Berthiaume N, Yanagisawa M, D'Orléans-Juste P
Institute of Pharmacology, Medical School, Université de Sherbrooke, Québec, Canada.
J Cardiovasc Pharmacol. 2000 Nov;36(5 Suppl 1):S72-4.
We observed that heterozygous knockout (+/-, KO) of either endothelin-A- (ET(A)) or -B- (ET(B)) receptors significantly reduced the pressor responses to systemically administered endothelin-1 (ET-1) in ET(A) or ET(B) (+/-) KO mice when compared to wild-type (WT) mice (data not shown). Also, we observed that basal mean arterial pressure (MAP) is significantly higher in ET(B) (+/-) (92.7 +/- 1.2 mmHg) (n = 53, p < 0.05) but not ET(A) (+/-) KO mice (70.6 +/- 1.8 mmHg) (n = 23) when compared to their anaesthetized WT littermates (70.1 +/- 0.7 mmHg) (n = 118). A 90 min treatment with either BQ-123 (10 mg/kg), an ET(A)-selective antagonist, or BQ-928 (10 mg/kg), a mixed ET(A)/ET(B) antagonist, administered intraperitoneally, significantly reduced basal MAP of ET(B) (+/-) KO mice almost to the level of their WT treated counterparts (94.9 +/- 4.9 mmHg) (n = 6) vs (+ BQ-123: 59.7 +/- 0.3 mmHg, n = 8); (+ BQ-928: 72.4 +/- 2.6 mmHg, n = 5). It is worthy of note that BQ-123 significantly reduced basal MAP in WT mice but to a lesser extent than in ET(B) (+/-) KO mice (69.6 +/- 2.3 mmHg, n = 8) vs (+ BQ-123: 57.3 +/- 1.4 mmHg, n = 8). In contrast, the ET(B)-selective antagonist, BQ-788 (10 mg/kg i.p.), had no significant effect on MAP even after 90 min of treatment (ET(B) (+/-) KO: (92.3 +/- 2.3 mmHg, n = 6) vs (+ BQ-788: 89.7 +/- 3.1 mmHg, n = 6); WT: (70.5 +/- 3.7 mmHg, n = 7) vs (+ BQ-788: 71.2 +/- 2.0 mmHg, n = 6). Therefore heterozygous KO of either ET(A)- or ET(B)-receptors significantly alters the phenotypic pressor properties of ET-1. We also suggest that there is less ET clearance in ET(B) (+/-) KO mice than in WT mice, which can explain the ET(A)-dependent hypertensive state of the former strain.
我们观察到，与野生型（WT）小鼠相比，内皮素A（ET(A)）或B（ET(B)）受体的杂合敲除（+/−，KO）显著降低了ET(A)或ET(B)（+/−）KO小鼠对全身给药内皮素-1（ET-1）的升压反应（数据未显示）。此外，我们观察到，与麻醉的WT同窝小鼠（70.1±0.7 mmHg）（n = 118）相比，ET(B)（+/−）（92.7±1.2 mmHg）（n = 53，p < 0.05）而非ET(A)（+/−）KO小鼠（70.6±1.8 mmHg）（n = 23）的基础平均动脉压（MAP）显著更高。腹腔注射ET(A)选择性拮抗剂BQ-123（10 mg/kg）或ET(A)/ET(B)混合拮抗剂BQ-928（10 mg/kg）进行90分钟治疗后，ET(B)（+/−）KO小鼠的基础MAP显著降低，几乎降至其WT治疗对应物的水平（94.9±4.9 mmHg）（n = 6），与之相比，注射BQ-123组为59.7±0.3 mmHg（n = 8）；注射BQ-928组为72.4±2.6 mmHg（n = 5）。值得注意的是，BQ-123显著降低了WT小鼠的基础MAP，但程度小于ET(B)（+/−）KO小鼠（69.6±2.3 mmHg，n = 8），与之相比，注射BQ-123组为57.3±1.4 mmHg（n = 8）。相反，ET(B)选择性拮抗剂BQ-788（10 mg/kg腹腔注射）即使在治疗90分钟后对MAP也没有显著影响（ET(B)（+/−）KO：（92.3±2.3 mmHg，n = 6），与之相比，注射BQ-788组为89.7±3.1 mmHg（n = 6）；WT：（70.5±3.7 mmHg，n = 7），与之相比，注射BQ-788组为71.2±2.0 mmHg（n = 6）。因此，ET(A)或ET(B)受体的杂合敲除显著改变了ET-1的表型升压特性。我们还认为，ET(B)（+/−）KO小鼠的ET清除率低于WT小鼠，这可以解释前一品系依赖ET(A)的高血压状态。
