Acute alcoholic intoxication and naloxone. Effects on visual evoked potential.

Experimental assays analyzing visual evoked potential (VEP) changes during an acute alcoholic intoxication were carried out in two groups of cats: One with continuous ethanol (0.06 g/kg.min) i.v. perfusion. Another one with a naloxone (400 micrograms/kg) i.v. injection 10 min before ethylic perfusion. Naloxone potentiates alcohol effects on VEP parameters, and on the appearance of isoelectric postpotential and flat VEP.     

Brain injury following cardiorespiratory arrest in cats. Effects of alphaxalone-alphadolone

The effects of alphaxalone-alphadolone acetate (27.07 microM/kg-7.68 microM/kg) on neurologic injury following acute cerebral ischemia induced by an 8 min cardiorespiratory arrest (CRA) were investigated in cats through the analysis of neurological deficit scores and brain electrical activity; i.e., electroencephalogram (EEG) from parieto-occipital cortices and EEG and multiunit activity (MUA) from mesencephalic reticular formation (MRF). The CRA resulted from electrically induced cardiac arrest and stopping of mechanical ventilation in paralyzed cats which were successfully resuscitated within the immediate 4 min after the end of CRA. Two groups of cats were studied: I. Untreated, which received saline iv; II. Treated, which received alphaxalone-alphadolone acetate iv, 7-9 min after the end of CRA. Neuromuscular blockade and mechanical ventilation were maintained until 8 h following the CRA; then the cats were allowed to recover spontaneous respiratory activity. EEG phenomena were different in untreated and treated cats during this immediate post-arrest period. The former showed rhythmic bursts of fast (12-20 Hz) EEG activity at 1-2 sec intervals from 15-20 min until 3-4 h after the CRA, abundant spikes and delta-like waves. By contrast, administration of alphaxalone-alphadolone acetate resulted in burst suppression EEG pattern during 1 h. Progressive recovery of background EEG activity occurred afterwards. MUA from MRF disappeared during the CRA, however 6 h later the mean MUA frequency in untreated cats ranged between 32-46% and in treated cats 18-27% of their control mean frequencies during paradoxical sleep (100%). Daily electrographic records were performed in all the cats during quiet attentive behavior at each of the five days following the CRA. Significant differences were found in the frequency distributions of MUA from MRF (1st day, p less than 0.01; 5th day, p less than 0.01) as well as in the cortical EEG waves (1st day, p less than 0.01; 5th day, p less than 0.05) before and after the CRA in the untreated group. A wide dispersion of MUA values, and increased proportions of delta and theta-like waves and spindle bursts, besides a significantly high (p less than 0.001) number of spikes occurred in these EEG records the days following the CRA. The frequency distributions of MUA and EEG did not significantly differ before and after the CRA in the treated group; however, a significantly high (p less than 0.05) number of spikes was found in treated cats following the CRA.(ABSTRACT TRUNCATED AT 400 WORDS)     

Splenopentin--modulator of immunological and behavioral reactions in secondary immunodeficiency state induced by experimental alcoholism

Effect of splenopentin on some patterns of immunity was studied in mice with chronic alcoholic intoxication. Splenopentin was administrated into animals once intraperitoneally (250 micrograms/kg). Administration of splenopentin was found to normalize several immunological patterns in animals with chronic alcoholic intoxication: the immune response to the thymus-dependent antigen sheep red blood cells and phagocytic activity of peritoneal macrophages. Also observations over C57B1/6 mice characterized by high level of alcoholic motivation showed that alcohol consumption in mice decreased after administration of splenopentin at a dose of 250 micrograms/kg during two weeks.     

