Targeting Adrenergic Receptors in Metabolic Therapies for Heart Failure

Perez, Dianne M.

doi:10.3390/ijms22115783

Cited by 17 publications

(11 citation statements)

References 415 publications

(542 reference statements)

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“…These catecholamines regulate blood pressure by binding to the α-adrenergic receptors present in blood vessels. Studies have shown that they have better affinity to α2-than α1 -adrenergic receptors ( Pecquery and Giudicelli, 1982 ; Perez, 2021 ). Moreover, the α2 subtype genes knock-out study has shown that their vasopressor activity is mediated probably through α2A as the effect of norepinephrine on arterial contraction was abrogated in α2A − mouse but not in α2B − or α2C − mouse ( Link et al, 1995 ; Link et al, 1996 ; Altman et al, 1999 ; Philipp et al, 2002 ).…”

Section: Targeting Adrenergic Receptors In Shockmentioning

confidence: 99%

Role of adrenergic receptors in shock

Geevarghese¹,

Patel

Gulati

et al. 2023

Front. Physiol.

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Shock is a severe, life-threatening medical condition with a high mortality rate worldwide. All four major categories of shock (along with their various subtypes)—hypovolemic, distributive, cardiogenic, and obstructive, involve a dramatic mismatch between oxygen supply and demand, and share standard features of decreased cardiac output, reduced blood pressure, and overall hypoperfusion. Immediate and appropriate intervention is required regardless of shock type, as a delay can result in cellular dysfunction, irreversible multiple organ failure, and death. Studies have shown that dysfunction and downregulation of adrenergic receptors (ARs) are often implicated in these shock conditions; for example, their density is shown to be decreased in hypovolemic and cardiogenic shock, while their reduced signaling in the brain and vasculature decrease blood perfusion and oxygen supply. There are two main categories of ARs, α, and β, each with its subtypes and distributions. Our group has demonstrated that a dose of .02 mg/kg body wt of centhaquine (CQ) specifically activates α2B ARs on venous circulation along with the central α2A ARs after hypovolemic/hemorrhagic shock. Activating these receptors by CQ increases cardiac output (CO) and reduces systemic vascular resistance (SVR), with a net increase in blood pressure and tissue perfusion. The clinical trials of CQ conducted by Pharmazz Inc. in India have demonstrated significantly improved survival in shock patients. CQ improved blood pressure and shock index, indicating better blood circulation, and reduced lactate levels in the blood compared to in-use standard resuscitative agents. After successful clinical trials, CQ is being marketed as a drug (Lyfaquin®) for hypovolemic/hemorrhagic shock in India, and United States FDA has approved the phase III IND application. It is anticipated that the phase III trial in the United States will begin in 2023. Thus, we have demonstrated that α2 ARs could be suitable targets for treating or managing hypovolemic/hemorrhagic shock. Further understanding of ARs in shock would help find new potential pharmacological targets.

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Section: Targeting Adrenergic Receptors In Shockmentioning

confidence: 99%

Role of adrenergic receptors in shock

Geevarghese¹,

Patel

Gulati

et al. 2023

Front. Physiol.

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“…32 An excellent recent review thoroughly examined the adrenergic regulation of metabolic substrate utilization in the heart. 35 Here, we describe the effects of a1-AR and b-AR activation on mitochondrial biogenesis, dynamics, calcium handling, and OXPHOS in uninjured and failing cardiomyocytes (summarized in Table 1).…”

Section: Introductionmentioning

confidence: 99%

Adrenergic Receptor Regulation of Mitochondrial Function in Cardiomyocytes

Sandroni

Fisher‐Wellman

Jensen

2022

Journal of Cardiovascular Pharmacology

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Adrenergic receptors (ARs) are G protein-coupled receptors that are stimulated by catecholamines to induce a wide array of physiological effects across tissue types. Both a1and b-ARs are found on cardiomyocytes and regulate cardiac contractility and hypertrophy through diverse molecular pathways. Acute activation of cardiomyocyte b-ARs increases heart rate and contractility as an adaptive stress response. However, chronic b-AR stimulation contributes to the pathobiology of heart failure. By contrast, mounting evidence suggests that a1-ARs serve protective functions that may mitigate the deleterious effects of chronic b-AR activation.Here, we will review recent studies demonstrating that a1and b-ARs differentially regulate mitochondrial biogenesis and dynamics, mitochondrial calcium handling, and oxidative phosphorylation in cardiomyocytes. We will identify potential mechanisms of these actions and focus on the implications of these findings for the modulation of contractile function in the uninjured and failing heart. Collectively, we hope to elucidate important physiological processes through which these well-studied and clinically relevant receptors stimulate and fuel cardiac contraction to contribute to myocardial health and disease.

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“…Beta-2 receptors are located in human bronchial smooth muscle cells, vascular smooth muscle cells and cardiac myocytes, albeit at a lower expression density compared to beta-1 receptors ( Brodde, 2008 ; Perez, 2021 ). While selective β-2 antagonists are not in clinical use in humans, a beta-2 blocking agent called butoxamine has been shown to decrease blood pressure and heart rate and increase airway resistance in animal studies ( Letts et al, 1983 ; Beiermeister et al, 2010 ).…”

Section: Adrenergic Modulationmentioning

confidence: 95%

Adrenergic Modulation of Erythropoiesis After Trauma

Munley

Kelly²,

Mohr³

2022

Front. Physiol.

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Severe traumatic injury results in a cascade of systemic changes which negatively affect normal erythropoiesis. Immediately after injury, acute blood loss leads to anemia, however, patients can remain anemic for as long as 6 months after injury. Research on the underlying mechanisms of such alterations of erythropoiesis after trauma has focused on the prolonged hypercatecholaminemia seen after trauma. Supraphysiologic elevation of catecholamines leads to an inhibitive effect on erythropoiesis. There is evidence to show that alleviation of the neuroendocrine stress response following trauma reduces these inhibitory effects. Both beta blockade and alpha-2 adrenergic receptor stimulation have demonstrated increased growth of hematopoietic progenitor cells as well as increased pro-erythropoietic cytokines after trauma. This review will describe prior research on the neuroendocrine stress response after trauma and its consequences on erythropoiesis, which offer insight into underlying mechanisms of prolonged anemia postinjury. We will then discuss the beneficial effects of adrenergic modulation to improve erythropoiesis following injury and propose future directions for the field.

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Targeting Adrenergic Receptors in Metabolic Therapies for Heart Failure

Cited by 17 publications

References 415 publications

Role of adrenergic receptors in shock

Role of adrenergic receptors in shock

Adrenergic Receptor Regulation of Mitochondrial Function in Cardiomyocytes

Adrenergic Modulation of Erythropoiesis After Trauma

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