Subject(s)
Myocardial Infarction , Myocardial Reperfusion Injury , Humans , Myocardium , NF-kappa B , TicagrelorABSTRACT
PURPOSE: We assessed the ability of Aliskiren (AL), a direct renin inhibitor, and Valsartan (VA), an angiotensin receptor blocker, to limit myocardial infarct size (IS) in mice with type-2 diabetes mellitus. METHODS: Db/Db mice, fed Western Diet, received 15-day pretreatment with: 1) vehicle; 2) AL 25 mg/kg/d; 3) AL 50 mg/kg/d; 4) VA 8 mg/kg/d; 5) VA 16 mg/kg/d; 6) AL 25+VA 16 mg/kg/d; or 7) AL 50+VA 16 mg/kg/d. Mice underwent 30 min coronary artery occlusion and 24 h reperfusion. Area at risk (AR) was assessed by blue dye and IS by TTC staining. Protein expression was assessed by immunobloting. RESULTS: IS in the control group was 42.9 ± 2.1% of the AR. AL at 25 (21.9 ± 2.9%) and 50 mg/kg/d (15.5 ± 1.3%) reduced IS. VA at 16 mg/kg/d (18.8 ± 1.2%), but not at 8 mg/kg/d (35.2 ± 4.0%), limited IS. IS was the smallest in the AL50+VA16 group (6.3 ± 0.9%). Both AL and VA reduced myocardial AT1R levels, without affecting AT2R levels, and increased the expression of Sirt1 and PGC-1α with increased phosphorylation of Akt and eNOS. CONCLUSIONS: AL, dose dependently limited myocardial IS in mice with type-2 diabetes mellitus. At doses shown to limit IS in non-diabetic animals, VA failed to reduce IS in Db/Db mice. However, at higher dose (16 mg/kg/d), VA reduced IS. Both drugs reduced the expression of AT1R and increased myocardial levels of the longevity genes Sirt1 and PGC-1α along with increased Akt and eNOS phosphorylation.
Subject(s)
Amides/therapeutic use , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Diabetes Mellitus, Experimental/complications , Fumarates/therapeutic use , Myocardial Infarction/prevention & control , Receptor, Angiotensin, Type 1/biosynthesis , Tetrazoles/therapeutic use , Valine/analogs & derivatives , Administration, Oral , Amides/administration & dosage , Angiotensin II Type 1 Receptor Blockers/administration & dosage , Animals , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/physiopathology , Drug Therapy, Combination , Fumarates/administration & dosage , Hemodynamics/drug effects , Immunoblotting , Male , Mice , Mice, Inbred Strains , Myocardial Infarction/etiology , Myocardial Infarction/metabolism , Myocardial Infarction/physiopathology , Myocardial Reperfusion Injury/etiology , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/physiopathology , Myocardial Reperfusion Injury/prevention & control , Renin/antagonists & inhibitors , Tetrazoles/administration & dosage , Valine/administration & dosage , Valine/therapeutic use , ValsartanABSTRACT
Neonatal hypoxia/ischemia (HI) is the most common cause of developmental neurological, cognitive and behavioral deficits in children, with hyperoxia (HHI) treatment being a clinical therapy for newborn resuscitation. Although cerebral edema is a common outcome after HI, the mechanisms leading to excessive fluid accumulation in the brain are poorly understood. Given the rigid nature of the bone-encased brain matter, knowledge of edema formation in the brain as a consequence of any injury, as well as the importance of water clearance mechanisms and water and ion homeostasis is important to our understanding of its detrimental effects. Knowledge of the pathological process underlying the appearance of dysfunctional outcomes after development of cerebral edema after neonatal HI in the developing brain and the molecular events triggered will allow a rational assessment of HHI therapy for neonatal HI and determine whether this treatment is beneficial or harmful to the developing infant.
