Peroxynitrite does not impair pulmonary and systemic vascular responses.

The effects of peroxynitrite (ONOO-) on vascular responses were investigated in the systemic and hindquarters vascular bed and in the isolated perfused rat lung. Intravenous injections of ONOO- decreased systemic arterial pressure, and injections of ONOO- into the hindquarters decreased perfusion pressure in a dose-related manner. Injections of ONOO- into the lung perfusion circuit increased pulmonary arterial perfusion pressure. Responses to ONOO- were rapid in onset, short in duration, and repeatable without exhibiting tachyphylaxis. Repeated injections of ONOO- did not alter systemic, hindquarters, or pulmonary responses to endothelium-dependent vasodilators or other vasoactive agonists and did not alter the hypoxic pulmonary vasoconstrictor response. Injections of sodium nitrate or nitrite or decomposed ONOO- had little effect on vascular pressures. Pulmonary and hindquarters responses to ONOO- were not altered by a cyclooxygenase inhibitor in a dose that attenuated responses to arachidonic acid. These results demonstrate that ONOO- has significant pulmonary vasoconstrictor, systemic vasodepressor, and vasodilator activity; that short-term repeated exposure does impair vascular responsiveness; and that responses to ONOO- are not dependent on cyclooxygenase product release.     

Insulin resistance does not influence gene expression in skeletal muscle

Insulin resistance is commonly observed in patients prior to the development of type 2 diabetes and may predict the onset of the disease. We tested the hypothesis that impairment in insulin stimulated glucose-disposal in insulin resistant patients would be reflected in the gene expression profile of skeletal muscle. We performed gene expression profiling on skeletal muscle of insulin resistant and insulin sensitive subjects using microarrays. Microarray analysis of 19,000 genes in skeletal muscle did not display a significant difference between insulin resistant and insulin sensitive muscle. This was confirmed with real-time PCR. Our results suggest that insulin resistance is not reflected by changes in the gene expression profile in skeletal muscle.     

Nifedipine does not impair the hormonal responses to graded exercise in healthy subjects

The aim of this study was to assess whether the potent calcium antagonist nifedipine was capable of modifying the hormonal response to graded exercise in 7 healthy young men. After fasting overnight, each subject came to the laboratory on 2 consecutive mornings. On one day he was given 10 mg of nifedipine sublingually and on the other an identical placebo capsule; the order was randomised in a double-blind fashion over the 2 days. Thereafter each subject performed 2 successive short treadmill runs, equivalent to 60 and 100%, respectively, of maximal aerobic power. While significantly blunting the rise in mean systolic blood pressure and inducing a greater fall in diastolic blood pressure during and after exercise compared with the placebo, nifedipine did not impair the brisk response to pituitary-adrenal hormones (ACTH, cortisol and total catecholamines). Nifedipine also did not modify the effects of short-term exercise in raising mean plasma glucose levels, stimulating pancreatic glucagon secretion and producing a delayed increase in plasma insulin concentrations. Nor did the drug blunt the significant rise of growth hormone and prolactin levels occurring during and after the treadmill run. It was concluded that, apart from inducing significant changes in blood pressure, a single dose of nifedipine does not appear to suppress the counterregulatory hormonal responses to short-term physical activity in healthy men.     

CS-US delay does not impair appetitive conditioning in Chasmagnathus

Habituation and appetitive conditioning have been already described in the crab Chasmagnathus. The purpose of this work is to study whether associative learning can be obtained despite a long conditioned stimulus-unconditioned stimulus interval. Results of the first experiment show that the weakening of temporal contiguity does not prevent appetitive conditioning to occur while after a long 4-h delay, conditioning wanes completely. A second experiment was conducted, after one and three days of training respectively, confirming the above results. Though initially neutral the context trace may be still available immediately after training and for the period of two but not after 4:00 h, demonstrating a forward limit for the conditioning window. After 3 days of training, a further decrease in the exploratory activity suggested that a longer training could increase the relative weight of habituation. Conditioning and habituation seem to work as opponent processes in the crab CHASMAGNATHUS GRANULATUS: if habituation training in the box is followed by the administration of reinforcement after a short period of time, appetitive conditioning will take place. However, as this interval is increased, habituation prevails. A persistent effect of the exposure to a given environment that may underlie trace conditioning in this crab is discussed in adaptive terms.     

