Author + information
- Carmel M McEniery, PhD*,* (, )
- Ahmad Qasem, PhD†,
- Matthias Schmitt, MB, MRCP‡,
- Albert P Avolio, PhD†,
- John R Cockcroft, BSc, MB, FRCP‡ and
- Ian B Wilkinson, MA, BM, MRCP*
- ↵*Reprint requests and correspondence:
Dr. Carmel M. McEniery, Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, United Kingdom.
Objectives 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 (ETA) 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 ETAreceptor 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 ETAreceptors may be effective in reducing large artery stiffness in humans, and thus cardiovascular risk.
☆ Dr. Wilkinson, Dr. McEniery, and Prof. Cockcroft are supported by the British Heart Foundation.
- American College of Cardiology Foundation