Hemorrhagic shock is associated with activation of renin-angiotensin system (RAS) and endoplasmic reticulum stress (ERS). Previous studies demonstrated that central RAS activation produced by various challenges sensitizes
angiotensin (Ang) II-elicited
hypertension and that ERS contributes to the development of neurogenic
hypertension. The present study investigated whether controlled
hemorrhage could sensitize Ang II-elicited
hypertension and whether the brain RAS and ERS mediate this sensitization. Results showed that hemorrhaged (HEM) rats had a significantly enhanced hypertensive response to a slow-pressor infusion of Ang II when compared to
sham HEM rats. Treatment with either
angiotensin-converting enzyme (ACE) 1 inhibitor,
captopril, or ACE2 activator,
diminazene, abolished the HEM-induced sensitization of
hypertension. Treatment with the ERS agonist,
tunicamycin, in
sham HEM rats also sensitized Ang II-elicited
hypertension. However, blockade of ERS with
4-phenylbutyric acid in HEM rats did not alter HEM-elicited sensitization of
hypertension. Either HEM or ERS activation produced a greater reduction in BP after ganglionic blockade, upregulated
mRNA and
protein expression of ACE1 in the hypothalamic paraventricular nucleus (PVN), and elevated plasma levels of Ang II but reduced
mRNA expression of the Ang-(1-7) receptor, Mas-R, and did not alter plasma levels of Ang-(1-7). Treatment with
captopril or
diminazene, but not phenylbutyric
acid, reversed these changes. No treatments had effects on PVN
protein expression of the ERS marker
glucose-regulated
protein 78. The results indicate that controlled
hemorrhage sensitizes Ang II-elicited
hypertension by augmenting RAS prohypertensive actions and reducing RAS
antihypertensive effects in the brain, which is independent of ERS mechanism.