Severity of Symptoms of Systemic Inflammatory Response Syndrome and Congestive Heart Failure Caused by Chronic Aortic Stenosis and Its Pharmacological Correction

Systemic inflammatory response syndrome (SIRS) is one of the key accompanied states that worsens severity of congestive heart failure (CHF) and leads refractory CHF to conventional therapy. We investigated whether the cessation of the symptoms and signs of SIRS prevents the progression of the CHF caused by chronic aortic stenosis in rabbits. 8 weeks after induced CHF by left descending coronary artery stenosis, all animals were randomly assigned into 3 groups: control (CG)—without therapy (infusion of 0.9% NaCl);main I— receive mg/kg of Adenocin®dissolved in water for injection i.v., once daily and main II—animals receive 0.25 mg/kg enalapril i.m, furosemide 1.0 mg/kg i.v. (bolus) and pimobendan 0.1 mg/kg i.v. once daily. All animals were euthanized after 14 days of the beginning of treatment. Long-term aortic stenosis leads to a simultaneously developing of CHF, diagnosed by developing cardiac hypertrophy, increased level of BNP and myocardial oedema and SIRS, confirmed by increasing markers and symptoms of endotoxemia, tissue dysoxia and decreasing reserve ability of intrinsic defense systems. Restoration of myocardium redox-potential and level of NAD under treatment with Adenocin®leads unlike combined treatment with enalapril, furosemide and pimobendan to restoration, the regulatory pathways of TNF-α synthesis, cessation of the hypoxic/ischemic, lysosomal dysfunction and free radical-induced damage in myocardium and symptoms of CHF. Potential important link between cellular metabolism (hypoxia/ischemia), endotoxemia and disturbances in intrinsic defense system is the level of redox-potentail, NAD/NADH in myocardium. Influence of oxidized form of NAD-containing positive inotropic drug Adenocin®leads to the decreasing symptoms of CHF and beneficial action occurs on all the key links of SIRS.

Deterioration in Hemodynamics Reaction, Baroreflex Sensitivity, Sympathetic Nerve Activity and Redox State of Thoracic Aorta in the Experimental Model of Nitrate Tolerance and Its Pharmacological Correction

Continuous treatment with organic nitrates causes nitrate tolerance and provides evidence for a relationship between mitochondrial complex 1 activity and mitochondrial aldehyde dehydrogenase-2 (ALDH-2) with disturbances of the hemodynamics reaction during nitroglycerin (NTG) tolerance (NTGT). The purpose of this study was the evaluation of efficacy of original oxidized form NAD-containing drug, NADCIN®, on hemodynamic reactions, baroreflex sensitivity (BRS) and reflex control of splanchnic sympathetic nerve activity (SSNA), level of redox-potential, activity of ALDH-2 and superoxide anion generation in aortic tissue in rat model of NTGT. Five groups (7 - 9 each) of male Wistar rats, including control, acute i.v. NTG (150 mcg/kg) administration, NTG tolerance NTGT treatment with NADCIN® 8 mg/kg and methylene blue (MB, 2.5 mg/kg) were used. NTGT in rats was accompanied with the greatly attenuation of hemodynamics reaction, BRS, the decreasing of the ability to reflex control of SSNA without pronounce overexpression of endothelin-1 in vessels (aorta). In NTGT rats i.v. NTG along induced less hypotensive reactions and alterations in heart period vs single NTG treated group, more expressively decreased BRS (-34%) and reflex control of SSNA (-18%). NADCIN® significantly inhibits tolerance-inducing properties of the prolonged nitroglycerin infusion (max decrease of blood pressure response to nitroglycerin injection, % of normal controls: NTGT 51.2%, NADCIN® 91.6%, MB 55.8%). NADCIN® in NTGT rats after NTG i.v. administration increased reduced BRS (+37.8%, p < 0,05), reflex control of SSNA (+29.4%, p < 0.05) and reversed the decreasing of NAD/NADH ratio, ALDH-2 activity and decreasing in superoxide generation in thoracic aortic tissue. Thus, course treatment with NADCIN® of NTGT rats restores hemodynamics changes, BRS and SSNA throughout the increasing of redox-potential NAD/NADH and cessates the NTGT developing.