Key result
Lower concentrations of endothelin-1 activate NSCC-1, whereas higher concentrations activate NSCC-1, NSCC-2, and SOCC, which can be discriminated using SK&F 96365 and LOE 908.
Endothelin-1 activates distinct voltage-independent Ca2+ channels in vascular smooth muscle cells depending on its concentration, which can be pharmacologically discriminated.
Should not change vascular therapy; hypothesis-generating for concentration-specific Ca2+ channel targeting in smooth muscle.
To clarify Ca2+ entry channels involved in the endothelin-1 (ET-1)-induced increase in the intracellular concentration ([Ca2+]i), we performed whole-cell recordings of patch-clamp techniques and monitoring of [Ca2+]i with Ca2+ indicators fura-2 and fluo-3 in A7r5 cells (a cell line derived from rat thoracic aortic smooth muscle cells). With whole-cell recordings, lower concentrations (< or = 1 nM) of ET-1 activated a Ca(2+)-permeable nonselective cation channel (designated NSCC-1). In contrast, higher concentrations (> or = 1 nM) of ET-1 activated two types of Ca(2+)-permeable nonselective cation channel (designated NSCC-1 and NSCC-2) and store-operated Ca2+ channel (SOCC). Importantly, we found that these Ca2+ channels can be pharmacologically discriminated using blockers of the so-called receptor operated Ca2+ influx such as SK&F 96365 and LOE 908. That is, NSCC-1 is resistant to SK&F 96365 but sensitive to LOE 908; NSCC-2 is sensitive to both SK&F 96365 and LOE 908; SOCC is sensitive to SK&F 96365 but resistant to LOE 908. Using these blockers, we analyzed the ET-1-induced increase in [Ca2+]i. The increase in [Ca2+]i induced by lower concentrations of ET-1 was resistant to SK&F 96365 but sensitive to LOE 908. In contrast, the increase in [Ca2+]i induced by higher concentrations of ET-1 was partially suppressed to approximately 30% of controls by either SK&F 96365 or LOE 908 alone, and it was abolished by their combination. These results show that the increase in [Ca2+]i induced by lower concentrations (< or = 1 nM) of ET-1 results from Ca2+ influx through NSCC-1, whereas the increase in [Ca2+]i induced by higher concentrations (> or = 10 nM) of ET-1 results from Ca2+ influx through NSCC-1, NSCC-2 and SOCC.
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Iwamuro et al. (1999) studied this question. Endothelin-1 (ET-1) vs. Baseline/Control was evaluated on Intracellular Ca2+ concentration ([Ca2+]i) and whole-cell currents. Lower concentrations of endothelin-1 activate NSCC-1, whereas higher concentrations activate NSCC-1, NSCC-2, and SOCC, which can be discriminated using SK&F 96365 and LOE 908.
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