45 Clinical Science (2001) 101, 45–51 (Printed in Great Britain) Effect of adrenomedullin on the production of endothelin-1 and on its vasoconstrictor action in resistance arteries: evidence for a receptor-specific functional interaction in patients with heart failure Chris HILLIER*, Mark C. PETRIE†, Michael P. LOVE†, Fiona JOHNSTON*, Margaret R. MACLEAN‡ and John J. V. MCMURRAY† *Department of Biological Sciences, Glasgow Caledonian University, Glasgow G4 0BA, Scotland, U.K., †Department of Cardiology, Western Infirmary, Glasgow G11 6NT, Scotland, U.K., and ‡Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, U.K. A B S T R A C T Endothelin-1 (ET-1) and adrenomedullin (ADM) are both produced in the arterial wall, but have opposing biological actions. Evidence from experimental animals suggests a functional interaction between ET-1 and ADM. We have tested this in humans. Small resistance arteries were obtained from gluteal biopsies taken from patients with chronic heart failure (CHF) due to coronary heart disease (CHD), or with CHD and preserved ventricular function. The contractile responses to big ET-1 and to ET-1 in both sets of vessels were studied in the absence (control) and presence of ADM at 20 pmol/l (low ADM) or 200 pmol/l (high ADM), using wire myography. ADM did not affect the conversion of big ET-1 into ET-1 in vessels from patients with either CHD or CHF. Low ADM did not alter the contractile response to ET-1 in vessels from patients with CHF. Low ADM was not tested in vessels from patients with CHD, but high ADM did not affect this response in arteries from these patients. High ADM did, however, significantly reduce the vasoconstrictor effect of ET-1 in vessels from patients with CHF. The maximum response, as a percentage of the response to high potassium, was 199 % (S.E.M. 25 %) in the control experiments (n  14), 205 % (27 %) in the low-ADM (n  7) studies and 150 % (17 %) in the high-ADM (n  6) experiments (P  0.001). Furthermore, the Hill coefficient increased from 0.570.05 in the absence of ADM to 1.160.15 in the high-ADM experiments, indicating that ADM at 200 pmol/l specifically antagonized one receptor type in vessels from patients with CHF. We conclude that there is a one-site receptor interaction between ADM and ET-1 that is specific for vessels from patients with CHF. This functional interaction between ADM and ET-1 in resistance arteries may be of pathophysiological importance in CHF. Key words: adrenomedullin, endothelin, heart failure, human, resistance arteries. Abbreviations: ACE, angiotensin-converting enzyme ; ADM, adrenomedullin ; CHD, coronary heart disease ; CHF, chronic heart failure ; ECE, endothelin-converting enzyme ; ET-1, endothelin-1 ; pD  , negative log of the concentration of agonist required to effect a 50 % response ; PSS, physiological salt solution ; RAMP, receptor-activity-modifying protein. Correspondence: Professor John J. V. McMurray, CRI in Heart Failure, Wolfson Building, University of Glasgow, Glasgow G11 6NT, U.K. (e-mail j.mcmurraybio.gla.ac.uk).  2001 The Biochemical Society and the Medical Research Society