Controlled hypotensive Hemorrhage sensitizes angiotensin II‐elicited hypertension

Abstract

Hemorrhagic shock is associated with increased renin‐angiotensin system (RAS) activity and elevated levels of proinflammatory cytokines (PICs) in the circulation and in central nervous system (CNS) regions controlling arterial pressure and vasopressin release. Using an Induction‐Delay‐Expression (IND‐DEL‐EXP) experimental paradigm, our previous studies demonstrated that activation of the central RAS and inflammation produced by various challenges sensitizes angiotensin (ANG) II‐elicited hypertension. The present study tested the hypothesis that controlled hypotensive hemorrhage also sensitizes the ANG II‐elicited hypertensive response. Male rats were prepared for telemetry recording of blood pressure (BP). During IND, rats were hemorrhaged (5 ml/rat at 1.5 ml/min) via the jugular vein on two occasions separated by 1 day. The blood was collected in heparin and centrifuged, and the cells re‐suspended in saline for re‐infusion. Hemorrhage lowered BP to ~40 mmHg that was maintained for 30 min after which time the rats were reinfused. After a one‐week DEL, the rats were administrated ANG II (120 ng/kg/min, SC) for 2 weeks (EXP). Hemorrhaged rats had a significantly enhanced hypertensive response to the ANG II infusion when compared to control rats (Δ52.3±3.8 mmHg vs. Δ29.8±2.8 mmHg). RT‐PCR analysis of tissue from the lamina terminalis and the hypothalamic paraventricular nucleus indicated that the ANG II treatment upregulated mRNA expression of several components of the RAS and PICs including angiotensinogen, angiotensin type 1 receptor, angiotensin converting enzyme, TNF‐α, interleukin (IL)‐1β and IL‐6 in both control and hemorrhaged rats. Notably, the increases in PIC expression were greater in hemorrhaged rats than that in control rats. The results indicate that controlled hypotensive hemorrhage sensitizes ANG II‐elicited hypertension and that this is associated with upregulation of the central RAS and of brain PICs.Support or Funding InformationNIH grants HL‐14388, HL‐98207 and MH‐80241