Left ventricular catecholamines during acute myocardial infarction in the dog

To determine whether changes in left ventricular catecholamine content occur during the first 30 to 90 min of acute myocardial infarction, myocardial catecholamine (radioenzymatic assay) over the interval was studied in the dog. In nine pentobarbital-anesthetized opened-chest dogs without coronary ligation, myocardial catecholamine at 2.5 h after pentobarbital (i) consisted mainly of norepinephrine (87% total catecholamine), (ii) showed a base to apex gradient in norepinephrine (1.44 +/- 0.10 vs. 1.03 +/- 0.10 micrograms/g, p less than 0.05) and dopamine (0.20 +/- 0.03 vs. 0.12 +/- 0.02 micrograms/g, p less than 0.05) but not epinephrine (0.017 vs. 0.016 micrograms/g), and (iii) showed no difference in norepinephrine, dopamine, or epinephrine across basal, mid, and apical left ventricular transverse planes spanning the vascular territories of the two coronary arteries. In 18 pentobarbital-anesthetized dogs with coronary ligation, (i) norepinephrine, measured in 14 regions across the mid left ventricle after 90 min ischemia in four dogs, was less in the ischemic center of the occluded bed than normal myocardium (1.01 +/- 0.04 vs. 1.29 +/- 0.04 micrograms/g, p less than 0.05), and (ii) norepinephrine was unchanged in normal myocardium of 14 dogs at 30, 60, 90 min, and 48 h but decreased in ischemic myocardium by 31% at 60 min (0.89 +/- 0.10 vs. 1.29 +/- 0.08 micrograms/g, p less than 0.025) and 79% at 48 h (0.27 +/- 0.04 vs. 1.26 +/- 0.08 micrograms/g, p less than 0.001). Thus, norepinephrine depletion from ischemic but not normal myocardium is detectable by 60 min during acute myocardial infarction.     

The effect of inhibitors of endogenous opioid degradation, bacitracin, bestatin, captopril, and D-phenylalanine, on digoxin-induced arrhythmias in guinea pigs

The purpose of this study was to investigate the effect of inhibition of endogenous opioid degradation on digitalis-induced arrhythmias, utilizing the inhibitors bacitracin, bestatin, captopril, and D-phenylalanine. Guinea pigs, anesthetized with pentobarbital, 50 mg/kg i.p., and breathing spontaneously received intracerebroventricular (i.c.v.) injection of bacitracin (6.8 mg/kg), bestatin (1 mg/kg), captopril (2 mg/kg), D-phenylalanine (1.2 mg/kg) or the diluent, saline. Digitalis arrhythmias were induced by a 50 micrograms/kg i.v. bolus of digoxin followed by 500 micrograms.kg-1.h-1 i.v. Bacitracin and bestatin, but not captopril or D-phenylalanine, significantly (p less than 0.05) altered the relationship between the digoxin dose and the first occurrence of arrhythmias, i.e., digoxin-induced ventricular arrhythmias became manifest at lower digoxin doses. The mean digoxin dose and ED50s, at which arrhythmias first occurred, were significantly (p less than 0.05) reduced by bacitracin and bestatin. The findings were similar for fatal arrhythmias, although D-phenylalanine appeared to decrease the digoxin dose at the development of fatal arrhythmias. The opioid antagonist naloxone, in a 50 micrograms/kg bolus and 50 micrograms.kg-1.h-1 i.c.v., completely prevented these effects of bacitracin and reduced the effect of bestatin. The relationship to arrhythmias could not be ascribed to an effect on blood pressure, as the blood pressure response to digoxin was the same in bestatin, D-phenylalanine, and control groups. To examine whether systemic administration of an inhibitor of opioid degradation had similar effects, a second protocol was selected with systemic administration of bacitracin because it altered the dose effect relationship after i.c.v. administration and systemic concentrations could be readily attained. Bacitracin, in a 13.5 mg/kg i.v. bolus and 135 mg.kg-1.h-1 i.v., was followed by 100 micrograms/kg digoxin i.v. every 15 min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal effects of dopamine and dopexamine in the newborn anesthetized rabbit.

