Endothelin-a Receptor Blockade Attenuates the Hypertension in a Rat Model of Pregnancy-Induced Hypertension.

Abstract

6 A rat model of pregnancy-induced hypertension (PIH) produced by chronic reductions in uterine perfusion pressure (RUPP) is associated with a significant elevation in mean arterial pressure and as previously reported by our laboratory, proteinuria and reductions in kidney function. The purpose of this study was to examine the role of endothelin in mediating the hypertension in response to chronic reductions in uterine perfusion pressure in conscious, chronically-instrumented pregnant rats. Mean arterial pressure in RUPP rats (n=7) was significantly higher (123.0 ± 0.8 vs 101.3 ± 1.5 mmHg) than control pregnant rats (n=8). Renal expression of preproendothelin was also significantly elevated (>45%, P<.05) in the medulla (44.1 ± 6.3 vs 24.0 ± 2.6 densitometric units, respectively) and in the cortex (>20%, 37.7 ± 2.4 vs 29.9 ± 2.8 densitometric units, respectively) of the RUPP animals as compared to normal pregnant animals. Chronic administration of the selective endothelin-A receptor antagonist (ABT-627, 5mg/kg/day for 10 days, n=9) markedly attenuated the increase in MAP observed in the RUPP animals (123.0 ± 0.8 mmHg in the RUPP animals vs. 103.3 ± 2.3 mmHg in RUPP animals with ET-A antagonist, P<.05). Endothelin-A receptor blockade had no significant effect on blood pressure in the normal pregnant animals (101.3 ± 1.5 mmHg in normal pregnant rats vs. 96.0 ± 0.9 mmHg in normal pregnant animals with ET-A antagonist, n=8). In summary, hypertension in the RUPP model of pregnancy-induced hypertension was associated with enhanced renal expression of preproendothelin. In addition, hypertension in the RUPP model of PIH was significantly attenuated by selective endothelin-A receptor blockade. These findings suggest that endothelin plays a major role in mediating the hypertension observed in this animal model of pregnancy-induced hypertension produced by chronic reductions in uterine perfusion pressure.