Effect of neutral endopeptidase inhibition on the actions of adrenomedullin and endothelin-1 in resistance arteries from patients with chronic heart failure

Adrenomedullin and endothelin are novel peptides that are produced in the b lood vessel wall and have contrasting biologic actions. Both may play a pat hophysiological role in atherosclerosis and chronic heart failure. It has a lso been suggested that both peptides may be metabolized by neutral endopep tidase and that pharmacological manipulation of this enzyme may be of thera peutic interest. We investigated the effect of thiorphan, a neutral endopep tidase inhibitor, on the vasodilator response to adrenomedullin and the vas oconstrictor response to endothelin in small resistance arteries taken from patients with heart failure caused by coronary heart disease. Small resist ance arteries were dissected from gluteal biopsy samples and studied with w ire myography. Thiorphan did not affect the vasodilator response to adrenom edullin in arteries preconstricted with norepinephrine. Maximal responses w ere 66% (SD 11%) and 72% (8%) in the absence and presence of thiorphan, res pectively (n=8). The vasoconstrictor response to endothelin was also unaffe cted. The maximum vasoconstrictor responses in the absence and presence of thiorphan were 152% (11%) and 132% (12%), respectively (n=8). The values of corresponding -log concentrations of agonist required to effect a 50% resp onse (pD(2)) were 8.52 (0.11) and 8.64 (0.15), respectively. We showed that the inhibition of neutral endopeptidase does not augment the vasodilator a nd vasoconstrictor activities of adrenomedullin and endothelin, respectivel y, in small resistance arteries from patients with chronic heart failure. T his suggests that neutral endopeptidase inhibition, as a therapeutic strate gy, will enhance neither the potentially desirable vascular actions of adre nomedullin nor the potentially unfavorable vascular effects of endothelin-1 in human cardiovascular disease states.