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.

Influence of stress on the expression of bcl-2/bax protein in spontaneously hypertensive rats

Objective To explore the influence of stress induced increased sympathetic nerve activity on cardiomyocyte apoptosis and on the development of congestive heart failure. Methods 45 male, 16 week old spontaneously hypertensive rats (SHRs) were studied, in which 6 as controls. After the 6 controlled SHRs were examined by echocardiography, they were anesthetized and killed by decapitation. The other 39 were divided into the stress group (n=20) and the control group (n=19), and both groups were observed from 16 week old to 36 week old. In the stress group, binding-stress model was used. Till 36 week, all animals were echocardiographied, weighed and killed as described above. Cardiac bcl 2 and bax protein were quantified by western blot. Circulating catecholamine and angiotensin II (Ang II) were detected by radioimmunoasssy. Results Left ventricular volume (P< 0.05), left ventricular mass (P< 0.05) and the ratio of ventricular mass to body weight were higher in 36 week than those of the 16 week SHRs, whereas the volumes of eject fraction (EF) manifested the trend of decline, P< 0.05, binding stress for 20 weeks made this trend significantly, P< 0.05. With the increase of age, the serum norepinephrine (NE), epinephrine (E) and Ang II increased, suggesting that the binding-stress triggered the activity of central sympathetic nerve system. The cardiac bcl 2 protein was higher in 36 week than 16 week, P >0.05, whereas the bax protein increased significantly with the increase of age, P< 0.05, and so was the ratio of bax to bcl 2, P< 0.05. Conclusions The model of binding stress can effectively activate central sympathetic system, thus and mimic the neuroendocrine states. From 16 to 36 week, the process of cardiac apoptosis aggravated and the increased sympathetic activity would exacerbate rather than relieve this trend.