Ursodeoxycholic and chenodeoxycholic bile acids attenuate systemic and liver inflammation induced by lipopolysaccharide in rats.

Bacterial lipopolysaccharide (LPS) induces general inflammation, by activating pathways involving cytokine production, blood coagulation, complement system activation, and acute phase protein release. The key cellular players are leukocytes and endothelial cells, that lead to tissue injury and organ failure. The aim of this study was to explore the anti-inflammatory, antioxidant, and cytoprotective properties of two bile acids, ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) in LPS-induced endotoxemia in rats. The experiment involved six distinct groups of Wistar rats, each subjected to different pretreatment conditions: control and LPS groups were pretreated with propylene glycol, as a bile acid solvent, while the other groups were pretreated with UDCA or CDCA for 10 days followed by an LPS injection on day 10. The results showed that both UDCA and CDCA reduced the production of pro-inflammatory cytokines: TNF-α, GM-CSF, IL-2, IFNγ, IL-6, and IL-1ß and expression of nuclear factor-κB (NF-κB) induced by LPS. In addition, pretreatment with these bile acids showed a positive impact on lipid profiles, a decrease in ICAM levels, an increase in antioxidant activity (SOD, |CAT, GSH), and a decrease in prooxidant markers (H2O2 and O2-). Furthermore, both bile acids alleviated LPS-induced liver injury. While UDCA and CDCA pretreatment attenuated homocysteine levels in LPS-treated rats, only UDCA pretreatment showed reductions in other serum biochemical markers, including creatine kinase, lactate dehydrogenase, and high-sensitivity troponin I. It can be concluded that both, UDCA and CDCA, although exerted slightly different effects, can prevent the inflammatory responses induced by LPS, improve oxidative stress status, and attenuate LPS-induced liver injury.

The pressor response to acute hyperlipidemia is enhanced in lean normotensive offspring of hypertensive parents.

Family history is an important predictor of the cardiovascular risk factor cluster associated with insulin resistance. The dyslipidemia associated with insulin resistance may contribute to elevated blood pressure (BP). This study was undertaken to further explore the link between family history, dyslipidemia, and BP regulation. Twenty-three lean normal volunteers with a negative family history (FH-, n = 11) or positive family history (FH+, n = 12) of hypertension were evaluated under baseline conditions and during a 4-h infusion of intralipid and heparin (acute hyperlipidemia). Fasting blood was drawn for lipids including nonesterified fatty acids (NEFA). After 2 and 4 h of intralipid and heparin, blood was drawn for NEFA. The BP was measured at baseline and every 30 min after starting the intralipid and heparin infusion. Baseline triglycerides and very low density lipoprotein cholesterol concentrations were higher in FH+ than FH- subjects (P < .05). However, NEFA increased similarly in both groups during the infusion of intralipid and heparin. The BP and heart rate increased with acute hyperlipidemia in all subjects combined (P < .05). Despite the similar increase of NEFA, mean BP, pulse pressure, and pressure-rate product increased significantly in FH+ subjects but not in FH- volunteers with acute hyperlipidemia. Although systolic BP increased in both groups, the increase was greater in FH+ than in FH- volunteers during acute hyperlipidemia (14 +/- 2 v 10 +/- 2 mm Hg, P < .05). These results suggest that higher plasma lipids combined with a greater pressor response to hyperlipidemia may contribute to the development of high BP in subjects with a family history of hypertension.

Modification of the rate of aging of diisopropylfluorophosphate-inhibited neuropathy target esterase of hen brain.

