Modeling regulation of cardiac KATP and L-type Ca2+ currents by ATP, ADP, and Mg2+

Changes in cytosolic free Mg(2+) and adenosine nucleotide phosphates affect cardiac excitability and contractility. To investigate how modulation by Mg(2+), ATP, and ADP of K(ATP) and L-type Ca(2+) channels influences excitation-contraction coupling, we incorporated equations for intracellular ATP and MgADP regulation of the K(ATP) current and MgATP regulation of the L-type Ca(2+) current in an ionic-metabolic model of the canine ventricular myocyte. The new model: 1), quantitatively reproduces a dose-response relationship for the effects of changes in ATP on K(ATP) current, 2), simulates effects of ADP in modulating ATP sensitivity of K(ATP) channel, 3), predicts activation of Ca(2+) current during rapid increase in MgATP, and 4), demonstrates that decreased ATP/ADP ratio with normal total Mg(2+) or increased free Mg(2+) with normal ATP and ADP activate K(ATP) current, shorten action potential, and alter ionic currents and intracellular Ca(2+) signals. The model predictions are in agreement with experimental data measured under normal and a variety of pathological conditions.     

The immuno-microbiological characteristics of the small intestine and the translocation of the enteral microflora in acute intestinal obstruction

The complex examination of 72 patients with acute ileus (AI) of nontumor nature with different severity of endotoxicosis was carried out. The study revealed that AI was accompanied by deep suppression of the immunosecretory and motor evacuatory function of the small intestine, as well as by its pronounced bacterial contamination, mainly due to the significant quantitative prevalence of Gram-negative microflora. The combination of these factors played the key role in the increase of the permeability of the enteric barrier for symbiotic microflora and its massive translocation from the intestinal tract to the internal organs of the body (peritoneal exudate, portal bed), which directly correlated with the severity of endotoxicosis in AI patients. The deficiency of the barrier function of the liver was accompanied by the penetration of infective agents into the general blood stream, thus causing the development of endotoxic shock in AI patients. The analysis of the results thus obtained made it possible to determine the main ways for the elimination of intestinogenic intoxication in AI; they should be aimed at the bacterial decontamination of the small intestine, the restoration of its motor evacuatory and protective barrier functions, the liquidation of portal and systemic bacteremia, the correction of the functional deficiency of the liver.     

Effect of budesonide and salbutamol on surfactant properties.

The objective of this study was to evaluate the in vitro effect of budesonide and salbutamol on the surfactant biophysical properties. The surface-tension properties of two bovine lipid extracts [bovine lipid extract surfactant (BLES) and Survanta] and a rat lung lavage natural surfactant were evaluated in vitro by the captive bubble surfactometer. Measurements were obtained before and after the addition of a low and high concentration of budesonide and salbutamol. Whereas salbutamol had no significant effect, budesonide markedly reduced the surface-tension-lowering properties of all surfactant preparations. Surfactant adsorption (decrease in surface tension vs. time) was significantly reduced (P < 0.01) at a high budesonide concentration with BLES, both concentrations with Survanta, and a low concentration with natural surfactant. At both concentrations, budesonide reduced (P < 0.01) Survanta film stability (minimal surface vs. time at minimum bubble volume), whereas no changes were seen with BLES. The minimal surface tension obtained for all surfactant preparations was significantly higher (P < 0.01), and the percentage of film area compression required to reach minimum surface tension was significantly lower after the addition of budesonide. In conclusion, budesonide, at concentrations used therapeutically, adversely affects the surface-tension-lowering properties of surfactant. We speculate that it may have the same adverse effect on the human surfactant.     

Trisomy for distal segments of the long arm of chromosome 1

Clinical genetic analysis of distal trisomies 1q, based on the study of a t(1; 6) (q42.1; p24) family and the literature data, was performed. It was demonstrated that phenotypical manifestations of the trisomy are formed by nonspecific anomalies, due to imbalance as such, and by rather specific anomalies caused by triplication of a "critical segment". 1q42-1qter appeared to be such a segment for distal trisomy 1q.     

