Vascular function and endothelin-1: tipping the balance between vasodilation and vasoconstriction

Abstract

Endothelin-1 (ET-1), a potent vasoconstrictor secreted by vascular endothelial cells, has been implicated in the pathophysiology of numerous cardiovascular diseases, yet the direct impact of ET-1 on vascular function remains unclear. Therefore, in seven young (23 ± 1 yr) healthy subjects, we investigated the effect of an intra-arterial infusion of ET-1 on reactive hyperemia (RH) and flow-mediated dilation (FMD) in the popliteal artery following 5 min of suprasystolic cuff occlusion. ET-1 infusion significantly attenuated basal leg blood flow (control: 62 ± 4 ml/min, ET-1: 47 ± 9 ml/min), RH [area-under-curve (AUC); control: 162 ± 15 ml, ET-1: 104 ± 16 ml], and peak RH (control: 572 ± 51 ml/min, ET-1: 412 ± 32 ml/min) (P < 0.05). Administration of ET-1 also reduced FMD (control: 2.4 ± 0.3%, ET-1: 0.5 ± 0.5%) and FMD normalized for shear rate (control: 10.5 × 10^-4 ± 2.0 × 10^-4%/s^-1, ET-1: 0.9 × 10^-4 ± 2.8 ×10^-4%/s^-1). These findings reveal that elevated levels of ET-1 have a significant impact on vascular function, indicating that studies employing RH and FMD as markers of microvascular function and nitric oxide bioavailability, respectively, should exercise caution, as ET-1 can impact these assessments by tipping the balance between vasodilation and vasoconstriction, in favor of the latter.NEW & NOTEWORTHY Endothelin-1 (ET-1) is recognized as the body's most potent endogenous vasoconstrictor, but the impact of this peptide on vascular function is not well understood. The present study revealed that the intra-arterial administration of ET-1 impaired both microvascular and conduit vessel function of the leg in young, healthy, humans. Studies employing vascular testing in patient cohorts that experience a disease-related increase in ET-1 should thus exercise caution, as ET-1 clearly impairs vascular function.

Keywords: cardiovascular disease; endothelium; flow-mediated dilation; vascular function.

Fig. 1.

Resting blood flow and reactive hyperemia following cuff release. *Significant differences in resting blood flow, reactive hyperemia, and peak reactive hyperemia between control flow-mediated dilation (FMD) and endothelin-1 (ET-1) infusion FMD trials (P < 0.05).

Fig. 2.

Baseline and peak change in popliteal artery diameter values during the flow-mediated dilation (FMD) test during control and endothelin-1 (ET-1) trials. †Significant change from baseline (P < 0.05).

Fig. 3.

Flow-mediated dilation (FMD; %diameter change; A), shear rate (area under curve; B), and FMD normalized for shear rate [area under curve (AUC); C]. *Significant difference between control FMD and endothelin-1 (ET-1) infusion FMD trials (P < 0.05).