This study was aimed to investigate the possibility of modifying the rate of aging of diisopropylfluorophosphate-inhibited neuropathy target esterase (NTE) of hen brain. This reaction on NTE occurs with a half-time of 7.4 min. Atropine was effective in decreasing the rate of aging on DFP-inhibited NTE and this effect was time- and concentration-dependent. Atropine was also a weak but progressive inhibitor of NTE activity (I50 = 80 mM) and this reaction appears to be reversible at lower atropine concentrations. Among compounds containing oxime functional groups only OPAB, having longer methylene chain and being more lipophylic than other oximes usually used in acetylcholinesterase (AChE) reactivation studies, was effective in decreasing the rate of aging on DFP-inhibited NTE. However, when atropine and oximes were used together we have obtained a potentiating and/or synergistic effect which was most significant with combination of atropine and TMB-4 giving up to a 15-fold decrease in the rate of aging reaction. The efficacy of this particular combination was concentration-dependent. We have also discussed similarities and differences in aging reaction occurring on NTE and AChE.

T-2 toxin affects proliferation of three different neoplastic cell lines.

The antiproliferative effect of T-2 toxin (T-2) towards mouse melanoma B16 cells, human myelogenous leukemia K562 cells, and human cervix carcinoma, HeLa cells, was studied. For the first four days of T-2 presence B16 cell survival was decreased in dose dependent fashion. However, cell survival after eleven days T-2 action may be dual: some stimulation of cell growth that was direct function of the number of seeded cells per well was observed and cell survival (for the highest number of seeded cells) six times greater than control, was noticed at 20 nM T-2 toxin concentration. A smaller cell growth stimulation (cell survival more than 3 times higher than control) was observed with a lower cell number seeded per well. Nevertheless, by eleventh day concentrations of T-2 higher than 35 nM completely inhibited B16 cell proliferation. The same trend was noticed for T-2 action towards K562 cells. Treatment of HeLa cells with various T-2 concentrations led to a marked inhibition of cell survival that was more pronounced at the end of 44th or 72nd hour, than after the 20th hour of agent's action. ICs50 values obtained in the present work, suggest that B16 cells were the most sensitive to T-2 antiproliferative action, while HeLa cells were the most resistant. When PBMC were cultured with HeLa cells the antagonism against various T-2 concentrations was observed; cell survival determined after 44, or 72 hours of cells incubation, was less decreased compared to cultures treated with T-2, or with PBMC only. In addition, it was shown that T-2 and cis-DDP had an antagonist effect on HeLa cells survival.

Moderate sodium restriction enhances the pressor response to hyperlipidemia in obese, hypertensive patients.

The effect of dietary sodium restriction on insulin, lipids, and blood pressure has been controversial. Evidence suggests that adverse short-term effects in response to very low-salt diets do not persist long-term with modest sodium restriction. In this study, the effects of modest dietary sodium restriction (60 and 120 mmol sodium) were measured for 3 weeks in 12 lean normotensives and 10 obese hypertensives. Blood pressure, plasma lipids, and the pressor response to an infusion of Intralipid and heparin were obtained. In contrast to previous reports concerning very low-salt diets, obese hypertensives did not manifest a pressor response or an adverse lipid effect with moderate salt restriction. Obese hypertensives were not more salt-sensitive than lean normotensives and did not manifest a different hemodynamic response to 4-hour infusion of Intralipid and heparin while on the 120-mmol/day salt diet. During the 60-mmol/day salt diet, however, plasma triglycerides increased more in obese than in lean volunteers during the Intralipid and heparin infusion (398+/-38 vs. 264+/-18 mg/dL; p<0.05), and there were greater increases in mean blood pressure (12+/-2 vs. 7+/-2 mm Hg; p<0.05) and systemic vascular resistance (111+/-38 vs. 225+/-44 dyne.sec.cm-5) as well as a larger decrease in small artery compliance (22.5+/-0.6 vs. 20.4+/-0.6 mL/mm Hg x 100; p<0.05). These data suggest that modest dietary sodium restriction in obese hypertensives does not adversely affect baseline blood pressure or lipids, but it does magnify their adverse lipid and hemodynamic response to fat loading.

[The effect of 4-aminopyridine on indirectly evoked contractions of the diaphragm in rats in situ]. / Uticaj 4-aminopiridina na indirektno izazvane kontrakcije dijafragme pacova in situ.

