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(Hypertension. 2003;41:1253.)
© 2003 American Heart Association, Inc.

Scientific Contributions

Effects of Endothelin-1 and Endothelin-1 Receptor Blockade on Cardiac Output, Aortic Pressure, and Pulse Wave Velocity in Humans

Tycho J.L. Vuurmans; Peter Boer; Hein A. Koomans

From the Department of Nephrology and Hypertension, University Medical Center Utrecht, The Netherlands.

Correspondence to Hein A. Koomans, Department of Nephrology and Hypertension, University Medical Center Utrecht, Room F03.226, PO Box 85500, 3805 GA Utrecht, The Netherlands. E-mail h.a.koomans{at}azu.nl

Endothelin-1 (ET-1) is a potent vasoconstrictor. Its effect on arterial wave reflections and central pressure augmentation is unknown. We studied whether ET-1, in plasma concentrations present in disease, increases pulse wave velocity (PWV) and augmentation index (AIx) and therefore compromises cardiac output, and whether the ET-1 receptor blocker VML-588 (previously AXV-034343 and Ro 61–1790) prevents such effects. Nine healthy men received a 2-hour infusion with ET-1 (2.5 ng · kg^-1 · min^-1) superimposed on vehicle or VML-588 (0.05, 0.20, or 0.40 mg · kg^-1 · h^-1) (randomized order). Arterial tonometry and pulse wave contour analysis were used to assess aortic PWV and central aortic pressures and impedance cardiography for cardiac output. ET-1 slightly increased mean arterial pressure and peripheral resistance but had no significant effect on systolic blood pressure and pulse pressure. PWV increased from 5.4±0.2 to 5.7±0.3 m/s (P<0.05), AIx from 9.9±3.3 to 17.2±3.8 (P<0.05), central systolic blood pressure by 8.7±1.7 mm Hg (P<0.05), and central pulse pressure by 5.1±1.9 mm Hg (P<0.05). This was associated with a fall in cardiac output by 18% (P<0.05). VML-588 caused a slight decrease in brachial mean arterial pressure, PWV, and AIx, and prevented the effects of ET-1 on central hemodynamics without a clear dose-response effect. In summary, ET-1 in plasma concentrations as found in renal failure and heart failure accelerates PWV, causes a disproportionate increase in central aortic systolic blood pressure and pulse pressure, and decreases cardiac output. These effects can be prevented with an ET-1 receptor blocker such as VML-588. This makes it worthwhile to focus on endothelin as a target to prevent ventricular hypertrophy and to maintain cardiac function in diseases associated with high ET-1.

Key Words: endothelin • vasoconstriction • pressure • cardiac output

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