Soluble guanylate cyclase-dependent relaxation is reduced in the adult rat bronchial smooth muscle

Cyclic nucleotides are relaxants of the airway smooth muscle, yet most of the available data were obtained in adult animals. The expression and activity of cyclases have been reported to be developmentally regulated in the lung, and little is known about the age-related changes in their bronchial muscle relaxation potential. We evaluated and compared the newborn and adult rat bronchial smooth muscle response to cyclic AMP- and GMP-dependent agonists in isometric mounted bronchial rings. In acetylcholine-precontracted bronchial muscle, the relaxant response to the cAMP agonist forskolin was not age dependent, but the relaxant response to the nitric oxide (NO) donor sodium nitroprusside (SNP) was significantly greater (P<0.01) in the newborn. To further evaluate the cGMP pathway, we stimulated the soluble guanylate cyclase (sGC) with the specific agonists BAY 41-2272 and YC-1. In keeping with the SNP dose-response curves, the sGC agonists significantly relaxed the newborn, but not the adult bronchial muscle. Protein expression of the sGC alpha1- and beta1-subunits were significantly lower (P<0.01) in the adult compared with the newborn bronchial tissue. Consistent with these results, the NO-stimulated sGC activity was significantly greater in the newborn compared with the adult (P<0.01). In conclusion, the bronchial smooth muscle cGMP-, but not cAMP-dependent, relaxant response is developmentally regulated and significantly reduced in the adult rat.     

Circadian fluctuations of the plasma corticosterone level and locomotion in rats subjected local hippocampectomy]

After bilateral lesion of dorsal hippocampus increase of the level of corticosterone and motility in night and decrease in daytime were observed.     

Developmental changes in arginase expression and activity in the lung

Arginases compete with nitric oxide (NO) synthases for L-arginine as common substrate. Pulmonary vascular and airway diseases in which arginase activity is increased are associated with decreased NO production and reduced smooth muscle relaxation. The developmental patterns of arginase activity and type I and II isoforms expression in the lung have not been previously evaluated. Hypothesizing that lung arginase activity is developmentally regulated and highest in the fetus, we measured the expression of both arginase isoforms and total arginase activity in fetal, newborn, and adult rat lung, pulmonary artery, and bronchial tissue. In addition, intrapulmonary arterial muscle force generation was evaluated in the absence and presence of the arginase inhibitor Nomega-hydroxy-nor-L-arginine (nor-NOHA). Arginase II content, as well as total arginase activity, was highest in fetal rat lung, bronchi, and pulmonary arterial tissue and decreased with age (P<0.05), and its lung cell expression was developmentally regulated. In the presence of nor-NOHA, pulmonary arterial force generation was significantly reduced in fetus and newborn (P<0.01). No significant change in force generation was noted in bronchial tissue following arginase inhibition. In conclusion, arginase II is regulated developmentally, and both expression and activity are maximal during fetal life. We speculate that the maintenance of a high pulmonary vascular resistance and decreased lung NO production prenatally may, in part, be dependent on increased arginase expression and/or activity.     

Chronic O2 exposure enhances vascular and airway smooth muscle contraction in the newborn but not adult rat.

