Role of endothelin receptors, calcium and nitric oxide in the potentiation by endothelin‐1 of the sympathetic contraction of rabbit ear artery during cooling

1 To examine further the potentiation by endothelin‐1 on the vascular response to sympathetic stimulation, we studied the isometric response of isolated segments, 2 mm long, from the rabbit central ear artery to electrical field stimulation (1–8 Hz), under different conditions, at 37°C and during cooling (30°C). 2 Electrical stimulation produced frequency‐dependent contraction, which was reduced (about 63% for 8 Hz) during cooling. At 30°C, but not at 37°C, endothelin‐1 (1, 3 and 10 n M ) potentiated the contraction to electrical stimulation in a dose‐dependent way (from 43±7% to 190±25% for 8 Hz). 3 This potentiation by endothelin‐1 was reduced by the antagonist for endothelin ET A receptors BQ‐123 (10 μ M ) but not by the antagonist for endothelin ET B receptors BQ‐788 (10 μ M ). The agonist for endothelin ET B receptors IRL‐1620 (0.1 μ M ) did not modify the contraction to electrical stimulation. 4 The blocker of L‐type Ca 2+ channels verapamil (10 μ M l −1 ) reduced (about 72% for 8 Hz) and the unspecific blocker of Ca 2+ ‐channels NiCl 2 (1 m M ) practically abolished (about 98%), the potentiating effects of endothelin‐1 found at 30°C. 5 Inhibition of nitric oxide synthesis with N G ‐nitro‐ L ‐arginine ( L ‐NOARG, 0.1 m M ) increased the contraction to electrical stimulation at 30°C more than at 37°C (for 8 Hz, this increment was 297±118% at 30°C, and 66±15% at 37°C). Endothelium removal increased the contraction to electrical stimulation at 30°C (about 91% for 8 Hz) but not at 37°C. Both L ‐NOARG and endothelium removal abolished the potentiating effects of endothelin‐1 on the response to electrical stimulation found at 30°C. 6 These results in the rabbit ear artery suggest that during cooling, endothelin‐1 potentiates the contraction to sympathetic stimulation, which could be mediated at least in part by increasing Ca 2+ entry after activation of endothelin ET A receptors. This potentiating effect of endothelin‐1 may require the presence of an inhibitory tone due to endothelial nitric oxide.British Journal of Pharmacology (1997) 121 , 1659–1664; doi: 10.1038/sj.bjp.0701324