Effect of adrenomedullin on the production of endothelin-1 and on its vasoconstrictor action in resistance arteries: evidence for a receptor-specificfunctional interaction in patients with heart failure

Endothelin-1 (Ef-1) and adrenomedullin (ADM) are both produced in the arter ial wall, but have opposing biological actions. Evidence from experimental animals suggests a functional interaction between ET-1 and ADM. We have tes ted this in humans. Small resistance arteries were obtained from gluteal bi opsies taken from patients with chronic heart failure (CHF) due to coronary heart disease (CHD), or with CHD and preserved ventricular function. The c ontractile responses to big ET-1 and to ET-1 in both sets of vessels were s tudied 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 conv ersion of big ET-1 into ET-1 in vessels from patients with either CHD or CH F. Low ADM did not alter the contractile response to ET-1 in vessels from p atients 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 percenta ge of the response to high potassium, was 199% (S.E.M. 25%) in the control experiments (r = 14), 205% (27%) in the low-ADM (n = 7) studies and 150% (1 7%) 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 specific ally antagonized one receptor type in vessels from patients with CHF. We co nclude that there is a one-site receptor interaction between ADM and ET-1 t hat is specific for vessels from patients with CHF. This functional interac tion between ADM and ET-1 in resistance arteries may be of pathophysiologic al importance in CHF.