Ca^<2+> Entry Channels in Rat Thoracic Aortic Smooth Muscle Cells Activated by Endothelin-1

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The contraction of the rat aorta induced by endothelin-1 (ET-1) requires entry of extracellur Ca<SUP>2+</SUP>, but involvement of voltage-operated Ca<SUP>2+</SUP> channel is minor. Using whole-cell recordings of patch-clamp and monitoring of the intracellular free Ca<SUP>2+</SUP> concentration ([Ca<SUP>2+</SUP>]<SUB>i</SUB>), we characterized Ca<SUP>2+</SUP> entry channels in A7r5 cells activated by ET-1. ET-1 activates three types of voltage-independent Ca<SUP>2+</SUP> entry channels: two types of Ca<SUP>2+</SUP>-permeable nonselective cation channels (designated NSCC-1 and NSCC-2) and a store-operated Ca<SUP>2+</SUP> channel (SOCC). Furthermore, it was found that these channels can be pharmacologically discriminated using Ca<SUP>2+</SUP> channel blockers such as SK&F 96365 and LOE 908. NSCC-1 is resistant to SK&F 96365, but sensitive to LOE 908, whereas 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 channel blockers, we analyzed Ca<SUP>2+</SUP> entry channels involved in the ET-1-induced contractions of rat thoracic aorta and increases in [Ca<SUP>2+</SUP>]<SUB>i</SUB> of single smooth muscle cells. The responses to lower concentrations of ET-1 (≤0.1 nM) were abolished by either SK&F 96365 or LOE 908 alone. In contrast, the responses to higher concentrations of ET-1 (≥1 nM) were suppressed by SK&F 96365 or LOE 908 to about 10% and 35% of controls, respectively, and abolished by combined treatment with SK&F 96365 and LOE 980. These results show that the responses of rat aorta to lower concentrations of ET-1 involve only one Ca<SUP>2+</SUP> channel that is sensitive to SK&F 96365 and LOE 908 (NSCC-2), whereas those to higher concentrations of ET-1 involve NSCC-1, NSCC-2 and SOCC, contributing 10%, 55% and 35%, respectively, to total Ca<SUP>2+</SUP> entry.


  • The Japanese Journal of Pharmacology

    The Japanese Journal of Pharmacology 80(4), 281-288, 1999-08-01

    The Japanese Pharmacological Society

References:  51

Cited by:  3


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