The renal effects of dopexamine, a new dopaminergic agonist with marked beta 2-adrenergic agonist properties, but no alpha-adrenergic effect, has been studied in 8 newborn New Zealand rabbits, whose renal functional characteristics show close similarities with those of premature infants. Six animals were used as controls. After a control period, dopexamine was infused intravenously at a rate of 4 micrograms/kg per min and after a wash-out period, at 10 micrograms/kg per min. The renal effects of dopamine were studied in similar conditions. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were determined by inulin and para-aminohippuric acid clearances, respectively. Dopexamine, 4 micrograms/kg per min, did not induce changes in cardiovascular and renal hemodynamics or in renal functions. At 10 micrograms/kg per min, a significant increase in urine flow rate (25 +/- 5%; p less than 0.01), urine sodium excretion (77 +/- 17%; p less than 0.01) and fractional sodium excretion (69 +/- 25%; p less than 0.05) was observed. The GFR, RPF and renal vascular resistance (RVR) were not affected. Heart rate increased slightly but significantly (8 +/- 3%; p less than 0.05), without change in mean blood pressure (MBP). Dopamine, 4 micrograms/kg per min, decreased slightly albeit significantly MBP (3 +/- 1%; p less than 0.05). At 10 micrograms/kg per min the only renal effect was a significant increase in RVR (19 +/- 6%; p less than 0.02). The different actions of these two dopaminergic agonists in this immature model could be explained by their respective ability to activate electively the adrenergic and dopaminergic peripheral receptors. The natriuretic and diuretic effect of dopexamine in normal immature rabbits, in the absence of changes in RPF or GFR is probably mediated by a direct action of this agent on dopaminergic tubular receptors. Failure of these two drugs to increase RPF may be related to an immaturity of the dopaminergic vascular receptors.     

Chronic clonidine treatment and its termination: effects on penile erection and ejaculation in the dog.

The effects of chronic administration (4 weeks) of the alpha-2 adrenoceptor agonist clonidine (CL) and its termination on penile erection and ejaculation were investigated in male dogs. Penile erection and ejaculation were elicited by manual penile stimulation (for 5 min). CL (10 micrograms/kg/hr, s.c.) was delivered via osmotic minipump (Alza, 2ML-4). 3 or 7 days after the minipump implantation, CL caused a significant decrease in the amount of ejaculate produced by the genital stimulation without affecting the erectile potency. Ejaculatory ability returned to pretreatment levels despite continued CL administration, becoming evident in tests 14 days after initiation of treatment. Further, chronic CL (23 days) antagonized the inhibitory effects of acute administration of CL (0.05 mg/kg, i.p.). These data indicate tolerance to continued delivery of low doses as well as to acute administration of a higher dose. In the acute drug experiments, the ejaculatory inhibition elicited by CL (0.05 mg/kg, i.p.) was completely antagonized by pretreatment with yohimbine (0.05 and 0.10 mg/kg, i.p.), an alpha-2 adrenoceptor antagonist, but not with naloxone (1.0 mg/kg, i.p.), an opioid receptor antagonist. Furthermore, DG-5128 (1.0 and 2.0 mg/kg, i.p.), a selective alpha-2 adrenoceptor antagonist that poorly penetrates the blood-brain barrier, failed to antagonize the CL-induced ejaculatory inhibition. This study suggests that functional alterations in the central alpha-2 adrenoceptor mechanism may be related to the changes in the ejaculatory capacity during chronic treatment with CL.     

Effect of naloxone on the secretion of LH in infantile and prepubertal Holstein bull calves

Administration of naloxone (100 mg i.v.; approximately 1.21 mg/kg body weight0.75) to 10 intact calves (24 weeks of age) caused an acute release of LH that was similar in amplitude and duration to spontaneous discharges of LH that occur at the same age. The naloxone-induced release of LH was abolished in 9/10 calves (intact and castrated) treated with oestradiol-17 beta. To determine the ontogeny of opioid control of secretion of LH, 12 calves were randomly assigned to receive saline or naloxone (1.21 mg/kg body weight0.75, i.v.) at 3, 5, 7, 9, 11, 13, 17 and 21 weeks of age. At each age, blood was collected at 10-min intervals for 4 h and saline or naloxone was administered (i.v.) after collection of the 120-min sample. Before administration of naloxone, plasma LH values increased with age (P less than 0.01) but did not differ between the control and naloxone groups (age x treatment, P greater than 0.05). Administration of naloxone caused concentrations of plasma LH to increase at 3, 11, 13, 17 and 21 weeks of age (treatment x time, P less than 0.001). Concentrations of LH (saline vs naloxone, ng/ml) reached a maximum within 20 min after treatment at Weeks 3 (0.3 vs 1.2), 11 (0.6 vs 2.6), 13 (0.6 vs 3.7), 17 (1.1 vs 2.6), and within 40 min after treatment at Week 21 (1.0 vs 3.5).(ABSTRACT TRUNCATED AT 250 WORDS)     

