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Impaired, Vasodilation leads to Increase, Vascular Resistance
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
|All life stages||Low|
Key Event Relationship Description
Vasodilation decreases systemic vascular resistance (SVR; also known previously as Total Peripheral Resistance; TPR), the resistance to blood flow offered by the peripheral circulation, and blood pressure through relaxation of vascular smooth muscle cells (VSMCs) (Siddiqui, 2011). When vasodilation is impaired due to decreased NO availability, SVR and blood pressure become elevated.
Evidence Collection Strategy
Evidence Supporting this KER
The overall weight of evidence for the KER was rated "moderate" due the fact that acute pharmacological manipulation of the NO pathway resulted in corresponding changes in SVR. However, in the context of the development of hypertension, the chronic effects of impaired vasodilation are much less clear.
It is well-accepted that vasodilation and SVR are negatively correlated; blood flow is increased when blood vessels dilate due to a decrease in vascular resistance (Siddiqui, 2011). When vasodilation is impaired, SVR increases, in turn increasing blood pressure. Agents that cause hyperpolarization are potent vasodilators and activate potassium channels, while factors causing depolarization increase vascular tone (Nelson, 1990). Vascular tone is governed by the contractile activity of VSMCs in the walls of small arteries and arterioles, and is the major determinant of the resistance to blood flow through the circulation (Jackson, 2000). VSMCs from hypertensive animals have decreased functional voltage-gated potassium channels, which may contribute to depolarization. Two studies demonstrated that blockade of potassium channels completely inhibited NO-dependent vasodilation and increased SVR (Dessy et al., 2004; Berg et al., 2011). Inhibitors of eNOS activity (L-NAME, L-NMMA), which have been shown to decrease acetylcholine-induced vasorelaxation in animal studies (Li et al., 2007; Paulis et al., 2008), also caused an increase in SVR in human studies (Wilkinson et al., 2002; McVeigh et al., 2001; Brett et al., 1998). Overall, these results provide strong biological plausibility for this link.
Uncertainties and Inconsistencies
As mentioned above, acute pharmacological manipulation of the NO pathway results in expected changes in SVR. However, the link between chronically impaired vasodilation and SVR (the context of this AOP) is much less clear due to gaps in the literature. Epidemiological studies tend to investigate linkages between impaired vasodilation and cardiovascular events, as opposed to SVR and/or hypertension - making assessment of this KER difficult.
Furthermore, the complexity in the mechanisms influencing vascular re-modelling over time has hampered understanding of the phenomenon to date. The study by Modena et al. 2002 highlights that members of the general population respond differently to hypertensive therapy in the context of FMD improvement.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
This relationship between impaired vasodilation and SVR was shown in human and rat studies.
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