Published Online
on May 12, 2003

A more recent version of this article appeared on June 1, 2003

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Submitted on January 30, 2003
Revised on February 27, 2003

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; and Hein A. Koomans^*

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

^* To whom correspondence should be addressed. E-mail: h.a.koomans{at}azu.nl.

Abstract--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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