Endogenous opioid peptides in the control of food intake in cats

In this report, we investigated the role of exogenous and endogenous enkephalins on food intake in the cat, using, respectively, exogenous [D-Ala2-Met5]-enkephalin (DAME) and acetorphan (Ac) in order to inhibit the degradation of endogenous enkephalins. In addition, the selective peripheral antagonist naltrexone methylbromide (NTxMB) and the nonselective antagonist naloxone (Nx) were used in an attempt to discriminate central and peripheral opioid receptors. In 18-hours food-deprived animals, Ac (5 mg/kg IV) increased milk intake during sham feeding (+18%, p less than 0.05), but did not modify it in feeding conditions. Nx (1 mg/kg SC) reduced milk intake in sham-feeding experiments (-67%, p less than 0.01) more than in milk-feeding conditions (-30%, p less than 0.01). NTxMB (1 mg/kg SC) did not modify milk intake in sham-feeding but decreased it in feeding experiments. In nonfasted animals, Ac did not modify food intake. IV infusion of DAME (50 micrograms/kg) resulted in a reduction of daily food intake (-32%, p less than 0.01). Nx (1 mg/kg SC) decreased the earlier 30 min intake followed by reduction of daily intake (-30%, p less than 0.01). NTxMB (1 and 4 mg/kg SC) increased the 30-min intake dose dependently, without significant change in daily intake. In conclusion, Ac increases food intake in sham-feeding conditions, suggesting that endogenous enkephalins are likely to be involved in the stimulation of food intake. The effects of Nx and NTxMB furthermore suggest both a central activation, and a peripheral inhibition of food intake by opiates when food is allowed to proceed normally through the digestive tract.     

Failure of naloxone to stimulate luteinizing hormone secretion during pregnancy and steroid treatment of ovariectomized beef cows

The response of serum luteinizing hormone (LH) to naloxone, an opiate antagonist, and gonadotropin-releasing hormone (GnRH) was measured in cows in late pregnancy to assess opioid inhibition of LH. Blood samples were collected at 15-min intervals for 7 h. In a Latin Square arrangement, each cow (n = 6) received naloxone (0, 0.5, and 1.0 mg/kg BW, i.v.; 2 cows each) at Hour 2 on 3 consecutive days (9 +/- 2 days prepartum). GnRH (7 ng/kg body weight, i.v.) was administered at Hour 5 to all cows on each day. Mean serum LH concentrations (x +/- SE) before naloxone injection were similar (0.4 +/- 0.1 ng/ml), with no serum LH pulses observed during the experiment. Mean serum LH concentrations post-naloxone were similar (0.4 +/- 0.1 ng/ml) to concentrations pre-naloxone. Mean serum LH concentrations increased (p less than 0.05) following GnRH administration (7 ng/kg) and did not differ among cows receiving different dosages of naloxone (0 mg/kg, 1.44 +/- 0.20; 0.5 mg/kg, 1.0 +/- 0.1; 1.0 mg/kg, 0.9 +/- 0.1 ng/ml). In Experiment 2, LH response to naloxone and GnRH was measured in 12 ovariectomized cows on Day 19 of estrogen and progesterone treatment (5 micrograms/kg BW estrogen: 0.2 mg/kg BW progesterone) and on Days 7 and 14 after steroid treatment. On Day 19, naloxone failed to increase serum LH concentrations (Pre: 0.4 +/- 0.1; Post: 0.4 +/- 0.1 ng/ml) after 0, 0.5, or 1.0 mg/kg BW.(ABSTRACT TRUNCATED AT 250 WORDS)     

Direct evidence that an increase in aortic norepinephrine level in response to insulin-induced hypoglycemia is due to increased adrenal norepinephrine output

