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      Effect of aminoguanidine on cardiovascular responses and survival time during blood loss: A study in normotensive and deoxycorticosterone acetate-salt hypertensive rats

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          Hemorrhagic shock causes more circulatory disturbances and mortality in hypertensive than normotensive subjects. In the late phase of hemorrhagic shock, nitric oxide (NO) overproduction leads to vascular decompensation. In this study, we evaluated the effect of inducible NO synthase (iNOS) inhibitor, aminoguanidine (AG), on hemodynamic parameters and serum nitrite concentration in decompensated hemorrhagic shock model in normotensive and hypertensive male rats.

          Materials and Methods:

          Twenty-four male rats were divided into hypertensive and normotensive groups ( n = 12 each). Hypertension was induced by subcutaneous injection of deoxycorticoesterone acetate (DOCA), 30 mg/kg in uninephrectomized rats. Decompensated hemorrhagic shock was induced by withdrawing blood until the mean arterial pressure (MAP) reached 40 mmHg. After 120 min, each group was assigned to aminguanidine (100 mg/kg) and control group. Hemodynamic parameters were monitored for next 60 min. Blood samples were taken before and after shock period and 60 min after treatment. Survival rate was monitored for 72 h.


          Infusion of AG in normotensive animals caused a transient increase in MAP and increase of heart rate, whereas it did not affect those parameters in hypertensive animals. Hemorrhagic shock caused a significant rise in serum nitrite concentration in normotensive and hypertensive rats and infusion of AG did not significantly change it in both groups. No significant differences observed in survival rate between AG-treated and not treated groups.


          It seems that inhibition of iNOS with AG does not have beneficial effects on hemodynamatic parameters and survival rate during decompensated hemorrhagic shock in normotensive and hypertensive animals.

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          Most cited references 30

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          Nitric oxide and oxidative stress in vascular disease.

          Endothelium-derived nitric oxide (NO) is a paracrine factor that controls vascular tone, inhibits platelet function, prevents adhesion of leukocytes, and reduces proliferation of the intima. An enhanced inactivation and/or reduced synthesis of NO is seen in conjunction with risk factors for cardiovascular disease. This condition, referred to as endothelial dysfunction, can promote vasospasm, thrombosis, vascular inflammation, and proliferation of vascular smooth muscle cells. Vascular oxidative stress with an increased production of reactive oxygen species (ROS) contributes to mechanisms of vascular dysfunction. Oxidative stress is mainly caused by an imbalance between the activity of endogenous pro-oxidative enzymes (such as NADPH oxidase, xanthine oxidase, or the mitochondrial respiratory chain) and anti-oxidative enzymes (such as superoxide dismutase, glutathione peroxidase, heme oxygenase, thioredoxin peroxidase/peroxiredoxin, catalase, and paraoxonase) in favor of the former. Also, small molecular weight antioxidants may play a role in the defense against oxidative stress. Increased ROS concentrations reduce the amount of bioactive NO by chemical inactivation to form toxic peroxynitrite. Peroxynitrite-in turn-can "uncouple" endothelial NO synthase to become a dysfunctional superoxide-generating enzyme that contributes to vascular oxidative stress. Oxidative stress and endothelial dysfunction can promote atherogenesis. Therapeutically, drugs in clinical use such as ACE inhibitors, AT(1) receptor blockers, and statins have pleiotropic actions that can improve endothelial function. Also, dietary polyphenolic antioxidants can reduce oxidative stress, whereas clinical trials with antioxidant vitamins C and E failed to show an improved cardiovascular outcome.
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            Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension.

            Tetrahydrobiopterin is a critical cofactor for the NO synthases, and in its absence these enzymes become "uncoupled," producing reactive oxygen species (ROSs) rather than NO. In aortas of mice with deoxycorticosterone acetate-salt (DOCA-salt) hypertension, ROS production from NO synthase is markedly increased, and tetrahydrobiopterin oxidation is evident. Using mice deficient in the NADPH oxidase subunit p47(phox) and mice lacking either the endothelial or neuronal NO synthase, we obtained evidence that hypertension produces a cascade involving production of ROSs from the NADPH oxidase leading to oxidation of tetrahydrobiopterin and uncoupling of endothelial NO synthase (eNOS). This decreases NO production and increases ROS production from eNOS. Treatment of mice with oral tetrahydrobiopterin reduces vascular ROS production, increases NO production as determined by electron spin resonance measurements of nitrosyl hemoglobin, and blunts the increase in blood pressure due to DOCA-salt hypertension. Endothelium-dependent vasodilation is only minimally altered in vessels of mice with DOCA-salt hypertension but seems to be mediated by hydrogen peroxide released from uncoupled eNOS, since it is inhibited by catalase. Tetrahydrobiopterin oxidation may represent an important abnormality in hypertension. Treatment strategies that increase tetrahydrobiopterin or prevent its oxidation may prove useful in preventing vascular complications of this common disease.
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              High-mobility group box 1 (HMGB1) protein: friend and foe.

              HMGB1 was originally identified as a DNA-binding protein that functions as a structural co-factor critical for proper transcriptional regulation in somatic cells. Recent studies indicate that HMGB1 can be "passively released" into the extracellular milieu by necrotic and damaged somatic cells. Extracellular HMGB1 represents an optimal "necrotic marker" selected by the innate immune system to recognize tissue damage and initiate reparative responses. HMGB1 in the extracellular milieu promotes maturation of myeloid and plasmacytoid dendritic cells, and induces myocardial regeneration after infarction. However, extracellular HMGB1 also acts as a potent pro-inflammatory cytokine that contributes to the pathogenesis of diverse inflammatory and infectious disorders. A growing number of studies indicate that HMGB1 is a successful therapeutic target in experimental models of ischemia/reperfusion, acute respiratory distress syndrome, rheumatoid arthritis, sepsis, and cancer. From a clinical perspective, HMGB1 represents a current challenge that can be exploited orchestrate reparative responses while preventing its pathological potential. This article focus on the immuno-regulatory role of HMGB1 and its contribution to infectious and inflammatory disorders.

                Author and article information

                Department of Physiology, Zabol University of Medical Sciences, Zabol, Iran
                [1 ]Department of Physiology, Isfahan University of Medical Sciences, Isfahan, Iran
                [2 ]Department of Physiology, Mashhad University of Medical Sciences, Mashhad, Iran
                Author notes
                Address for correspondence: Dr. Majid Khazaei, Department of Physiology, Isfahan University of Medical Sciences, Hezar Jarib Ave., Isfahan, Iran. E-mail: khazaei@
                Int J Appl Basic Med Res
                Int J Appl Basic Med Res
                International Journal of Applied and Basic Medical Research
                Medknow Publications & Media Pvt Ltd (India )
                Jan-Apr 2015
                : 5
                : 1
                : 12-17
                Copyright: © International Journal of Applied and Basic Medical Research

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Original Article

                nitric oxide, hypertension, hemorrhagic shock


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