], may also mediate Epi’s superior potency & efficacy. Being able to exert this lifesaving action in the extremely dire situation of cardiac arrest via \beta₂AR activation might be one of the reasons why only the \beta₁AR (not the \beta₂AR) is downregulated in human chronic heart failure; however, \beta₂AR may also be desensitized and dysfunctional in this disease [43]. It could also explain why circulating Epi, contrary to NE, is not elevated in chronic human heart failure [44]: perhaps the body keeps Epi levels low in this disease state, so it can increase them to activate the \beta₂AR only at moments of absolute life-or-death emergencies, such as cardiac arrest or asphyxiation due to acute airway obstruction.

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Funding

National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) grant(R01 #HL155718-01)

American Foundation for Pharmaceutical Education (AFPE) Gateway to Research Scholarship(#333609-2025)