The aim of the present study was to investigate the influence of three doses of 4-aminopyridine (1, 3 and 10 mg/kg i.v.) on the amplitude of contraction of rat diaphragm indirectly stimulated by electrical impulses of various frequencies (0.1, 1, 10, 50 and 100 Hz). All the doses used significantly augmented the post-tetanic single twitch potentiation after stimulation with 100 Hz (by 35-40%). Doses of 3 and 10 mg/kg i.v. of 4-aminopyridine significantly increased the contractile response to the 10 Hz stimulation (by 73-77%), while only 3 mg/kg i.v. significantly (by 35-39%) increased the amplitude of initial single twitches. It is concluded that the 4-aminopyridine-induced blockade of presynaptic potassium channels caused potentiation of the indirectly evoked contractions of rat diaphragm in situ, which is both dose- and frequency-dependent.

[Esmolol--beta-adrenergic blocking agent with ultrashort action]. / Esmolol--novi beta adrenergicki blokator sa ultrakratkim delovanjem.

Esmolol is a new, highly efficient, cardioselective beta-adrenergic receptor blocking agent for intravenous use only. Its action commences rapidly and its duration is very short (about 15 min). It is very quickly metabolized in the body into an inactive product, and hence its therapeutic effect can be easily controlled. Indications for its use are supraventricular tachyarrhythmias and hypertension during the perioperative period and noncompensated sinus tachycardia. Esmolol is considered as drug of choice in its indicational domain and hence it is being introduced into materia medica in the increasing number of countries. Its therapeutic range is wide. Hypotension is the most frequent side effect of esmolol, while bradycardia, congestive heart failure, hypotension and cardiogenic shock are the most important contraindications for its use.

[Adverse effects and toxicity of beta blockers]. / Nezeljeni efekti i toksicnost beta blokatora.

The adverse effects and interactions as well as clinical manifestations and treatment of beta blocker overdosage are reviewed. The most common adverse effects of these drugs arise from their pharmacological action and can be predicted and avoided. The serious unexpected adverse effects, like the so-called "practolol syndrome", are rare and do not occur in asso- ciation with currently available beta blockers. Drug interactions with beta blockers are not very common and have only minor clinical significance. Beta blockers have an extremly high benefit/risk ratio. Most patients who take an overdose of beta blockers are successfully treated.

[The effect of preliminary administration of dimethylsulfoxide on the development of experimental myocardial necrosis in rats treated with isoprenaline]. / Dejstvo prethodne primjene dimetilsulfokcida na razvoj eksperimentalne nekroze miokarda kod pacova tretiranih izoprenalinom.

It has been suggested that in the genesis of isoprenaline-induced myocardial necrosis in rats, along with the intracellular calcium homeostasis and energy production breakdown, the mechanism of cytotoxic oxygen free radical generation is also included. The effects of dimethylsulphoxide, a hydroxyl radical scavenger, on the appearance of isoprenaline-induced myocardial necrosis in rats, were investigated. The verification of the efficacy of such pretreatment was based upon the monitoring of changes in plasma activity of enzymes creatine kinase, lactate dehydrogenase and alpha-hydroxybutyrate dehydrogenase, and upon the heart muscle sample light microscopy. The results have shown that the total plasma activity of all the observed enzymes was six hours after isoprenaline application several times increased, as compared with the control values. Histopathological changes in unprotected animals were evident and consisted of coagulation necrosis and myocytolysis. In both dimethylsulphoxide and isoprenaline treated groups of rats only a statistically insignificant increase in enzyme plasma activity was observed, while heart histopathological changes showed considerable reduction both in extensity and intensity of the tissue damage. The evident efficiency of dimethylsulphoxide in the prevention of the extent of myocardial necrosis in rats after the administration of the toxic dose of isoprenaline suggests that the generation of hydroxyl anion radicals, probably via autooxidation of isoprenaline, is a possible mechanism of the tissue injury in this experimental model.

[The effect of calcium antagonists on the cardiotoxic effects of isoprenaline in rats]. / Uticaj kalcijumskih antagonista na kardiotoksicne efekte izoprenalina u pacova.

