Abstract
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 ® of NTGT rats restores hemodynamics changes, BRS and SSNA throughout the increasing of redox-potential NAD/NADH and cessates the NTGT developing.
Highlights
Organic nitrates and nitroglycerin in has long been one of the key medicines for cardiovascular diseases including coronary artery disease, acute myocardial infarction and congestive heart failure for more than 100 years
Acute single dose of NTG (150 mcg/kg i.v) administration was accompanied with significant hypotensive reactions in non-tolerance normal rats and in group treated with NADCIN
Our experiments showed that in NTG tolerant rats baroreflex sensitivity (BRS) was greatly attenuated with reduction of its cardiochronotropic vagal component that correlated with decreased ability to cause reflex bradycardia and an inhibition of splanchnic sympathetic nerve activity (SSNA)
Summary
Organic nitrates and nitroglycerin (glyceryl trinitrate, GTN) in has long been one of the key medicines for cardiovascular diseases including coronary artery disease, acute myocardial infarction and congestive heart failure for more than 100 years. Propose mechanisms include neurohormonal counterregulatory mechanisms to maintain blood pressure [2], increased production of superoxide anions [3]-[5] and oxidative stress as a result, reduced biotransformation of NTG to NO, and alterations in cyclic GMP metabolism [6], endothelial dysfunction, inhibition of nitroglycerin metabolizing enzyme, changes in GNT-signaling or endogenous active substances, and so on [7]. It is likely that prolonged exposure to GTN tolerance manifested as increased ROS generation accompanied by alterations in NAD+ availability and/or altered NADH/NAD+ ratio, might provoke conformational (and other) changes in ALDH-2 undermining its activity [11] [12]. The aim of the study was to investigated the ability of original reduced form NAD-containing drug, NADCIN 1 [13], on the hemodynamic reactions, baroreflex sensitivity, reflex control of sympathetic nerve activity and level of redox-potential, NAD/NADH and NADP/NADPH and ALDH activity in thoracic aorta tissue in nitroglycerin-induced tolerant rats
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