API

Relationship: 983

Title

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Increase, Vascular Resistance leads to Hypertension

Upstream event

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Increase, Vascular Resistance

Downstream event

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Hypertension

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
Peptide Oxidation Leading to Hypertension adjacent Moderate Low

Taxonomic Applicability

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Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI
Rattus norvegicus Rattus norvegicus Low NCBI

Sex Applicability

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Sex Evidence
Unspecific High

Life Stage Applicability

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Term Evidence
Adults High

Key Event Relationship Description

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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 Supporting this KER

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Biological Plausibility

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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

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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

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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.

Quantitative Understanding of the Linkage

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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

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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

References

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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.