This study reports on the major source of circulating norepinephrine that is known to increase, progressively, during sustained hypoglycemia induced by intravenous insulin administration. Plasma concentrations of epinephrine, norepinephrine, and dopamine were simultaneously determined for adrenal venous and aortic blood in dogs anesthetized with sodium pentobarbital. The model used allowed us to perform a functional adrenalectomy (ADRX), while continuously monitoring the adrenal medullary secretory function. Under basal conditions, the net output (micrograms/min) of adrenal epinephrine, norepinephrine, and dopamine were 0.169 +/- 0.074, 0.067 +/- 0.023, and 0.011 +/- 0.003, respectively. Plasma concentrations (ng/mL) of aortic epinephrine, norepinephrine, and dopamine were 0.132 +/- 0.047, 0.268 +/- 0.034, and 0.034 +/- 0.009. Following insulin injection (0.15 IU/kg, i.v.), the net output (micrograms/min) of adrenal epinephrine, norepinephrine, and dopamine increased gradually (p less than 0.05), reaching the values of 0.918 +/- 0.200, 0.365 +/- 0.058, and 0.034 +/- 0.007 30 min after insulin administration. Similarly, aortic epinephrine, norepinephrine, and dopamine concentrations (ng/mL) increased significantly (p less than 0.05) to 0.702 +/- 0.144, 0.526 +/- 0.093, and 0.066 +/- 0.024. The aortic glucose concentration (mg/dL) was diminished from 81.8 +/- 4.1 to 36.9 +/- 3.4 (p less than 0.01). After taking the blood sample at 30 min following insulin administration, ADRX was immediately performed. Five minutes after the onset of ADRX, the net output (micrograms/min) of adrenal epinephrine, norepinephrine, and dopamine increased further to 1.707 +/- 0.374 (p less than 0.05), 0.668 +/- 0.139 (p less than 0.05), and 0.052 +/- 0.017.(ABSTRACT TRUNCATED AT 250 WORDS)     

Electroencephalogram is activated by addition of pentobarbital in the isolated perfused head of the rat

To evaluate the direct effects of a barbiturate on cerebral functions without its influence on brain perfusion pressure, circulatory hormones and metabolites, the electroencephalogram (EEG) was studied in the isolated rat head. Male Wistar rats were anesthetized, and EEG electrodes were inserted into the cranium. A Krebs-Ringer bicarbonate buffer solution containing heparinized rat whole blood, 20 mmol/l glucose, 200 mmol/l mannitol and 0.1 mg/ml dexamethasone was used for the perfusate. The bilateral common carotid arteries were cannulated, pumped at a rate of 6 ml/min and the head was isolated. The venous effluent was reoxygenated and recirculated into the brain. Twenty-five min after isolation of the heads pentobarbital was added to the perfusate at concentrations of 0.1, 0.5 and 2.5 mg/ml. EEG was recorded before and during perfusion. EEG activity could be recorded for more than 25 min after the beginning of perfusion. EEG activity gradually declined from 42+/-5 microV before perfusion (in vivo) to 4+/-1 microV at 25 min after the beginning of perfusion. Then, 3 min after the addition of pentobarbital, the EEG activity became significantly higher in the high dose groups; 12+/-3 microV in the 0.5 mg/ml group (p<0.05) and 12+/-1 microV in 2.5 mg/ml group (p<0.05) compared with the group without pentobarbital (2+/-2 microV). The present study suggests that a barbiturate has mitigating effects on the brain damage induced by the in vitro brain perfusion.     

Acute and long-term TNF-alpha administration increases pulmonary vascular reactivity in isolated rat lungs.

Tumor necrosis factor-alpha (TNF-alpha) causes pulmonary hypertension and arterial hypoxemia, but the mechanisms are unknown. We conducted two experiments to test the hypothesis that TNF-alpha alters pulmonary vascular reactivity, which in turn could cause either pulmonary hypertension or arterial hypoxemia. In experiment 1, rats were given acute or long-term injections of TNF-alpha (recombinant human) in vivo. Rats treated acutely received either saline or TNF-alpha (40 micrograms/kg iv in saline) 3 min (TNF-3 min; n = 8), 20 min (TNF-20 min; n = 8), or 24 h (TNF-24 h; n = 5) before the lungs were isolated. Rats treated chronically received injections of either saline or TNF-alpha (250 micrograms/kg ip in saline) two times per day for 7 days (TNF-7 days; n = 9). Lungs were isolated and perfused with Earle's salt solution (+2 g/l NaHCO3 + 4 g/100 ml Ficoll), and vascular reactivity was tested with acute hypoxia (3 min; 3% O2) and angiotensin II (ANG II; 0.025-0.40 micrograms). Pulmonary pressor responses to hypoxia were greater (P less than 0.05) in TNF-20 min and TNF-7 day groups. ANG II responses were increased (P less than 0.05) in TNF-7 day rats. In experiment 2, lungs were isolated and perfused and received direct pulmonary arterial injections of TNF-alpha (0.2, 2.0, and 20 micrograms) or saline, after stable responses to hypoxia and ANG II (0.10 microgram) were attained. Reactivity was not different between control and TNF-alpha rats before the injections, but TNF-alpha increased (P less than 0.05) responses to hypoxia and ANG II.(ABSTRACT TRUNCATED AT 250 WORDS)     