Short tertatolol treatment does not impair the hormone and metabolic responses to exercise and hypoglycemia in diabetics

Beta-blockers can precipitate hypoglycemia and mask its warning signs. Ten male insulin-dependent, otherwise healthy diabetic patients underwent two submaximal exercise tests and two insulin-induced hypoglycemic events (0.2 u/Kg short-acting insulin IV) after six days administration of placebo followed by tertatolol, a non selective beta-blocker (5 mg once daily). Tertatolol modified neither the exercise-induced changes in blood glucose, lactate and plasma unesterified fatty acid levels, nor those of counter regulatory hormones (glucagon, growth hormone, cortisol), while blood pressure, heart rate and plasma renin activity were significantly reduced, proving that tertatolol had actually been ingested, and was active. During the insulin-induced hypoglycemia, similarly tertatolol did not modify the course of the plasma fuels and hormones. Particularly, hypoglycemia was neither deeper nor more prolonged in the presence than in the absence of tertatolol. Warning symptoms were not affected except for palpitations which were not perceived. These results suggest that tertatolol did not precipitate hypoglycemia following exercise, and did not aggravate insulin-induced hypoglycemia in short term administration, and in otherwise healthy diabetic patients.     

Ultra-acute exposure to cadmium does not impair whitefish sperm motility

Cadmium (Cd) exposure can impair the traits of aquatic animals associated with reproduction. In natural lakes Cd is typically detected at concentrations below 0.001 mg l⁻¹. The authors investigated the impact of ultra-acute Cd exposure on sperm motility in European whitefish (Coregonus lavaretus). They activated sperm with water containing various nominal concentrations of Cd and recorded sperm motility parameters. Only the highest Cd concentration (500 mg l⁻¹) was associated with decreased sperm swimming velocity and increases in both the percentage of static cells and curvature of the sperm swimming trajectory. The results indicate that environmentally realistic concentrations of Cd during the sperm motility activation are not critically harmful to male C. lavaretus fertilization potential.     

Hypohydration does not impair skeletal muscle glycogen resynthesis after exercise

The purpose of this investigation was to examine the effects of moderate hypohydration (HY) on skeletal muscle glycogen resynthesis after exhaustive exercise. On two occasions, eight males completed 2 h of intermittent cycle ergometer exercise (4 bouts of 17 min at 60% and 3 min at 80% of maximal O2 consumption/10 min rest) to reduce muscle glycogen concentrations (control values 711 +/- 41 mumol/g dry wt). During one trial, cycle exercise was followed by several hours of light upper body exercise in the heat without fluid replacement to induce HY (-5% body wt); in the second trial, sufficient water was ingested during the upper body exercise and heat exposure to maintain euhydration (EU). In both trials, 400 g of carbohydrate were ingested at the completion of exercise and followed by 15 h of rest while the desired hydration level was maintained. Muscle biopsy samples were obtained from the vastus lateralis immediately after intermittent cycle exercise (T1) and after 15 h of rest (T2). During the HY trial, the muscle water content was lower (P less than 0.05) at T1 and T2 (288 +/- 9 and 265 +/- 5 ml/100 g dry wt, respectively; NS) than during EU (313 +/- 8 and 301 +/- 4 ml/100 g dry wt, respectively; NS). Muscle glycogen concentration was not significantly different during EU and HY at T1 (200 +/- 35 vs. 251 +/- 50 mumol/g dry wt) or T2 (452 +/- 34 vs. 491 +/- 35 mumol/g dry wt). These data indicate that, despite reduced water content during the first 15 h after heavy exercise, skeletal muscle glycogen resynthesis is not impaired.     

NUMB does not impair growth and differentiation status of experimental gliomas

The cell fate determinant NUMB orchestrates asymmetric cell division in flies and mammals and has lately been suggested to have a tumor suppressor function in breast and lung cancer. Here, we studied NUMB in the context of malignant gliomas. We used ectopic expression of NUMB in order to inhibit proliferation and induce differentiation in glioma cells by alteration of Notch, Hedgehog and p53 signaling. We found that NUMB is consistently expressed in glioma biopsies with predominance of NUMB2/4 isoforms as determined by isoform-specific real-time PCR and Western blotting. Upon lentiviral overexpression, in vitro proliferation rate and the grade of differentiation as assessed by morphology and expression of neural and glial markers remained unchanged. Orthotopic xenografts of NUMB-transduced human U87 glioma cells could be established in nude rats without impairing engraftment or causing significant changes in morphology based on magnetic resonance imaging (MRI). The previously reported alteration of Hedgehog and p53 signaling by NUMB could not be recapitulated in glioma cells. We thus show that in experimental gliomas, NUMB overexpression most likely does not exert a tumor suppressor function such as seen in epithelial cancers.     

