There are two main types of α receptors: α1 and α2. α1 receptors are predominantly located on vascular smooth muscle. Activation of α1 receptors in the cardiovascular system by NE and EPI leads to vasoconstriction, increasing SVR and blood pressure. This mechanism is particularly important during the “fight or flight” response, where increased blood flow to essential organs including heart, brain, and skeletal muscles is necessary for survival (Borkar and Fadok, 2024). However, activation of α1 receptor in the bladder and gastrointestinal (GI) tract causes contraction of smooth muscles, inhibiting non-essential functions during stress (Michel and Vrydag, 2006). In contrast, α2 receptors primarily function as inhibitory autoreceptors located on presynaptic nerve terminals (Zhang et al., 2009). When activated, they decrease the release of NE, providing a negative feedback mechanism that modulates sympathetic activity. This action can lead to a reduction in blood pressure and heart rate when drugs like clonidine or dexmedetomidine are used, which selectively activate central α2 receptors to treat hypertension and manage anxiety (Pichot et al., 2012). Moreover, α2 receptor activation in the central nervous system (CNS) can produce sedation and analgesia, contributing to their role in pain modulation (Giovannitti et al., 2015).

β adrenergic receptors are further subdivided into three types: β1, β2, and β3. β1 receptors are primarily found in the heart, mediating increases in heart rate (chronotropy) and myocardial contractility (inotropy) upon stimulation by catecholamines. This response enhances CO during stressful situations. Furthermore, β1 receptor activation in the kidneys stimulates renin release, leading to increased blood volume and pressure through the renin-angiotensin-aldosterone system (Sandilands and O'Shaughnessy, 2019). β2 receptors are predominantly located in smooth muscle tissues, including bronchioles and blood vessels. Activation of β2 receptors results in relaxation of smooth muscles, leading to bronchodilation and vasodilation (Kotlikoff and Kamm, 1996). This effect is crucial for improving airflow during respiratory distress and enhancing blood flow to skeletal muscles during physical exertion. Importantly, β2 receptor activation can counteract some of the vasoconstrictive effects mediated by α1 receptors in certain vascular beds (Wachter and Gilbert, 2012). While less commonly discussed, β3 receptors are involved in lipolysis in adipose tissue and may play a role in regulating energy metabolism (Cero et al., 2021). Their activation can lead to increased energy expenditure and thermogenesis.

The interplay between α and β adrenergic receptors allows for a finely tuned physiological response to stressors. During a fight-or-flight situation, α1-mediated vasoconstriction ensures that vital organs receive adequate blood flow while β2-mediated vasodilation enhances oxygen delivery to skeletal muscles. This balance is essential for optimizing performance under stress. Moreover, the distribution of these receptors varies across different tissues, allowing for localized responses tailored to specific physiological needs. While both α1 and β2 receptors may be present in a given tissue (e.g., blood vessels), their differential activation can result in opposing effects—vasoconstriction versus vasodilation—depending on the prevailing hormonal environment (Ahlquist, 1976; Richards et al., 2017).

Vasopressin acts primarily through three receptor subtypes: V1a, V1b, and V2 receptors. Activation of V1a receptors leads to vasoconstriction and also influences various non-cardiovascular functions, including enhancing platelet aggregation and promoting renal vasoconstriction (Honda and Takano, 2009). V2 receptors mediate the antidiuretic effects of vasopressin by promoting water reabsorption (Carty et al., 2024). This action is crucial for maintaining fluid balance and osmotic homeostasis. Additionally, V2 receptor activation may have implications for fluid retention in states of hypovolemia or dehydration (Lemmens-Gruber and Kamyar, 2006). V1b receptors are involved in stimulating adrenocorticotropic hormone (ACTH) release, which plays a role in stress responses. The activation of these receptors can influence cortisol secretion, thereby affecting metabolic processes and immune responses (Meijer et al., 2011).

Angiotensin II (Ang II) is a potent vasoconstrictor primarily acting through two main receptor subtypes: AT1 and AT2 receptors. AT1 receptors mediate most of the well-known effects of Ang II, including vasoconstriction, increased blood pressure, and stimulation of aldosterone secretion from the adrenal cortex. The activation of AT1 receptors not only regulates blood pressure but also mediates non-cardiovascular effects such as promoting inflammation, fibrosis, and cellular hypertrophy in various tissues (Ruiz-Ortega et al., 2006). This pro-inflammatory action can contribute to the pathogenesis of conditions like hypertension and heart failure (Carter et al., 2024). In contrast to AT1 receptors, AT2 receptors generally mediate opposing effects, including vasodilation and inhibition of cell growth. They are involved in tissue repair processes and may exert protective effects against hypertrophy and fibrosis (Namsolleck et al., 2014). The balance between AT1 and AT2 receptor activation is crucial for maintaining cardiovascular homeostasis and influencing non-cardiovascular outcomes.

