Key result
Systemic ET(B) blockade with A-192621 increased mean arterial pressure from 79 to 89 mmHg, a hypertensive response that was reversed by coadministration of the ET(A) antagonist atrasentan.
Why the study?
Does ET(B) blockade induce hypertension mediated by ET(A) receptors in conscious nonhuman primates?
Does ET(B) blockade induce hypertension mediated by ET(A) receptors in conscious nonhuman primates?
Systemic ET(B) blockade produces sustained hypertension in conscious nonhuman primates that is mediated by ET(A) receptors, highlighting the importance of ET(B) receptors in clearing plasma ET-1.
ET(B) blockade may promote ET(A)-mediated hypertension in primates; leaves open relevance to human endothelin therapies.
The role of endothelin-B (ET(B)) receptors in circulatory homeostasis is ambiguous, reflecting vasodilator and constrictor effects ascribed to the receptor and diuretic and natriuretic responses that could oppose the hypertensive effects of ET excess. With the use of conscious, telemetry-instrumented cynomolgus monkeys, we characterized the hypertension produced by ET(B) blockade and the role of ET(A) receptors in mediating this response. Mean arterial pressure (MAP) and heart rate (HR) were measured 24 h/day for 24 days under control conditions and during administration of the ET(B)-selective antagonist A-192621 (0.1, 1.0, and 10 mg/kg bid, 4 days/dose) followed by coadministration of the ET(A) antagonist atrasentan (5 mg/kg bid) + A-192621 (10 mg/kg bid) for another 4 days. High-dose ET(B) blockade increased MAP from 79 +/- 3 (control) to 87 +/- 3 and 89 +/- 3 mmHg on the first and fourth day, respectively; HR was unchanged, and plasma ET-1 concentration increased from 2.1 +/- 0.3 pg/ml (control) to 7.24 +/- 0.99 and 11.03 +/- 2.37 pg/ml. Atrasentan + A-192621 (10 mg/kg) decreased MAP from hypertensive levels (89 +/- 3) to 75 +/- 2 and 71 +/- 4 mmHg on the first and fourth day, respectively; plasma ET-1 and HR increased to 26.64 +/- 3.72 and 28.65 +/- 2.89 pg/ml and 113 +/- 5 (control) to 132 +/- 5 and 133 +/- 7 beats/min. Thus systemic ET(B) blockade produces a sustained hypertension in conscious nonhuman primates, which is mediated by ET(A) receptors. These data suggest an importance clearance function for ET(B) receptors, one that influences arterial pressure homeostasis indirectly by reducing plasma ET-1 levels and minimizing ET(A) activation.
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Reinhart et al. (2002) studied Hypertension. ET(B)-selective antagonist A-192621 and ET(A) antagonist atrasentan vs. Control conditions was evaluated on Mean arterial pressure (MAP). Systemic ET(B) blockade with A-192621 increased mean arterial pressure from 79 to 89 mmHg, a hypertensive response that was reversed by coadministration of the ET(A) antagonist atrasentan.
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