Blockade of Endothelin Receptors by Sulfisoxazole Improves Blood Pressure and Neuronal Norepinephrine Transporter Activity in DOCA-Salt Hypertension: Role of the Endoplasmic Reticulum Stress

The endoplasmic reticulum (ER) stress is triggered by the accumulation of unfolded or misfolded proteins in the lumen of the ER, caused by factors like calcium depletion, oxidative imbalance, or high cellular protein demand. Current evidence suggests that ER stress is involved in the onset of diverse cardiovascular diseases, including hypertension. We previously showed that in normotensive and hypertensive animals, endothelins (ETs) regulate norepinephrine transporter (NET) activity and expression through impaired calcium management and oxidative stress. In the present study we sought to establish whether the ER stress was involved in ETs-induced NET impairment in salt-dependent hypertension. Hypertension was induced in rats by DOCA injections and NaCl in the drinking water. At week 4, sulfisoxazole (dual ET receptor antagonist) was orally administered for seven days. Blood pressure and heart rate were weekly monitored. At the end of the experiment, the adrenal medulla was dissected to perform electron microscopy studies and to assess NET expression and activity, ER stress markers, and ER-dependent apoptosis. Hypertensive rats showed elevated systolic blood pressure, reduced NET activity and expression, and significant ultrastructural changes in the adrenal medulla compatible with ER stress that were reversed by sulfisoxazole administration. Markers of ER stress (Bip, pPERK, p-eIF2α, CHOP, XBP1and IRE-1) were enhanced in DOCA-salt rats but decreased by sulfisoxazole. Furthermore, increased ER-dependent apoptosis was attenuated by the ETA/ETB antagonist. Sulfisoxazole treatment reduced blood pressure and ER stress improving NET function. These findings suggest that NET impairment in DOCA-salt hypertension results from ET-induced ER stress and ER-dependent apoptosis.