Catecholamines are well-known for their role in the “fight or flight” response, where they prepare the body for stressful situations. NE, in particular, has been implicated in mood regulation and cognitive functions. It is a key neurotransmitter in the brain’s arousal system and is associated with attention, learning, and memory (Maletic et al., 2017). Dysregulation of NE levels has been linked to mood disorders such as depression and anxiety. For example, increased NE activity is often observed in states of heightened stress or anxiety, while decreased levels can contribute to depressive symptoms (Craske and Stein, 2016; Heller et al., 2019). Dopamine is also a key neurotransmitter in CNS function, regulating processes including reward, movement, and cognition (Channer et al., 2023).

Vasopressin also influences mood and social behaviors. Research indicates that vasopressin can affect social recognition and bonding, particularly in species like voles, where it plays a role in pair bonding behaviors in a sex-specific manner, with effects typically being stronger in males than in females (Rigney et al., 2023). In humans, vasopressin’s effects on mood may be less pronounced but still significant; its release can be influenced by social interactions and stress levels (Hu et al., 2024). Additionally, vasopressin has been associated with analgesic effects that may indirectly affect mood by modulating pain perception, and these effects have been shown to be more significant in women (Colloca et al., 2016).

The impact of vasoactive agents extends to neurological function as well. NE is involved in modulating alertness and attention through its action on adrenergic receptors in various brain regions. This modulation can enhance cognitive performance under certain conditions but may also lead to neurotoxicity if levels become excessively high or prolonged (Troadec et al., 2001; Álvarez-Diduk and Galano, 2015).

Vasopressin’s role in the CNS includes modulating circadian rhythms and influencing stress responses. The release of vasopressin in the brain can enhance the body’s ability to cope with stressors by promoting adaptive behaviors. Furthermore, the interaction of vasopressin with its receptors in the brain suggests potential neuroprotective effects by reducing neuronal excitability and promoting resistance against stress-induced damage (Corbani et al., 2018).

While vasoactive agents have beneficial effects on mood and cognition, there is also potential for neurotoxicity. High levels of catecholamines can lead to neuronal damage due to oxidative stress and excitotoxicity. For instance, excessive catecholamine release during chronic stress can lead to neurotoxic effects on neurons due to oxidative stress and excitotoxicity (Álvarez-Diduk and Galano, 2015). Chronic exposure to elevated NE levels has been associated with neuronal apoptosis and impaired neurogenesis (Jhaveri et al., 2010; Flint et al., 2013). Similarly, excessive vasopressin release can result in adverse effects on neuronal function, particularly when it leads to increased blood pressure and vascular resistance that may compromise cerebral perfusion (Sharshar and Annane, 2008).

Additionally, while vasopressin can enhance social bonding and reduce anxiety under normal conditions, its dysregulation may contribute to maladaptive behaviors or exacerbate anxiety disorders (Hu et al., 2024).

Vasoactive agents can alter GI motility through their actions on smooth muscle and neuronal pathways. For instance, catecholamines like NE and EPI primarily act on α and β adrenergic receptors, leading to varied effects on motility. Activation of α1-adrenergic receptors generally promotes smooth muscle contraction, resulting in decreased motility in the GI tract. Conversely, β2-adrenergic receptor activation can lead to relaxation of smooth muscle and increased motility in certain contexts, such as during physical stress when blood flow is redirected to essential organs (Tank and Lee Wong, 2015; Mittal et al., 2017).

Vasopressin can activate V1 receptors within the hepato-splanchnic vascular bed, triggering potent vasoconstriction that reduces blood flow in patients with portal hypertension. There was evidence that low to moderate doses of vasopressin resulted in significant reductions in portal blood flow (by 26%–37%) while having no impact on portal or hepatic venous pressures (Bown et al., 2016). Therefore, when treating septic shock, despite achieving hemodynamic stability with vasopressin, there was a notable decrease in mesenteric and portal vein blood flow, which could compromise gut health and function. Whether this reduction in blood flow can lead to ischemia of the GI mucosa, impairing its ability to secrete digestive enzymes and even absorb nutrients, remained unclear (Martikainen et al., 2003).