Single millimeter wave treatment does not impair gastrointestinal transit in mice

Millimeter wave treatment (MWT) is based on those biological effects that develop following skin exposure to low power electromagnetic waves. This method of treatment is in wide clinical use in several Eastern European countries for treatment of a variety of conditions, including pain syndromes. However, most treatment modes of MWT were developed empirically, and certain indications and contraindications for the use of MWT remain to be established. In our previous blind experiments we have shown that the hypoalgesic effect of MWT may be quantitatively evaluated, and most probably mediated by the neural system in general, and the system of endogenous opioids in particular. Taking in consideration a well-known ability of opioids to cause gastrointestinal disturbances, which could limit clinical application of MWT, the main aim of the present study was to investigate whether a single MWT, that can produce opioid-related hypoalgesia, may also retard gut transit and colorectal passage in mice. The charcoal meal test was used to quantitatively evaluate upper gastrointestinal transit, and the glass bead test was employed to examine colonic propulsion in mice. MWT was applied to the nose area of mice. The MWT characteristics were: frequency = 61.22 GHz; incident power density = 15 mW/cm(2); and duration = 15 min. The results obtained have shown that MWT does not significantly change small intestinal or colonic transit in mice, and thus suppression of gastrointestinal motility should not be a setback in the clinical use of MWT.     

Insulin resistance does not diminish eNOS expression, phosphorylation, or binding to HSP-90

Previously, using an animal model of syndrome X, the obese Zucker rat (OZR), we documented impaired endothelium-dependent vasodilation. The aim of this study was to determine whether reduced expression or altered posttranslational regulation of endothelial nitric oxide synthase (eNOS) underlies the vascular dysfunction in OZR rats. There was no significant difference in the relative abundance of eNOS in hearts, aortas, or skeletal muscle between lean Zucker rats (LZR) and OZR regardless of age. There was no difference in eNOS mRNA levels, as determined by real-time PCR, between LZR and OZR. The inability of insulin resistance to modulate eNOS expression was also documented in two additional in vivo models, the ob/ob mouse and the fructose-fed rat, and in vitro via adenoviral expression of protein tyrosine phosphatase 1B in endothelial cells. We next investigated whether changes in the acute posttranslational regulation of eNOS occurs with insulin resistance. Phosphorylation of eNOS at S632 (human S633) and T494 was not different between LZR and OZR; however, phosphorylation of S1176 was significantly enhanced in OZR. Phosphorylation of S1176 was not different in the ob/ob mouse or in fructose-fed rats. The association of heat shock protein 90 with eNOS, a key regulatory step controlling nitric oxide and aberrant O2- production, was not different between OZR and LZR. Taken together, these results suggest that changes in eNOS expression or posttranslation regulation do not underlie the vascular dysfunction seen with insulin resistance and that other mechanisms, such as altered localization, reduced availability of cofactors, substrates, and the elevated production of O2-, may be responsible.     

Aviation noise does not impair the reproductive success of farmed blue foxes

The aim of our study was to assess the effects of aviation noise on reproduction and cub mortality in farmed blue foxes. Eighty artificially inseminated blue fox vixens (45 primiparous and 35 multiparous) were exposed to aviation noise on 5 days when they were pregnant or had cubs. The noise during the exposures varied from 85 to 121 dB (L(AFmax)). Vixens (45 primiparous and 34 multiparous) on a farm without flight action acted as controls. Cubs were counted 1, 3, 7, 14 and 49 days postpartum and at the beginning of July. Litter size (cubs per whelped vixen), reproductive performance (cubs per mated vixen) and cub losses (lost cubs per whelped vixen) were analyzed from both experimental farms (A and C). The flight action had no effect on reproductive success. Reproductive performance in primiparous vixens was 4.2+/-3.8 and 4.3+/-3.6 cubs (ns, Mann-Whitney U-test) in the control and aviation group, respectively, while in multiparous vixens the corresponding figures were 7.1+/-4.4 and 7.3+/-3.8 cubs (ns). In general, litter size declined from birth to weaning (in primiparous vixens from 8.1+/-3.8 to 5.4+/-3.2 cubs, and in multiparous from 9.7+/-3.8 to 7.2+/-3.8 cubs, P<0.001, GLM for repeated measures). The decline was greater in primiparous than in multiparous vixens (P<0.01). There were no differences in total cub losses between the experimental groups (ns). Accordingly, the present results show that exposure to severe and repeated aviation noise does not impair the reproductive success of farmed blue foxes.     

