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1Using conventional microelectrodes, the perforated patch clamp technique and fluorescence microscopy with fura‐2, we investigated the relationship between the cell membrane potential, whole‐cell currents and the free cytoplasmic Ca2+concentration ([Ca2+]i) in response to 10 nM endothelin‐1 (ET) in a rat respiratory epithelial cell line (L2).2Microelectrode experiments revealed that ET caused an immediate depolarization of the cell membrane potential (Vm) by 25 mV, which was unaffected by Na+replacement with N‐methyl‐D‐glucamine+(NMDG+) or by omission of bath Ca2+. In contrast, ET depolarized the cells by 61 mV in the presence of low Cl−(6 mM), resulting in a complete breakdown of Vm.3In perforated patch clamp experiments, the ET‐induced whole‐cell current (IET) exhibited a slight outward rectification with a reversal potential (Vrev) of ‐22·7 mV. IETwas reduced by 85 % in low Cl−(6 mM), but was unaffected by Ca2+removal, Na+replacement with NMDG+, pipette K+replacement with Cs+or 1 mM Ni2+in the bath.4IETwas unaffected by (+)‐isradipine (100 nM), a specific L‐type Ca2+channel (L‐VDCC) blocker. Transient inward Sr2+currents through L‐VDCCs were blocked by ET.5ET induced a biphasic Ca2+signal, consisting of a ‘peak’ and a ‘plateau’ elevation of [Ca2+]i. Simultaneous patch clamp and fura‐2 measurements revealed that IETcoincided with intracellular Ca2+release but clearly outlasted the elevation of [Ca2+]i. When the rise of [Ca2+]iwas prevented by pretreatment with thapsigargin in a Ca2+‐free bath, both activation time and amplitude of IETwere reduced. Under these conditions, ET caused a decrease of [Ca2+]i.6The Cl−channel blocker mefenamic acid (MFA) had a dual, concentration‐dependent effect on both IETand the ET‐induced ‘plateau’ elevation of [Ca2+]i: an increase at 10 μM, but an almost complete block at 100 μM. The effect of MFA on IETpreceded the effect on [Ca2+]i.7The ET‐induced ‘plateau’[Ca2+]ifell below control values in a low‐Cl−(6 mM) solution.8These data indicate an amplifying function of intracellular Ca2+release on an otherwise Ca2+‐independent, unique Cl−current by ET. Moreover, this Cl−current appears to be functionally coupled with dihydropyridine (DHP)‐insensitive Ca2+entry, suggesting a modulatory role for long‐lasting effects of ET.