Valsartan ameliorates hypothalamic indicators of inflammation and stress in Lewis and Fischer rats with ischemia‐induced heart failure

Abstract

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 (L) and Fischer 344 (F) rats underwent coronary ligation to induce HF (EF: F, 44.2±8.9%; L, 43.6±6.9%) or sham and were studied 6 weeks later. As expected, immunohistochemistry revealed that F but not L HF rats had increased (P<0.05, vs SHAM) corticotropin releasing hormone (CRH)-positive neurons in hypothalamic paraventricular nucleus (PVN). Both F and L HF rats had more (P<0.05, vs SHAM) PVN neurons positive for Fra-LI (indicator of chronic activation), angiotensin converting enzyme (ACE), cyclooxygenase (COX)-2, nuclear factor kappa B (NF-κB) p50 and interleukin (IL)-1β, and more (P<0.05, vs SHAM) ACE, angiotensin type 1 receptor (AT1-R), COX-2 and NF-κB p50 protein by Western blot in hypothalamus, more (P<0.05) in F than L. Treatment with AT1-R blocker valsartan (VAL, 30 mg/kg/day orally) reduced (P<0.05) the increases in Fra-LI-, ACE-, NF-κB p50- and IL-1β- positive PVN neurons, hypothalamic NF-κB p50 protein, and plasma norepinephrine in F and L HF rats, more effectively (P<0.05) in L than F. Thus, L rats have impaired CRH, RAS and inflammatory responses to HF in hypothalamus and PVN. The results suggest one of two interpretations: either an increase in CRH is required for the full expression of brain RAS and the associated inflammatory responses, or L rats have an innately compromised brain RAS.