Strong vasoconstriction caused by NE, phenylephrine, angiotensin II and vasopressin could lead to decreased splanchnic blood flow, resulting in non-occlusive acute mesenteric ischemia. A case series highlighted the potential for high doses of NE to contribute to splanchnic vasoconstriction, leading to non-occlusive mesenteric ischemia in patients with severe acute pancreatitis (Reichling et al., 2020). Similarly, vasopressin, which acts on V1 a receptors to induce vasoconstriction, can also affect splanchnic hemodynamics. In a porcine model of septic shock, a low-dose vasopressin of 0.006 U/kg/h caused a decrease in mesenteric blood flow, resulting in elevated lactate levels and signs of intestinal ischemia (Hiltebrand et al., 2007). Furthermore, the risk of GI bleeding is heightened in patients with increased catecholamine levels due to potential mucosal ischemia and impaired healing responses (Krag et al., 2013). The balance between maintaining adequate perfusion pressure while avoiding excessive vasoconstriction is critical in preventing these complications.

Vasoactive agents influence RBF primarily through their actions on specific receptors located in the renal vasculature. Vasopressin acts predominantly through V1a receptors, which are distributed heterogeneously in the renal circulation. At low doses, vasopressin induces vasoconstriction mainly in the efferent arterioles of the glomeruli, which can theoretically increase glomerular perfusion pressure and enhance glomerular filtration rate (GFR). This mechanism is beneficial in states of hypotension or shock, where maintaining renal perfusion is critical. A study comparing the effects of vasopressin and NE in ovine models of septic AKI demonstrated that NE transiently improved renal function but worsened renal medullary ischemia and hypoxia. In contrast, vasopressin provided a sustained improvement in creatinine clearance without significantly affecting renal medullary perfusion or oxygenation (Okazaki et al., 2020). This suggests that vasopressin may be more beneficial in preserving renal function during septic conditions. Post-hoc analyses from the Vasopressin and Septic Shock Trial (VASST) revealed that patients classified as being at risk for kidney injury had lower rates of progression to more severe forms of AKI when treated with vasopressin compared to NE (Gordon et al., 2010; Lucchese, 2010). Specifically, among patients in the “Risk” category according to RIFLE criteria, those receiving vasopressin showed a significantly reduced need for renal replacement therapy and lower mortality rates (Gordon et al., 2010).

Dopamine is known to exert a dose-dependent effect on RBF. At low doses (1–5 μg/kg/min), dopamine primarily stimulates D1-like receptors, leading to renal vasodilation and increased RBF. This effect is attributed to the dilation of afferent arterioles, which enhances GFR and promotes natriuresis (Elkayam et al., 2008; Olivares-Hernández et al., 2021). Low-dose dopamine infusion has been shown to increase mean RBF by approximately 20% in animal models without affecting systemic hemodynamics (Di Giantomasso et al., 2004).

However, the benefits of low-dose dopamine in clinical practice have been challenged. Research indicates that while it may increase RBF in healthy individuals, its efficacy diminishes in patients with AKI or those at risk for renal failure. Studies found that low-dose dopamine worsened renal perfusion in patients with acute renal failure, increasing renal vascular resistance rather than decreasing it (Kellum and Decker, 2001; Lauschke et al., 2006). Therefore, the routine use of low-dose or “renal dose” dopamine for the treatment or prevention of acute renal failure cannot be justified since it has no benefit in either preventing or ameliorating AKI in critically ill patients (Friedrich et al., 2005; Karthik and Lisbon, 2006; Joannidis et al., 2017).

The use of vasoactive agents carries inherent risks for developing AKI or exacerbating existing renal dysfunction. Key factors include: (1) Vasoconstriction: Renal vasoconstriction induced by vasoactive agents is a well-known phenomenon that may contribute to AKI (Redfors et al., 2011). When vasoactive agents are used to restore systemic blood pressure during shock, they can inadvertently cause renal vasoconstriction, leading to a reduction in RBF, a decline in the GFR, and ultimately, AKI. (2) Hemodynamic Instability: In critically ill patients, fluctuations in blood pressure due to the use of vasoactive agents can contribute to periods of inadequate renal perfusion. Sustained hypotension or rapid changes in vascular resistance can compromise kidney function (Busse and Ostermann, 2019). (3) Underlying Conditions: Patients with conditions such as heart failure, cirrhosis, or sepsis are at higher risk for AKI when treated with vasoactive agents. These conditions often involve complex hemodynamic changes that can exacerbate the effects of these drugs on renal circulation (Ronco et al., 2019). (4) Duration and Dosage: The dosage of vasoactive agents and duration of treatment are critical factors influencing the risk of AKI (Martin et al., 2015). High doses or prolonged use may lead to cumulative adverse effects on kidney function. Current guidelines recommend NE as the first-line agent, but in cases of high NE requirements, the addition of nonadrenergic vasopressors is advised (Venkatesh et al., 2019). This miscellaneous therapies for catecholamine sparing, while physiologically plausible, require careful consideration of patient-specific characteristics to avoid potential adverse effects on renal function.

