Prenatal Endothelin or Thromboxane Receptor Antagonism Surpasses Sympathoinhibition in Managing Cardiovascular and Renal Malfunctions in Preeclamptic Rats

Abstract

Current therapies for hypertension and end-organ damage caused by preeclampsia (PE) are limited and defective. Considering the importance of endothelin (ET) and thromboxane A2 (TXA2) signaling in PE pathophysiology, we tested the hypothesis that pharmacologic blockade of ETA or TXA2 receptors improves preeclamptic cardiovascular and renal insults. PE was induced by daily oral administration of L-NAME (50 mg/kg) to pregnant rats for 7 consecutive days starting from gestational day 14. The effects of co-exposure to atrasentan (ETA receptor blocker, 10 mg/kg/day) or terutroban (TXA2 receptor blocker, 10 mg/kg/day) on cardiovascular and renal anomalies induced by PE were assessed at gestational day 20 (GD20) and weaning time and compared to those evoked by α-methyldopa (10 mg/kg/day), the prototypic drug for PE management. Among all 3 drugs, terutroban was basically the most potent in ameliorating PE-evoked increments in blood pressure and decrements in urine sodium and creatinine clearance. The gene expression of ETA, but not TXA2, receptors was significantly increased in cardiac and renal tissues of PE rats both at GD20 and weaning and these effects disappeared after co-treatment with individual protective drugs. By contrast, ETB receptor expression was reduced in PE renal tissues and restored back to non-PE levels by atrasentan, but not α-methyldopa or terutroban. Signs of histopathological damage in cardiac and renal tissues of PE rats were indiscriminately improved by all therapies. Together, pharmacologic elimination of ETA or TXA2 receptors offers a relatively better prospect than α-methyldopa in controlling perinatal cardiovascular and renal complications sparked by PE.