Iron-induced oxidative DNA damage in rat sperm cells in vivo and in vitro

We investigated whether acute iron intoxication causes oxidative DNA damage, measured in terms of 7-hydro-8-oxo-2'-deoxyguanosine, 8-oxodG, in nuclear DNA in testes and epididymal sperm cells in vivo and in vitro in rats. In addition, we investigated levels of the modified nucleoside in liver and kidney and measured its urinary excretion. Sperm cells were isolated from the epididymides and the testes cells were isolated after homogenisation. In vitro, the sperm and testes cells were incubated with increasing concentrations of FeCl2 ranging from 0 to 600 microM. The median (range) levels of 8-oxodG/10(5) dG in the epididymal sperm cells increased from 0.48 (0.42-0.90) to 15.1 (11.4-17.6) (p < 0.05), whereas the level rose from 0.63 (0.22-0.81) to 8.8 (4.5-11.6) (p < 0.05) at 0 and 600 microM, respectively, in the testicular cells. In vivo groups of 7-8 rats received 0, 200 or 400 mg iron/kg as dextran i.p. After 24 h, epididymal sperm cells, testes, kidneys and liver were collected for analysis. Kidney and sperm DNA showed a significant increase in 8-oxodG in the iron-treated animals. The median (range) values of the 8-oxodG/10(5) dG in the epididymal sperm cells rose from 0.66 (0.38-1.09) to 1.12 (0.84-5.88) (p < 0.05) at 0 and 400 mg iron/kg, respectively, whereas the values in the testes and liver showed no significant change. In the kidneys the 8-oxodG/10(5) dG median (range) values were 0.98 (0.73-1.24), 1.21 (1.13-1.69) and 1.34 (1.12-1.66) after 0, 200 and 400 mg iron/kg, respectively (p < 0.05). The 8-oxodG-excretion rate was measured in 24h urine before and after iron treatment. The rate of urinary 8-oxodG excretion increased from 129 (104-179) pmol/24 h before treatment to 147 (110-239) pmol/24 h after treatment in the group receiving 400 mg iron/kg (p < 0.05). The results indicate that acute iron intoxication may increase oxidative damage to sperm and kidney DNA.     

Beneficial effect of chronic treatment with the selective bradykinin B1 receptor antagonists, R-715 and R-954, in attenuating streptozotocin-diabetic thermal hyperalgesia in mice

Kinins are important mediators of cardiovascular homeostasis, inflammation and nociception. Bradykinin (BK) B(1) receptors (BKB1-R) are over-expressed in pathological conditions including diabetes, and were reported to play a role in hyperglycemia, renal abnormalities, and altered vascular permeability associated with type 1 diabetes. Recent studies from our laboratory demonstrated that BKB1-R are implicated in streptozotocin (STZ)-diabetes-mediated hyperalgesia, since acute administration of the selective BKB1-R antagonists significantly and dose-dependently inhibited such hyperalgesic activity. In the present study, we examined the effect of chronic treatment of STZ-diabetic mice with the selective BKB1-R agonist desArg9bradykinin (DBK) and two specific antagonists R-715 and R-954, on diabetic hyperalgesia. Diabetes was induced in male CD-1 mice by injecting a single high dose of STZ (200mg/kg, i.p.) and nociception was assessed using the hot plate, plantar stimulation, tail immersion and tail flick tests. Drugs were injected i.p. twice daily for 7 days, starting 4 days after STZ. We showed that chronically administered R-715 (400 micrograms/kg) and R-954 (200 micrograms/kg), significantly attenuated the hyperalgesic effect developed in STZ-diabetic mice as measured by the four thermal nociceptive tests. Further, chronic treatment with DBK (400 micrograms/kg) produced a marked potentiation of the hyperalgesic activity, an effect that was reversed by both R-715 and R-954. The results from this chronic study confirm a pivotal role of the BKB1-R in the development of STZ-diabetic hyperalgesia and suggest a novel approach to the treatment of this short-term diabetic complication using BKB1-R antagonists.     