Vasoactive agents can modulate the secretion of key hormones involved in glucose metabolism, notably insulin and glucagon. Activation of α2-adrenergic receptors in pancreatic β-cells inhibits insulin secretion, which can lead to increased blood glucose levels during stress responses. This is possibly caused by decreasing calcium influx through voltage-dependent calcium channels (Hsu et al., 1991). Conversely, β-adrenergic receptor stimulation enhances insulin secretion during exercise or stress response to facilitate glucose uptake and utilization by muscles, although this effect can be overshadowed by the inhibitory actions of α2 receptors during acute stress (Singh et al., 2018).

Recent studies have highlighted dopamine’s role in regulating pancreatic hormone release (Aslanoglou et al., 2021; Bonifazi et al., 2024). Dopamine acts on both α- and β-cell adrenergic receptors, influencing the secretion of glucagon and insulin (Bonifazi et al., 2024). Notably, dopamine functions as a biased agonist at α2A-adrenergic receptors, preferentially signaling through G protein-mediated pathways to inhibit insulin release (Aslanoglou et al., 2021). This dual action highlights the complexity of hormonal regulation in response to vasoactive agents.

In experiments on mouse islets, it has been shown that vasopressin can significantly amplify glucose-induced insulin release (Szczepanska-Sadowska et al., 2024). Vasopressin also potentiates the stimulatory effects of glucose and ACTH on insulin secretion (Szczepanska-Sadowska et al., 2024). It enhances the release of insulin by glucose in the pancreas via potentiation of paracrine production of glucagon. Glucagon subsequently activates GLP-1 receptors, which play an important role in promoting insulin release (Szczepanska-Sadowska et al., 2024). In addition, stimulation of V1b receptor is essential for the appropriate regulation of the hypothalamic-pituitary-adrenal (HPA) axis during inflammatory stress. Mice deprived of V1b receptor show significantly lower increases in ACTH and corticosterone during acute immune stress, which in turn may affect insulin release (Szczepanska-Sadowska et al., 2024). This indicates that vasopressin, through its regulation of the HPA axis, has also an indirect impact on insulin release.

The impact of vasoactive agents extends beyond immediate hormone secretion to broader metabolic processes. Catecholamines stimulate glycogenolysis in the liver through β-adrenergic receptor activation, leading to increased glucose availability during stress (Wang et al., 2024). The role of catecholamines in hepatic glycogenolysis is further mediated by their interaction with the cAMP-protein kinase A (PKA) signaling pathway. Upon activation of β-adrenergic receptors, there is an increase in cAMP levels, which subsequently activates PKA. PKA then phosphorylates glycogen phosphorylase, the enzyme responsible for breaking down glycogen into glucose-1-phosphate, which is eventually converted to glucose (Xu et al., 2014). This pathway highlights the importance of catecholamines in regulating glucose metabolism and ensuring an adequate supply of glucose during stress.

Vasoactive agents also play a significant role in the mobilization of free fatty acids (FFAs) from adipose tissue, which is crucial during periods of stress or fasting when the body requires alternative energy sources. The mechanism through which catecholamines enhance FFA release involves the activation of β-adrenergic receptors, which leads to the phosphorylation of specific proteins that promote lipolysis (Reilly et al., 2020). This process results in the breakdown of triglycerides stored in adipocytes into FFAs and glycerol, which are then released into the bloodstream to be used as energy substrates by various tissues, including the heart and skeletal muscle (Reilly et al., 2020). In addition to their role in FFA mobilization, catecholamines also influence the metabolic fate of these fatty acids. For instance, catecholamines can suppress the re-esterification of FFAs back into triglycerides within adipocytes, thereby favoring their oxidation. This is achieved through the activation of signal transducer and activator of transcription 3 (STAT3), which is phosphorylated upon catecholamine stimulation, promoting FFA oxidation over storage (Reilly et al., 2020).

Research has demonstrated that vasopressin receptor-deficient mice exhibit altered lipid metabolism, characterized by changes in lipid accumulation and metabolism in tissues such as brown adipose tissue and skeletal muscle (Harada et al., 2025). These findings suggest that vasopressin’s regulatory effects on lipid metabolism are mediated through its action on V receptors, highlighting its extensive role in metabolic homeostasis. Further exploration into the molecular interaction between vasopressin and insulin revealed that vasopressin can modulate metabolic processes by influencing insulin secretion and action (Szczepanska-Sadowska et al., 2024). Vasopressin stimulates glycogenolysis and fatty acid synthesis in the liver, while also promoting insulin release from pancreatic cells (Szczepanska-Sadowska et al., 2024). This interaction suggests that vasopressin may play a role in coordinating energy balance and lipid metabolism, potentially impacting conditions such as obesity and diabetes.