Neonatal rats exposed to 60% O(2) for 14 days develop lung changes compatible with human bronchopulmonary dysplasia and pulmonary hypertension. Our aim was to evaluate and compare the newborn and adult rat pulmonary vascular and airway smooth muscle force generation and relaxation potential after exposure to 60% O(2) for 14 days. Vascular and airway intrapulmonary rings 100 microm in diameter were mounted on a myograph and bathed in Krebs-Henseleit solution bubbled with air- 6% CO(2) at 37 degrees C. Significant age-dependent changes in intrapulmonary arteries and their neighboring airway muscle properties were observed. Whereas hyperoxia enhanced force in neonatal vascular and airway muscle, the opposite was seen in adult samples. No changes in endothelium-dependent vascular relaxation were observed at either age, but the dose response to an endothelium-independent NO donor was altered. In the newborn experimental animals, the relaxation was reduced, whereas, in their adult counterparts, it was enhanced. After O(2) exposure, the bronchial muscle relaxation response to epithelium-dependent and -independent stimulation was not altered in either age group, whereas the epithelium-dependent response was decreased only in the adult. The antioxidant Trolox, or an endothelin-A and -B receptor antagonist, reversed the vascular and airway muscle's hyperoxia-induced changes. We conclude that chronic O(2) exposure in the newborn rat results in enhanced lung vascular and airway muscle contraction potential via a mechanism involving reactive oxygen species and the endothelin pathway. The present findings also suggest that the newborn is more susceptible to airway hyperresponsiveness after chronic O(2) exposure.     

Chronic in ovo hypoxia decreases pulmonary arterial contractile reactivity and induces biventricular cardiac enlargement in the chicken embryo

Although chronic prenatal hypoxia is considered a major cause of persistent pulmonary hypertension of the newborn, experimental studies have failed to consistently find pulmonary hypertensive changes after chronic intrauterine hypoxia. We hypothesized that chronic prenatal hypoxia induces changes in the pulmonary vasculature of the chicken embryo. We analyzed pulmonary arterial reactivity and structure and heart morphology of chicken embryos maintained from days 6 to 19 of the 21-day incubation period under normoxic (21% O(2)) or hypoxic (15% O(2)) conditions. Hypoxia increased mortality (0.46 vs. 0.14; P < 0.01) and reduced the body mass of the surviving 19-day embryos (22.4 +/- 0.5 vs. 26.6 +/- 0.7 g; P < 0.01). A decrease in the response of the pulmonary artery to KCl was observed in the 19-day hypoxic embryos. The contractile responses to endothelin-1, the thromboxane A(2) mimetic U-46619, norepinephrine, and electrical-field stimulation were also reduced in a proportion similar to that observed for KCl-induced contractions. In contrast, no hypoxia-induced decrease of response to vasoconstrictors was observed in externally pipped 21-day embryos (incubated under normoxia for the last 2 days). Relaxations induced by ACh, sodium nitroprusside, or forskolin were unaffected by chronic hypoxia in the pulmonary artery, but femoral artery segments of 19-day hypoxic embryos were significantly less sensitive to ACh than arteries of control embryos [pD(2) (= -log EC(50)): 6.51 +/- 0.1 vs. 7.05 +/- 0.1, P < 0.01]. Pulmonary vessel density, percent wall area, and periarterial sympathetic nerve density were not different between control and hypoxic embryos. In contrast, hypoxic hearts showed an increase in right and left ventricular wall area and thickness. We conclude that, in the chicken embryo, chronic moderate hypoxia during incubation transiently reduced pulmonary arterial contractile reactivity, impaired endothelium-dependent relaxation of femoral but not pulmonary arteries, and induced biventricular cardiac hypertrophy.     

Faunogenetic structure of the Palearctic avifauna

On the basis of known views on the types of faunas and faunistic complexes regarded as subordinated categories of faunogenetic classification, an integrated typological concept of the Palearctic fauna is proposed. Seven types of avifauna are distinguished: Arctic, Siberian, European, Chinese, Nomadic, and Himalay an types characteristic of the corresponding subregions of the Palearctic and the connecting Euro-Chinese type, each usually including two to three zonal and one or two intrazonal faunistic complexes. Their volume, geographic and ecological connections, and history of formation are considered, and typical representatives are listed. This classification may be applied in zoogeographic research, zoning of the Palearctic, and analysis and typing of the fauna. Methodological aspects of practical applications of the proposed concept are discussed.