Effects of nimodipine on multiunit activity of several brain structures following acute global cerebral ischemia-anoxia in cats.

The effects of nimodipine, a 1,4-dihydropyridine calcium channel blocker, on multiunit activity (MUA) of several brain structures were investigated in cats during 6 h immediately following acute global cerebral ischemia-anoxia induced by a 10 min cardiorespiratory arrest (CRA), as well as in cats exposed to sham procedures corresponding to CRA. Four groups of cats were studied: 1) CRA and continuous administration of nimodipine, 1 microgram/kg/min iv during 6 h; 2) CRA and continuous administration of vehicle; 3) sham and continuous administration of nimodipine as in group 1; 4) sham and vehicle as in group 2. MUA and electroencephalogram disappeared during ischemia-anoxia; their progressive recovery occurred throughout the hours following CRA, although 6 h after CRA MUA was still lower than its control prearrest values in all the recorded subcortical structures. Delta-like waves, isolated spikes, and bursts of fast EEG waves occurred during the recovery of EEG activity. Nimodipine inhibited the otherwise increasing MUA in mesencephalic reticular formation, hippocampus and putamen, but not in ventromedial hypothalamus, during the hours following acute global cerebral ischemia-anoxia. Absence of isolated spikes and bursts of fast EEG activity was noted in the EEG of CRA-, nimodipine-treated cats. Nimodipine significantly reduced MUA in hippocampus but not in other cerebral structures in cats of the sham treated group. The results suggest the involvement of 1,4 dihydropyridine sensitive calcium channels in the cellular mechanisms related to neuronal activity after cerebral ischemia-anoxia, and the possible relationship between the effects of nimodipine on MUA and better functional conditions of the central nervous system after acute global cerebral ischemia-anoxia.     

Reversibility of the haemodynamic effects of anabolic steroids in rats

The haemodynamic effects of 6 weeks nandrolone decanoate treatment (total dose 30 mg.kg-1) (SG I, n = 12) and their reversibility were studied in anaesthetised, open-chest male rats exposed to 5 min isoproterenol (2.5 micrograms.kg-1) and CaCl2 (25.0 mg.kg-1) loads. In SG I, the heart weight and its ratio to body weight were greater than in the untreated rats (CG I, n = 13) (p less than 0.05 and p less than 0.01 respectively). The initial heart rate and the inotropic and chronotropic responses to isoproterenol were lower in SG I than in CG I (p less than 0.05 in all cases). Peripheral resistance decreased during both infusions in SG I but remained unaltered in CG I (p less than 0.05). 6 weeks after finishing anabolic steroid treatment (SG II, n = 11), in the CaCl2-test the ejection fraction (p less than 0.05) and stroke index were smaller than in control rats of the same age (CG II, n = 12). Mean aortic pressure was lower in SG II than in CG II. In the CaCl2-test peripheral resistance was initially higher, but decreased during the infusion in SG II while it increased in CG II (p less than 0.05 in both cases). In conclusion, anabolic steroid treatment reversibly reduces the left ventricular response to isoproterenol. It decreases peripheral vascular tone during inotropic loads. Six weeks after the cessation of treatment, the pumping efficiency of the heart is reduced.     

