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Relationship: 3645

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

A1AR Agonism leads to Increased cortisol

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

A1AR Agonism

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Increased cortisol

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Binding of Alpha 1-Adrenergics to Agonists Leading to Depression	adjacent	High	Moderate	LUANA GOMES (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
rat	Rattus norvegicus	High	NCBI
human	Homo sapiens	High	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Male	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
Adult	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

A systematic literature search was conducted in databases such as PubMed, ScienceDirect, Scopus, and Web of Science to identify studies that investigated the relationship between alpha 1 adrenergic receptors and the agonists phenylephrine and/or methoxamine, and the correlation with increased cortisol and/or corticosterone in humans and animals.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

The relationship between activation of α1-adrenergic receptors and increased cortisol/corticosterone is biologically plausible because alpha-1 adrenergic receptors are widely expressed in central structures involved in stress control, including:

Hypothalamus (paraventricular nucleus – PVN)
Brainstem (ascending noradrenergic neurons)
Autonomic response modulating regions

This distribution allows alpha-1 activation to function as a central excitatory signal associated with physiological stress, integrating sympathetic and neuroendocrine responses.

Agonists activate α1 receptors in hypothalamic and associated regions. This activation increases the activity of PVN neurons, promoting the release of CRH (corticotropin-releasing hormone). CRH stimulates the anterior pituitary, leading to the release of ACTH (adrenocorticotropic hormone). ACTH acts on the adrenal cortex, promoting increased cortisol levels in humans and corticosterone in animals.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Administration of methoxamine in humans has demonstrated significant activation of the hypothalamic-pituitary-adrenal axis, with increased ACTH and subsequent elevation of plasma cortisol in men, showing that stimulation of α1-adrenergic receptors can directly modulate glucocorticoid secretion (Al-Damluji, 1987);
Alpha-1 adrenergic stimulation by methoxamine resulted in a consistent increase in cortisol, while pharmacological blockade of alpha-1 receptors reduced this response, reinforcing the functional role of these receptors in the control of the HPA axis in humans (Al-Damluji, 1987);
It has been observed that the cortisol and ACTH response to methoxamine varies according to the circadian rhythm, being more intense in the morning, indicating that the sensitivity of the HPA axis to α1 stimulation is dependent on the basal physiological state (Naylor, 1988);
Stimulation with methoxamine also confirmed direct modulation of the pituitary-adrenal axis, with a concomitant increase in ACTH and cortisol, reinforcing the participation of α1 receptors in human neuroendocrine regulation. (Radant, 1992)
In experimental rat models, phenylephrine induced a significant increase in ACTH, leading to a subsequent elevation of corticosterone, demonstrating that activation of α1 receptors is sufficient to activate the complete HPA axis. (Proulx-Ferland, 1982);
Further studies have shown that phenylephrine activates the HPA axis under both basal and stress conditions, with a consistent increase in corticosterone, indicating a relevant role of α1 receptors in the adaptive stress response (Gadek-Michalska, 2008);
Methoxamine infusion induced a significant increase in plasma ACTH levels (peak at 75 min) and serum cortisol (peak at 120 min) in male volunteers, demonstrating that direct stimulation of alpha-1-adrenergic receptors strongly activates the HPA axis in humans (Delitala et al, 1994).

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Fator Modulador (FM)	Especificação MF	Efeito(s) no KER	Referência(s)

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

References

List of the literature that was cited for this KER description. More help

AL-DAMLUJI et al. Alpha-adrenergic stimulation of corticotropin secretion by a specific central mechanism in man. Neuroendocrinology, v. 45, n. 1, p. 68-76, 1987;
AL‐DAMLUJI et al. The effect of alpha adrenergic manipulation on the 24 hour pattern of cortisol secretion in man. Clinical endocrinology, v. 26, n. 1, p. 61-66, 1987;
NAYLOR et al. Circadian rhythm of adrenergic regulation of adrenocorticotropin and cortisol secretion in man. The Journal of Clinical Endocrinology & Metabolism, v. 67, n. 2, p. 404-406, 1988;
RADANT et al. Neurohypophyseal and pituitary-adrenocortical responses to the alpha1 agonist methoxamine in humans. Neuroendocrinology, v. 55, n. 4, p. 361-366, 1992;
PROULX-FERLAND, L.; BREAULT, M.; COTE, J. Alpha1-adrenergic stimulation of ACTH secretion in vivo in the rat. Progress in Neuro-Psychopharmacology and Biological Psychiatry, v. 6, n. 4-6, p. 433-438, 1982;
GADEK-MICHALSKA, A.; BUGAJSKI, A. J.; BUGAJSKI, J. Prostaglandins and interleukin-1beta in the hypothalamic-pituitary-adrenal response to systemic phenylephrine under basal and stress conditions. Journal of physiology and pharmacology, v. 59, n. 3, p. 563-575, 2008;
DELITALA, G. et al. Opioid peptide and α-adrenoceptor pathways in the regulation of the pituitary-adrenal axis in man. Journal of endocrinology, v. 141, n. 1, p. 163-168, 1994.