Central administration of corticotropin releasing hormone (CRH) elicits cardiovascular and sympathetic excitation in normal rats.In rats with heart failure (HF), CRH expression increases in paraventricular nucleus of hypothalamus (PVN), the central representation of the "stress response".We hypothesized that "stress" contributes to upregulation of the brain renin-angiotensin system (RAS) and the expression of inflammatory mediators in rats with ischemia-induced heart failure (HF).Lewis and Fischer 344 (Fischer)rats underwent coronary ligation to induce HF or sham and were studied 4 weeks later.As expected, immunohistochemistry revealed that Fischer but not Lewis HF rats had increased corticotropin releasing hormone (CRH)-positive neurons in hypothalamic paraventricular nucleus (PVN).Both Fischer and Lewis HF rats had more PVN neurons positive for Fra-LI (indicator of chronic neuronal activation), angiotensin converting enzyme (ACE), nuclear factor kappa B (NF-κB) activation marker p-IKKβ and interleukin (IL)-1β, and more ACE,angiotensin type 1 receptor (AT1-R), cyclooxygenase-2 (COX-2) and p-IKKβ protein by Western blot in hypothalamus, more in Fischer than Lewis rats.Treatment with bilateral PVN AT1-R blocker losartan reduced the increases in Fra-LI-, ACE-, p-IKKβ-and IL-1β-positive PVN neurons, PVN p-IKKβ protein, and plasma norepinephrine in Fischer and Lewis HF rats,more effectively in Lewis than Fischer rats.Thus, Lewis rats have impaired CRH, RAS and inflammatory responses to HF in hypothalamus and PVN.The results suggest either an increase in CRH is required for the full expression of brain RAS and the associated inflammatory responses, or Lewis rats have an innately compromised brain renin-angiotensin system.