Löffler B M, Breu V, Clozel M
Pharma Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
FEBS Lett. 1993 Oct 25;333(1-2):108-10. doi: 10.1016/0014-5793(93)80384-7.
The goal of our study was to evaluate and compare the effects of receptor blockade with different endothelin (ET) receptor antagonists on plasma concentrations of ET-1, big ET-1 and ET-3 in conscious rats. Ro 46-2005 10 mg/kg, i.v.), a novel non-peptide antagonist of both ETA and ETB receptors, increased the concentrations of ET-1 in plasma to 200 +/- 13% of basal levels (P < 0.001). This effect was dose- and time-dependent and reached a maximum at 15 min. Ro 46-2005 had no effect on plasma concentrations of big ET-1 and only a minor effect on those of ET-3. In contrast to Ro 46-2005, the selective peptide ETA antagonists BQ-123 and FR-139317 had no effect on plasma ET-1 concentrations. The increase in plasma ET-1 concentrations by Ro 46-2005 was most likely not due to de novo synthesis, since big ET-1 levels were not increased and peak levels were reached early after compound injection, but perhaps to displacement of ET-1 from the ETB receptors.
我们研究的目的是评估和比较不同内皮素（ET）受体拮抗剂进行受体阻断对清醒大鼠血浆中ET-1、大ET-1和ET-3浓度的影响。新型非肽类ETA和ETB受体拮抗剂Ro 46-2005（静脉注射10mg/kg）使血浆中ET-1浓度升高至基础水平的200±13%（P<0.001）。该效应呈剂量和时间依赖性，在15分钟时达到最大值。Ro 46-2005对血浆中大ET-1浓度无影响，对ET-3浓度仅有轻微影响。与Ro 46-2005不同，选择性肽类ETA拮抗剂BQ-123和FR-139317对血浆ET-1浓度无影响。Ro 46-2005使血浆ET-1浓度升高很可能不是由于从头合成，因为大ET-1水平未升高且在注射化合物后早期即达到峰值水平，而可能是由于ET-1从ETB受体上被置换下来。