Rats were pretreated with either verapamil or nifedipine five minutes prior to isoprenaline injection in order to prevent the development of myocardial necrosis which was verified by biochemical, electrophysiological and histological changes in the control animals. Verapamil embolised completely the elevation of creatine-kinase, lactate-dehydrogenase and alpha-hydroxybutyrate-dehydrogenase plasma activity, Q-waves and ST-segment elevations in ECG as well as the coagulation necrosis and myocytolysis. Nifedipine failed to exerts any protective effect, making the biochemical alteration even more pronounced.

[Efficacy of pretreatment with adrenergic beta-receptor blockers in the prevention of cardiotoxic effects of isoprenaline in rats]. / Efikasnost predtretmana blokatorima beta-adrenergickih receptora u suzbijanju kardiotoksicnih efekata izoprenalina u pacova.

Protective effects of beta-blockers, propranolol and atenolol, have been investigated in rats treated with cardiotoxic dose of isoprenaline. In saline-pretreated animals isoprenaline produced all morphological, biochemical and electrophysiological signs of myocardial necrosis: massive coagulation necrosis of cardiomyocytes, 2.6 to 3.5-fold increase of creatine-kinase, lactate-dehydrogenase and alpha-hydroxybutyrate-dehydrogenase plasma activity and Q-wave and ST-segment elevation in ECG. Both beta-blockers protected only partly the rats heart muscle from the cardionecrogenic action of isoprenaline while propranolol has been slightly more efficient, probably due to its combined beta-blocking and antiperoxidative activity.

[Cardiovascular effects of induction doses of the intravenous anesthetics, propofol, etomidate and thiopentone]. / Kardiovaskularni efekti indukcione doze intravenskih anestetika propofola, etomidata i tiopentona.

After reviewing the results of published comparative studies by numerous authors we have noticed that propofol, among the other intravenous anesthetics, has the strongest cardiovascular effects. The aim of this study was to compare the cardiovascular effects of induction doses of propofol, etomidate and thiopentone. A total of 165 female patients were randomly divided into three groups, and each one received a different anesthetic agent: propofol 2.5 mg/kg (n = 58), etomidate 0.3 mg/kg (n = 54) or thiopentone 5 mg/kg (n = 53). the patients were scheduled for abortion (gravidity up to 12 weeks of gestation) in out-patient conditions. Indirect registration of systolic and diastolic blood pressure and palpatory registration of radial pulse was performed: on admittance, immediately before the induction of anaesthesia and 2, 5 and 10 min thereafter. Following the administration of induction dose of propofol, a significantly greater decrease of systolic and diastolic blood pressure was observed then after the administration of etomidate or thiopentone. Slowing down of radial pulse was also more marked in propofol, then in etomidate or thiopentone group. The results of our study had shown that the induction dose of propofol had stronger effects on cardiovascular system, compared to the induction doses of etomidate or thiopentone.

[Adverse effects reported after inductive doses of the intravenous anesthetics, thiopentone, etomidate and propofol]. / Nezeljane dejstva registrovana posle indukcijske doze intravenskih anestetika tiopentona, etomidata i propofola.

It was confirmed that even 10 minutes long general anesthesia necessary for surgery can cause postoperative morbidity. This fact is of the utmost importance for the choice of anesthetics, especially when the operation is to take place in out-patient conditions. The aim of this study was to compare clinical efficacy, tolerability and adverse effects of thiopental, etomidate and propofol. The study comprised 165 out-patients scheduled for legal abortion under general intravenous anaesthesia. Patients were randomly divided into three groups. In patients from the first group (n = 53) anesthesia was induced with thiopental 5 mg/kg, in the second group (n = 54) with etomidate 0.3 mg/kg, and in the third group (n = 58) with propofol 2.5 mg/kg. Blood pressure, heart rate and adverse effects were monitored during anesthesia and operation and immediately thereafter. The best quality of anesthesia and the best working conditions of gynaecologist were after the use propofol, then after thiopental, followed by etomidate. Frequency of adverse effects was significantly greater after anesthesia with etomidate (26.06%), when compared to propofol (9.69%) and thiopental (9.09%). Immediately after induction to anesthesia, adverse effects were found after the use of thiopental, etomidate and propofol in 7.5%, 9.07% and 5.1% of patients, respectively. During anaesthesia, adverse effects were registered in 5.6%, 37.03% and 5.1% of patients in thiopental, etomidate and propofol group, respectively. In the same three groups, frequency of adverse effects in the immediate post-anesthetic recovery period was 15.09%, 62.09% and 17.06%, respectively. It could be concluded that in this study, out of the three anesthetics investigated, propofol had the greatest clinical efficacy and tolerability and the lowest incidence of adverse effects.