Melatonin potentiates contractile responses to serotonin in isolated porcine coronary arteries

The present study was designed to determine the effects of melatonin on coronary vasomotor tone. Porcine coronary arteries were suspended in organ chambers for isometric tension recording. Melatonin (10(-10)-10(-5) M) itself caused neither contraction nor relaxation of the tissues. Serotonin (10(-9)-10(-5) M) caused concentration-dependent contractions of coronary arteries, and in the presence of melatonin (10(-7) M) the maximal response to serotonin was increased in rings with but not without endothelium. In contrast, melatonin had no effect on contractions produced by the thromboxane A(2) analog U-46619 (10(-10)-10(-7) M). The melatonin-receptor antagonist S-20928 (10(-6) M) abolished the potentiating effect of melatonin on serotonin-induced contractions in endothelium-intact coronary arteries, as did treatment with 1H-[1, 2,4]oxadiazolo[4,3-a]quinoxalin-1-one (10(-5) M), methylene blue (10(-5) M), or N(G)-nitro-L-arginine (3 x 10(-5) M). In tissues contracted with U-46619, serotonin caused endothelium-dependent relaxations that were inhibited by melatonin (10(-7) M). Melatonin also inhibited coronary artery relaxation induced by sodium nitroprusside (10(-9)-10(-5) M) but not by isoproterenol (10(-9)-10(-5) M). These results support the hypothesis that melatonin, by inhibiting the action of nitric oxide on coronary vascular smooth muscle, selectively potentiates the vasoconstrictor response to serotonin in coronary arteries with endothelium.     

Licorice extract does not impair the male reproductive function of rats.

The effect of water extract of licorice (Glycyrrhiza uralensis), one of the most widely used medicinal plants in Oriental nations and in Europe, on male reproductive function was investigated in rats. Licorice extract was prepared as in Oriental clinics and orally administered at doses of 500, 1,000 or 2,000 mg/kg, the upper-limit dose (2,000 mg/kg) recommended in the Toxicity Test guideline of the Korea Food and Drug Administration, to 6-week-old male rats for 9 weeks. Licorice extract neither induced clinical signs, nor affected the daily feed consumption and body weight gain. There were no significant changes in testicular weights, gross and microscopic findings, and daily sperm production between vehicle- and licorice-treated animals, in spite of slight decreases in prostate weight and daily sperm production at the high dose (2,000 mg/kg). In addition, licorice did not affect the motility and morphology of sperm, although the serum testosterone level tended to decrease without significant difference, showing a 28.6% reduction in the high-dose (2,000 mg/kg) group. The results suggest that the no observed adverse-effect level of licorice extract is higher than 2,000 mg/kg, the upper-limit dose, and that long-term exposure to licorice might not cause profound adverse effects.     

Endothelium attenuates contractile responses of goat saphenous arteries to adrenergic nerve stimulation

1. Field electrical stimulation of perfused segments (15 mm long) of the goat saphenous artery caused frequency-dependent increases in perfusion pressure which were blocked by tetrodotoxin, phentolamine or prazosin. 2. Mechanical removal of the endothelium augmented both resting perfusion pressure and responses to electrical stimulation. 3. Methylene blue enhanced responses with intact endothelium only. It is likely that the endothelium exerts part of its inhibitory influence through the activation of guanylate cyclase.     

Low sodium intake does not impair renal compensation of hypoxia-induced respiratory alkalosis.

Acute hypoxia causes hyperventilation and respiratory alkalosis, often combined with increased diuresis and sodium, potassium, and bicarbonate excretion. With a low sodium intake, the excretion of the anion bicarbonate may be limited by the lower excretion rate of the cation sodium through activated sodium-retaining mechanisms. This study investigates whether the short-term renal compensation of hypoxia-induced respiratory alkalosis is impaired by a low sodium intake. Nine conscious, tracheotomized dogs were studied twice either on a low-sodium (LS = 0.5 mmol sodium x kg body wt-1 x day-1) or high-sodium (HS = 7.5 mmol sodium x kg body wt-1 x day-1) diet. The dogs breathed spontaneously via a ventilator circuit during the experiments: first hour, normoxia (inspiratory oxygen fraction = 0.21); second to fourth hour, hypoxia (inspiratory oxygen fraction = 0.1). During hypoxia (arterial PO2 34.4 +/- 2.1 Torr), plasma pH increased from 7.37 +/- 0.01 to 7.48 +/- 0.01 (P < 0.05) because of hyperventilation (arterial PCO2 25.6 +/- 2.4 Torr). Urinary pH and urinary bicarbonate excretion increased irrespective of the sodium intake. Sodium excretion increased more during HS than during LS, whereas the increase in potassium excretion was comparable in both groups. Thus the quick onset of bicarbonate excretion within the first hour of hypoxia-induced respiratory alkalosis was not impaired by a low sodium intake. The increased sodium excretion during hypoxia seems to be combined with a decrease in plasma aldosterone and angiotensin II in LS as well as in HS dogs. Other factors, e.g., increased mean arterial blood pressure, minute ventilation, and renal blood flow, may have contributed.