salicylates and Hypertension--Pulmonary

Topics: Animals; Blood Circulation; Ductus Arteriosus; Female; Fetal Blood; Fetus; Humans; Hypertension, Pulmonary; Indomethacin; Infant; Infant, Newborn; Maternal-Fetal Exchange; Oxygen; Papillary Muscles; Pregnancy; Prostaglandins; Pulmonary Circulation; Salicylates; Species Specificity; Tricuspid Valve; Vascular Resistance

Patients with pulmonary hypertension (PH) suffer from inspiratory insufficiency, which has been associated with intrinsic contractile dysfunction in diaphragm muscle. Here, we examined the role of redox stress in PH-induced diaphragm weakness by using the novel antioxidant, EUK-134. Male Wistar rats were randomly divided into control (CNT), CNT + EUK-134 (CNT + EUK), monocrotaline-induced PH (PH), and PH + EUK groups. PH was induced by a single intraperitoneal injection of monocrotaline (60 mg/kg body weight). EUK-134 (3 mg/kg body weight/day), a cell permeable mimetic of superoxide dismutase (SOD) and catalase, was daily intraperitoneally administered starting one day after induction of PH. After four weeks, diaphragm muscles were excised for mechanical and biochemical analyses. There was a decrease in specific tetanic force in diaphragm bundles from the PH group, which was accompanied by increases in: protein expression of NADPH oxidase 2/gp91phox, SOD2, and catalase; 3-nitrotyrosine content and aggregation of actin; glutathione oxidation. Treatment with EUK-134 prevented the force decrease and the actin modifications in PH diaphragm bundles. These data show that redox stress plays a pivotal role in PH-induced diaphragm weakness. Thus, antioxidant treatment can be a promising strategy for PH patients with inspiratory failure.

Topics: Actins; Animals; Antioxidants; Biomimetic Materials; Catalase; Diaphragm; Disease Models, Animal; Glutathione; Hypertension, Pulmonary; Male; Monocrotaline; Muscle Contraction; Muscle Weakness; Organometallic Compounds; Oxidative Stress; Rats; Rats, Wistar; Salicylates; Superoxide Dismutase

Gene expression profiles of Sprague-Dawley (SD) rats treated with a standardized willow bark extract (WB), its salicin rich ethanol fraction (EtOH-FR) or the tricyclic antidepressant imipramine were evaluated for their potential to induce adverse events. Treatments had shown antidepressant-like effects.. Gene expression profiles (Agilent Whole Genome Array, n=4/group) obtained from the peripheral blood of male SD rats treated with WB (STW 33-I), EtOH-FR (30 mg/kg bw) or imipramine (20 mg/kg bw) were analysed comparatively by the Ingenuity Systems Programme, which allows to conduct model calculations of thresholds for theoretical potential adverse events (AE).. The number of genes regulated by the three treatments were 1673 (WB), 117 (EtOH-FR) and 1733 (imipramine). The three treatments related to 47 disease clusters. The WB extract reached the threshold for a potential AE in one disease cluster (cardiac hypertrophy), whereas the EtOH-FR exceeded the threshold in 5 disease clusters (cardiac arteriopathy and stenosis, glomerular injury, pulmonary hypertension, alkaline phosphatase levels ⇑). Imipramine treatment hit 13 disease clusters: tachycardia, palpitation, myocardial infarction, arrhythmias, heart block, precipitation of congestive heart failure; urinary retention, altered liver functions. Those correspond to known potential adverse events. Glomerular injury and altered liver functions are part of the side effect profile of salicylic acid derivatives in agreement with the findings for the salicin rich EtOH-FR.. There is no linear relationship between the number of constituents of a drug (preparation) and the number of different targets hit in a biological system on the gene expression level. Therefore, the number of genetic targets in a biological system does not necessarily increase with the complexity of the treatment corresponding to the non-linear behaviour of biological systems. Regarding gene expression levels AE of single treatments are not necessarily additive in combination treatments. The applied method appears to be an interesting screening tool for the prediction of potential AE. The phenomena that imipramine crossed the potential threshold for AEs several times whereas the WB extract did reach the threshold level only once, however not backed by clinical data for this AE, deserves to be further investigated. It questions the commonly assumed principle that substances with low number or without AE will have a poor efficacy.

Topics: Animals; Antidepressive Agents, Tricyclic; Benzyl Alcohols; Chemical and Drug Induced Liver Injury; Ethanol; Gene Expression Profiling; Gene Expression Regulation; Glucosides; Heart Diseases; Hypertension, Pulmonary; Imipramine; Male; Nephritis; Phytotherapy; Plant Bark; Plant Extracts; Rats; Rats, Sprague-Dawley; Salicylates

ROS have been implicated in the development of pathological ventricular hypertrophy and the ensuing contractile dysfunction. Using the rat monocrotaline (MCT) model of pulmonary arterial hypertension (PAH), we recently reported oxidative stress in the failing right ventricle (RV) with no such stress in the left ventricle of the same hearts. We used the antioxidant EUK-134 to assess the role of ROS in the pathological remodeling and dysfunction of the RV. PAH was induced by an injection of MCT (80 mg/kg, day 0), treatment with EUK-134 (25 mg/kg, once every 2 days) of control and MCT-injected animals [congestive heart failure (CHF) group] was started on day 10, and animals were analyzed on day 22. EUK-134 treatment of the CHF group attenuated cardiomyocyte hypertrophy and associated changes in mRNA expression (myosin heavy chain-beta and deiodinase type 3). It also reduced RV oxidative stress and proapoptotic signaling and prevented interstitial fibrosis. Cardiac MRI showed that ROS scavenging did not affect the 37% increase in end-diastolic volume of the RV in the CHF relative to the control group, but the threefold increase in end-systolic volume was reduced by 42% in the EUK-134-treated CHF group. The improved systolic function was confirmed using echocardiography by an assessment of tricuspid annular plane systolic excursion. These data indicate an important role of ROS in RV cardiomyocyte hypertrophy and contractile dysfunction due to PAH and show the potential of EUK-class antioxidants as complementary therapeutics in the treatment of RV dysfunction in PAH.

Topics: Animals; Antioxidants; Disease Models, Animal; Heart Failure; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Monocrotaline; Organometallic Compounds; Rats; Rats, Wistar; Reactive Oxygen Species; Salicylates; Ventricular Dysfunction, Right; Ventricular Remodeling

The data implicating prostaglandin synthesis inhibitors as an etiology for PPHN are reviewed. Consideration is given to the pharmacology of prostaglandin synthesis inhibitors in the fetus and newborn, the role of prostaglandins in the fetal and neonatal circulation, and the effect of closure of the ductus arteriosus on the fetal pulmonary vasculature.

Topics: Animals; Blood Pressure; Ductus Arteriosus, Patent; Female; Fetus; Humans; Hypertension, Pulmonary; Indomethacin; Infant, Newborn; Lung; Naproxen; Persistent Fetal Circulation Syndrome; Pregnancy; Prostaglandins; Pulmonary Circulation; Salicylates; Sheep; Vasoconstriction