[Propofol and thiopentone in elective cesarean section: effect on the mother and neonate]. / Propofol i tiopenton kod elektivnog carskog reza: uticaj na majku i novorodjeno dete.

All the anesthetics used for induction of anesthesia in cesarean section cross the placenta and can induce neonatal depression. The aim of this investigation was to compare intravenous anesthetics propofol and thiopentone as induction agents in patients scheduled for elective cesarean section and studying of their affection of mothers and new-born children. A total of 40 female patients were scheduled for elective cesarean section. They were randomly divided in two equal groups, each of them was to receive different anesthetic: propofol 2.5 mg/kg (n = 20) or thiopentone 5 mg/kg (n = 20). Orotracheal intubation was facilitated with suxamethonium 1.5 mg/kg. Anesthesia was maintained by controlled ventilation with mixture of nitrous oxide and oxygen (50%:50%) and pancuronium 4 mg. After extraction of the foetus, anesthesia was maintained with mixture of nitrous oxide and oxygen (70%:30%), fentanyl 0.15-0.20 mg and pancuronium 1-2 mg. At the end of operation, competitive neuromuscular block was antagonised with neostigmine. There were no significant differences among the groups, as regards age, body weight and height, ASA classification grade and week of gestation. Following induction of anesthesia, a significantly greater decrease of blood pressure and heart rate was found in the propofol group, when compared with the patients in thiopentone group. During the induction and maintenance of anesthesia, the frequency of adverse effects was greater in thiopentone, than in propofol group (6/20 versus 2/20 patients). There was no significant difference between the groups when induction-delivery (l-D) interval was concerned. The new-borns from the propofol group had significantly higher Apgar score in the 1st minute (8.35) and 5th minute (9.25), than the new-borns in thiopentone group (7.90 and 8.90, respectively).

Hemodynamic effects of lipids in humans.

Evidence suggests lipid abnormalities may contribute to elevated blood pressure, increased vascular resistance, and reduced arterial compliance among insulin-resistant subjects. In a study of 11 normal volunteers undergoing 4-h-long infusions of Intralipid and heparin to raise plasma nonesterified fatty acids (NEFAs), we observed increases of blood pressure. In contrast, blood pressure did not change in these same volunteers during a 4-h infusion of saline and heparin. To better characterize the hemodynamic responses to Intralipid and heparin, another group of 21 individuals, including both lean and obese volunteers, was studied after 3 wk on a controlled diet with 180 mmol sodium/day. Two and four hours after starting the infusions, plasma NEFAs increased by 134 and 111% in those receiving Intralipid and heparin, P < 0.01, whereas plasma NEFAs did not change in the first group of normal volunteers who received saline and heparin. The hemodynamic changes in lean and obese subjects in the second study were similar, and the results were combined. The infusion of Intralipid and heparin induced a significant increase in systolic (13.5 +/- 2.1 mmHg) and diastolic (8.0 +/- 1.5 mmHg) blood pressure as well as heart rate (9.4 +/- 1.4 beats/min). Small and large artery compliance decreased, and systemic vascular resistance rose. These data raise the possibility that lipid abnormalities associated with insulin resistance contribute to the elevated blood pressure and heart rate as well as the reduced vascular compliance observed in subjects with the cardiovascular risk factor cluster.