Contribution of Endogenous Endothelin-1 and Endothelin-A-receptors to the Hypertensive State of Endothelin-B Heterozygous (+/−) Knockout Mice

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Abstract
We observed that heterozygous knockout (+/−, KO) of either endothelin-A- (ETA) or -B- (ETB) receptors significantly reduced the pressor responses to systemically administered endothelin-1 (ET-1) in ETA or ETB (+/−) 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 ETB (+/−) (92.7 ± 1.2 mmHg) (n = 53, p < 0.05) but not ETA (+/−) 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 ETA-selective antagonist, or BQ-928 (10 mg/kg), a mixed ETA/ETB antagonist, administered intraperitoneally, significantly reduced basal MAP of ETB (+/−) 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 ETB (+/−) KO mice (69.6 ± 2.3 mmHg, n = 8) vs (+ BQ-123: 57.3 ± 1.4 mmHg, n = 8). In contrast, the ETB-selective antagonist, BQ-788 (10 mg/kg i.p.), had no significant effect on MAP even after 90 min of treatment (ETB (+/−) 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 ETA- or ETB-receptors significantly alters the phenotypic pressor properties of ET-1. We also suggest that there is less ET clearance in ETB (+/−) KO mice than in WT mice, which can explain the ETA-dependent hypertensive state of the former strain.

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