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