Analysis of two pharmacologically predicted endothelin B receptor subtypes by using the endothelin B receptor gene knockout mouse

Abstract

1. This study was performed to clarify whether the endothelin (ET) receptor subtypes mediating two pharmacologically heterogeneous response to ET_B receptor agonists in normal mice are the product(s) of a single ET_B receptor gene.

2. Vasodilator responses to sarafotoxin S6c (S6c) in the thoracic aorta and contractile responses to ET-1 and IRL1620 in the stomach were examined in tissues from normal and ET_B receptor gene knockout mice, in the absence and presence of an ET_A receptor antagonist, BQ-123, or an ET_A/ET_B receptor antagonist, PD142893.

3. In the normal mouse aorta precontracted with phenylephrine, S6c (0.1100 nM) caused concentration-dependent relaxations (pD₂=8.4). BQ-123 had no effect on these responses. However, PD142893 almost abolished the relaxations induced by 0.1300 nM S6c.

4. In aortae taken from ET_B receptor gene knockout mice, S6c up to 1 μM failed to cause relaxations, confirming that ET_B receptors are involved in mediating this response.

5. In normal mouse gastric fundus, 0.1 nM1 μM ET-1, S6c or IRL1620 caused dose-dependent, BQ-123-insensitive contractions, which were much more resistant to PD142893 than S6c-induced relaxations of the aorta. The pD₂ values for S6c in the absence and presence of PD142893 (10 μM) were 8.12±0.11 and 7.70±0.11, respectively.

6. In the gastric fundus of the ET_B receptor gene knockout mouse, S6c and IRL1620 caused no contractions. ET-1 (0.1 nM1 μM) caused contractions sensitive to both BQ-123 and PD142893, indicating that only ET_A receptors mediate ET-1-induced contractions of the knockout mouse gastric fundus.

7. Since both the PD142893-sensitive vasodilator response of the aorta and the PD142893-resistant contractile response of the gastric fundus to S6c were completely absent in the ET_B receptor gene knockout mouse, we conclude that the two pharmacologically heterogeneous responses to S6c are mediated by receptors derived from the same ET_B receptor gene.

Full Text

The Full Text of this article is available as a PDF (300.5 KB).