Unique Response of Human Arteries to Endothelin B Receptor Agonist and Antagonist

1. The role of the ET_B receptor in human arteries has not been well studied because of the lack of specific ET_B receptor antagonists. In the present studies the specific ET_B receptor antagonist BQ-788 and the specific ET_B agonist IRL-1620 were used to characterize the function of the ET_B receptor in human radial arteries and internal mammary arteries.

2. The results showed that the ET_B antagonist BQ-788 significantly inhibited endothelin-1-induced contraction in internal mammary arteries, but not in radial arteries. In internal mammary arteries, BQ-788 at a concentration of 10 μmol/l shifted the endothelin-1-induced concentration-dependent curve to the right by one order. By comparison, the ET_A receptor antagonist BQ-610 at 1 μmol/l produced a much more potent inhibitory effect (three-order shifting) on endothelin-1-induced contraction in internal mammary arteries, and also potently inhibited the contraction in radial arteries.

3. The ET_B agonist IRL-1620 caused a contraction in internal mammary arteries, but not in radial arteries, although the response of radial arteries to endothelin-1 was very strong. The contraction induced by IRL-1620 was weaker than that induced by endothelin-1; however, the maximal contraction to IRL-1620 was obtained at 3 nmol/l, which was lower than that with endothelin-1 (maximal contraction at 10 nmol/l).

4. In internal mammary arteries the contraction to endothelin-1 and IRL-1620 gradually changed to relaxation with high concentrations of endothelin-1 (from 30 nmol/l) and IRL-1620 (from 3 nmol/l), whereas it did not in radial arteries; suggesting that the ET_B receptor on human arterial smooth muscle cells may mediate contraction at low agonist concentrations and relaxation at high agonist concentrations.

5. The ET_B agonist IRL-1620, endothelin-1 and endothelin-3 did not cause endothelium-dependent relaxation in either precontracted radial arteries or internal mammary arteries, although endothelium-dependent relaxation was fully induced by acetylcholine in these two arterial preparations.

6. In conclusion, the present studies demonstrate that the responses of internal mammary arteries and radial arteries to an ET_B antagonist and an ET_B agonist are significantly different from those of animal vascular vessels, and also from each other. The ET_B receptor may play only a minor role in endothelium-dependent relaxation of these human arteries. Endothelin-1-induced contraction is mediated by both the ET_A (major) and the ET_B (minor) receptors in internal mammary arteries, but only by the ET_A receptor in radial arteries. These studies may help to determine therapeutic strategy.