Influence of stage of the estrous cycle on endogenous opioid modulation of luteinizing hormone, prolactin, and cortisol secretion in the gilt

Fourteen gilts that had displayed one or more estrous cycles of 18-22 days (onset of estrus = Day 0) and four ovariectomized (OVX) gilts were treated with naloxone (NAL), an opiate antagonist, at 1 mg/kg body weight in saline i.v. Intact gilts were treated during either the luteal phase (L, Day 10-11; n = 7), early follicular phase (EF, Day 15-17; n = 3), or late follicular phase (LF, Day 18-19; n = 4) of the estrous cycle. Blood was collected at 15-min intervals for 2 h before and 4 h after NAL treatment. Serum luteinizing hormone (LH) concentrations for L gilts averaged 0.65 +/- 0.04 ng/ml during the pretreatment period and increased to an average of 1.3 +/- 0.1 ng/ml (p less than 0.05) during the first 60 min after NAL treatment. Serum prolactin (PRL) concentrations for L gilts averaged 4.8 +/- 0.2 ng/ml during the pretreatment period and increased to an average of 6.3 +/- 0.3 ng/ml (p less than 0.05) during the first 60 min after NAL treatment. Serum PRL concentrations averaged 8.6 +/- 0.7 ng/ml and 7.6 +/- 0.6 ng/ml in EF and LF gilts, respectively, prior to NAL treatment, and decreased (p less than 0.05) to an average of 4.1 +/- 0.2 ng/ml and 5.6 +/- 0.4 ng/ml in EF and LF gilts, respectively, during the fourth h after NAL. Naloxone treatment failed to alter serum LH concentrations in EF, LF, or OVX gilts and PRL concentrations in OVX gilts.(ABSTRACT TRUNCATED AT 250 WORDS)     

Fentanyl and medetomidine anaesthesia in the rat and its reversal using atipamazole and either nalbuphine or butorphanol.

The intraperitoneal injection of anaesthetic agents is a simple and convenient method of anaesthetizing rats. However, all of the anaesthetic combinations in current use which are administered by intraperitoneal injection produce prolonged sedation, and full recovery of consciousness may take several hours. Fentanyl, a mu agonist opioid, and medetomidine, an alpha 2-adrenoceptor agonist were mixed and administered as a single intraperitoneal injection. Combinations of 300 micrograms/300 micrograms/kg and 300 micrograms/200 micrograms/kg of fentanyl/medetomidine were shown to produce surgical anaesthesia in the rat. This anaesthetic regimen produced significant respiratory depression (P less than 0.01) and animals did not regain their righting reflex until 193 +/- 21 min (mean +/- 1 SD) after injection. Administration by intraperitoneal injection of atipamezole, a specific alpha 2-adrenoceptor antagonist (1 mg/kg) mixed with a mu antagonist/k agonist opioid (nalbuphine, 2 mg/kg or butorphanol 0.4 mg/kg), resulted in a rapid (less than 8 min) reversal of anaesthesia and the associated respiratory depression, and apparent full recovery of consciousness.     

Anti-DNA antibodies bind directly to renal antigens and induce kidney dysfunction in the isolated perfused rat kidney

The pathogenesis of SLE is commonly attributed to the deposition of circulating immune complexes consisting of DNA and anti-DNA autoantibodies. However, recent work has shown multiple cross-reactions between anti-DNA antibodies and a variety of cellular and extracellular Ag. To test the possibility that these antibodies interact directly with glomerular Ag and induce kidney dysfunction, we applied mouse and human anti-DNA IgG to the isolated perfused rat kidney. The NZB/NZW mouse monoclonal anti-DNA bound to glomerular Ag with a concomitant induction of proteinuria and a decrease in inulin clearance. The albumin excretion was 2301 +/- 734 micrograms/min at 160 min of perfusion, as compared with 85 +/- 21 micrograms/min in controls (p less than 0.001). The inulin clearance was reduced to 0.17 +/- 0.02 ml/min as compared with 0.28 +/- 0.09 ml/min in controls (p less than 0.05). Polyclonal anti-DNA IgG obtained from patients with lupus nephritis bound to rat glomeruli and induced albumin excretion of 542 +/- 217 micrograms/min at 160 min of perfusion, as compared with 163 +/- 77 micrograms/min in controls (p = NS). The addition of plasma as a source of C to the human IgG increased the proteinuria markedly (albumin excretion of 1115 +/- 195 micrograms/min at 160 min of perfusion, p less than 0.02), probably due to C activation. Preincubation of the reactive mouse and human IgG with DNA completely abolished their binding to renal tissue and its physiologic consequences. These results suggest that direct binding of anti-DNA antibodies to renal Ag may play an important role in the induction of lupus nephritis.