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Relationship: 983

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

Increase, Vascular Resistance leads to Hypertension

Upstream event

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

Increase, Vascular Resistance

Downstream event

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

Hypertension

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
Peptide Oxidation Leading to Hypertension	adjacent	Moderate	Low	Frazer Lowe (send email)	Not under active development	Under Development

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
Homo sapiens	Homo sapiens	High	NCBI
Rattus norvegicus	Rattus norvegicus	Low	NCBI

Sex Applicability

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

Sex	Evidence
Unspecific	High

Life Stage Applicability

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

Term	Evidence
Adults	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

Hypertension is characterized partly by elevated systemic vascular resistance which is caused by alterations to vascular tone (towards vasoconstriction) over time (Lee and Griendling, 2008). As blood vessels constrict, the available volume in the vessel lumen for blood flow is restricted, resulting in elevated blood pressure.

Note : The role of the heart in the maintenace (and change) of blood pressure over time is not part of this AOP, however it is of critical importance for the development of hypertension.

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

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

It is well-established that increased systemic vascular resistance (SVR), increased vascular stiffness and increased vascular reactivity contribute to the pathophysiology of hypertension (Foëx and Sear, 2004; Mayet and Hughes, 2003; Brandes et al., 2014); thus biological plausibility is strong for increased SVR leading to hypertension. This is observed in patients with hypertension (Chan et al., 2016).

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

Include consideration of temporal concordance here

Empirical support for SVR leading to hypertension is moderate based on several human studies showing a dose-dependent change in SVR and hypertension following treatment with eNOS inhibitors L-NMMA and L-NAME. Whilst the acute changes in SVR on blood pressure in the context of endothelial NO production is well characterised, the linkage between chronically elevated SVR and hypertension is more complicated, due to the roles of the heart, nervous system and kidneys. Given that this AOP is focused on endothelial NO production, other AOPs are required to capture the roles of these other important biological processes on chronic SVR changes and hypertension, hence the rating of "moderate".

Intravenous infusion of L-NMMA (0.1, 1.0, 3.0 mg/kg/min) for 15 minutes led to a dose-dependent increase in SVR and mean arterial pressure compared to saline infusion in eight healthy men (Wilkinson et al., 2002). SVR increased from 31±2 (arbitrary units) at baseline to 57±4 at the highest dose, while mean arterial pressure increased from 86±2 mmHg baseline to 91±2 mmHg at the highest concentration. Infusion of L-NMMA (1.0 mg/kg/min) caused an increase in systolic blood pressure by 15% and SVR by 63% in 11 healthy volunteers after three minutes (Stamler et al., 1994). The study also demonstrated a dose-dependent increase in both events with five different doses of L-NMMA (0.01, 0.03, 0.1, 0.3 and 1 mg/kg/min). In another study, fifteen healthy men were intravenously infused with L-NAME at lower doses (0.25-0.75 mg/kg) for eight minutes, resulting in increased arterial pressure and SVR (McVeigh et al., 2001). Infusion with L-arginine, an eNOS substrate, restored function, specifically SVR and small artery compliance to baseline. L-NMMA (3 mg/kg) for five minutes increased mean arterial pressure by 10% and increased SVR by 46% in eight healthy subjects (Haynes et al., 1993). One experiment in rats showed that L-NAME increased SVR, aortic stiffness, and blood pressure (Nakmareong et al., 2012). Overall, these studies demonstrated that SVR and hypertension are modulated together by eNOS inhibitors.

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

One study showed that infusion of L-NMMA (6 mg/kg) resulted in increased SVR and only a modest increase in blood pressure. Changes in diastolic blood pressure were observed to be more pronounced in healthy men, than systolic blood pressure (Brett et al., 1998), and infusion of L-arginine (an eNOS substrate) had no significant effect.

As mentioned above, other AOPs are necessary to capture understanding and assess the evidence surrounding the roles of the heart, kidney and nervous system in order to get the full picture of the linkage between chronic changes in SVR and hypertension.

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

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

Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?

Mean arterial pressure is calculated from cardiac output and SVR. Therefore, theoretically, any change in SVR will impact the mean arterial pressure. The studies mentioned above showed that a small change for SVR such as from 31±2 (arbitrary units) at baseline to 35 ± 2 was able to change the arterial pressure from 86±2 mmHg to 91±2 mmHg (Wilkinson et al., 2002). This trend was also observed by Stamler et al. (1994) and McVeigh et al. (2001).

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

Studies supporting this key event relationship were performed in humans and rats.

References

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

Brandes, R.P. (2014). Endothelial dysfunction and hypertension. Hypertension 64, 924–928.

Brett, S.E., Cockcroft, J.R., Mant, T.G., Ritter, J.M., and Chowienczyk, P.J. (1998). Haemodynamic effects of inhibition of nitric oxide synthase and of L-arginine at rest and during exercise. J. Hypertens. 16, 429–435.

Chan, S.S., Tse, M.M., Chan, C.P., Tai, M.C., Graham, C.A., and Rainer, T.H. (2016). Haemodynamic changes in emergency department patients with poorly controlled hypertension. Hong Kong Med. J. Xianggang Yi Xue Za Zhi Hong Kong Acad. Med. 22, 116–123.

Foëx, P., and Sear, J.W. (2004). Hypertension: pathophysiology and treatment. Contin. Educ. Anaesth. Crit. Care Pain 4, 71–75.

Haynes, W.G., Noon, J.P., Walker, B.R., and Webb, D.J. (1993). Inhibition of nitric oxide synthesis increases blood pressure in healthy humans. J. Hypertens. 11, 1375–1380.

Lee, M.Y., and Griendling, K.K. (2008). Redox signaling, vascular function, and hypertension. Antioxid. Redox Signal. 10, 1045–1059.

Mayet, J., and Hughes, A. (2003). Cardiac and vascular pathophysiology in hypertension. Heart Br. Card. Soc. 89, 1104–1109.

McVeigh, G.E., Allen, P.B., Morgan, D.R., Hanratty, C.G., and Silke, B. (2001). Nitric oxide modulation of blood vessel tone identified by arterial waveform analysis. Clin. Sci. Lond. Engl. 1979 100, 387–393.

Nakmareong, S., Kukongviriyapan, U., Pakdeechote, P., Kukongviriyapan, V., Kongyingyoes, B., Donpunha, W., Prachaney, P., and Phisalaphong, C. (2012). Tetrahydrocurcumin alleviates hypertension, aortic stiffening and oxidative stress in rats with nitric oxide deficiency. Hypertens. Res. Off. J. Jpn. Soc. Hypertens. 35, 418–425.

Silva, B.R., Pernomian, L., and Bendhack, L.M. (2012). Contribution of oxidative stress to endothelial dysfunction in hypertension. Front. Physiol. 3, 441.

Stamler, J.S., Loh, E., Roddy, M.A., Currie, K.E., and Creager, M.A. (1994). Nitric oxide regulates basal systemic and pulmonary vascular resistance in healthy humans. Circulation 89, 2035–2040.

Wilkinson, I.B., MacCallum, H., Cockcroft, J.R., and Webb, D.J. (2002). Inhibition of basal nitric oxide synthesis increases aortic augmentation index and pulse wave velocity in vivo. Br. J. Clin. Pharmacol. 53, 189–192.