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CLINICAL RESEARCH: ARTERIAL DYNAMICS

Endothelin-1 regulates arterial pulse wave velocity in vivo

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^*

^* Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom
Graduate School of Biomedical Engineering, University of New South Wales, Sydney, Australia
Department of Cardiology, Wales Heart Research Institute, Cardiff, United Kingdom

^* Reprint requests and correspondence: Dr. Carmel M. McEniery, Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, United Kingdom.
cmm41{at}cam.ac.uk

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 (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.

Abbreviations and Acronyms   ETA = endothelin-A   ET-1 = endothelin-1   HR = heart rate   LNMMA = NG-monomethyl-L-arginine   MAP = mean arterial pressure   NA = noradrenaline   NO = nitric oxide   PWV = pulse wave velocity   TT = transit time

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