Effects of endothelin-1 and endothelin-1 receptor blockade on cardiac output, aortic pressure, and pulse wave velocity in humans.
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 x kg(-1) x min(-1)) superimposed on vehicle or VML-588 (0.05, 0.20, or 0.40 mg x kg(-1) x 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 approximately 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.
Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.
Tycho J L
TJ
Vuurmans
Peter
P
Boer
Hein A
HA
Koomans
D000293:Adolescent; D000328:Adult; D001011:Aorta / Q000187:drug effects / Q000502:physiology*; D001775:Blood Circulation / Q000187:drug effects; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects*; D004146:Dioxanes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000097:blood; D006801:Humans; D008297:Male; D011673:Pulsatile Flow / Q000187:drug effects*; D011725:Pyridines; D011743:Pyrimidines / Q000494:pharmacology*; D044022:Receptor, Endothelin A; D013449:Sulfonamides; D013777:Tetrazoles
D004146:Dioxanes; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011725:Pyridines; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D013449:Sulfonamides; D013777:Tetrazoles; C109641:clazosentan