Endothelin-1 regulates arterial pulse wave velocity in vivo.
OBJECTIVE
The aim of this study was to investigate whether endothelin-1, acting locally, regulates arterial distensibility, assessed by measuring pulse-wave velocity in vivo.


BACKGROUND
Arterial stiffness is a key determinant of cardiovascular risk. Several lines of evidence support a role for the endothelium in regulating arterial stiffness by release of vasoactive mediators. However, the role of endothelin-1 (ET-1) in the regulation of arterial stiffness has not been investigated.


METHODS
All studies were conducted in anesthetized sheep. Pulse wave velocity (PWV) was calculated using the foot-to-foot methodology from two pressure waveforms simultaneously recorded with a high-fidelity, dual pressure-sensing catheter placed in the common iliac artery.


RESULTS
Intra-arterial infusion of ET-1 significantly increased iliac PWV by 12 +/- 5% (mean +/- STD; p < 0.001), whereas infusion of the endothelin-A (ET(A)) receptor antagonist BQ-123 significantly reduced PWV by 12 +/- 4% (p < 0.001). After BQ-123 infusion, exogenously infused ET-1 did not significantly change PWV compared with infusion of saline (change of -0.08 +/- 0.11% vs. -0.01 +/- 0.07%; p = 0.53). Importantly, infusion of BQ-123 or ET-1 distal to the common iliac artery did not affect PWV.


CONCLUSIONS
These results demonstrate, for the first time, that endogenous ET-1 production directly regulates large artery PWV in vivo. In addition, exogenous ET-1 increases PWV, and this can be blunted by ET(A) receptor blockade. These observations explain, in part, why conditions that exhibit up-regulation of ET-1 are also associated with arterial stiffening. Therefore, drugs that block ET(A) receptors may be effective in reducing large artery stiffness in humans, and thus cardiovascular risk.
McEniery
Carmel M
CM
Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom. cmm41@cam.ac.uk
Qasem
Ahmad
A
Schmitt
Matthias
M
Avolio
Albert P
AP
Cockcroft
John R
JR
Wilkinson
Ian B
IB
D000818:Animals; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D010456:Peptides, Cyclic / Q000494:pharmacology; D011674:Pulse; D012756:Sheep; D015854:Up-Regulation; D014664:Vasodilation / Q000502:physiology*
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; C072247:cyclo(Trp-Asp-Pro-Val-Leu)