Differential adrenomedullin release and endothelin receptor expression in distinct subpopulations of human airway smooth-muscle cells

Although adrenomedullin (ADM) is implicated in the control of airway tone, regulation of ADM release from airway smooth-muscle cells (ASMCs) has not b een explored. Preliminary experiments have indicated that human ASMC popula tions were heterogeneous in their rate of ADM release and expression of end othelin (ET)(A) and ETB receptors. We isolated these phenotypically distinc t ASMCs from explants derived from the same airway segment. ASMCs possessin g exclusively ETA receptors appeared smaller and proliferated faster than E TA/ETB isolates. Macroautoradiographic analysis confirmed the presence of b oth receptors in human bronchi. ADM release and messenger RNA expression wa s greater in ETA/ETB isolates compared with ETA isolates. No measurable ET release was detected from ASMCs. Exogenous ET-1 (1 to 100 nM) more potently stimulated the release of ADM from ETA/ETB compared with ETA isolates. In addition, ET-3 (1 to 100 nM) stimulated ADM release only from ETA/ETB isola tes, implicating the ETB receptor in this response. Exogenous ET-1 potentia ted platelet-derived growth factor-stimulated [H-3]thymidine uptake in ETA/ ETB but not ETA isolates. ET-3 did not affect [H-3]thymidine uptake in eith er cell type. Possession of ETA/ETB receptors is associated with higher rat es of ADM release and slower proliferation, but a capacity for ET-1 stimula ted DNA synthesis via ETA receptors. These results support a paracrine role for the regulation of ADM release predominantly via the ETB receptor in hu man ASMCs.