Dose-dependent effects of adenosine on interstitial fluid adenosine and postischemic function in the isolated rat heart

Exogenous adenosine produces numerous beneficial effects in ischemic myocardium, but pharmacological doses of adenosine are required to exert these effects. This is thought to be due to the rapid metabolism of adenosine by coronary endothelium, although there is no direct evidence supporting this hypothesis in the ischemic/reperfused heart. The purpose of this study was to determine the relationship between vascular and interstitial fluid (ISF) adenosine levels during adenosine-induced cardioprotection. Isolated perfused rat hearts were submitted to 30-min global normothermic ischemia and 30- min reperfusion. Left ventricular developed pressure (LVDP) was measured with a fluid-filled latex balloon, and ISF adenosine was estimated with cardiac microdialysis. Control hearts were compared with hearts treated with increasing doses of adenosine (1, 10 and 100 microM) for 10 min immediately preceding ischemia. Adenosine produced dose-dependent increases in coronary effluent adenosine levels, but only 10 and 100 microM adenosine increased dialysate adenosine concentrations. All adenosine doses increased coronary flow to the same extent, but only the two higher doses decreased spontaneous heart rate. Control and 1 microM adenosine-treated hearts recovered 60 +/- 3% and 46 +/- 7% of preischemic LVDP, respectively, whereas 10 and 100 microM adenosine improved recovery to 80 +/- 5% and 90 +/- 4% of preischemic LVDP, respectively, after 30-min reperfusion. Because ISF bathes the cardiac myocytes, these results are consistent with the hypothesis that adenosine protects the ischemic rat heart via the activation of cardiac myocyte adenosine receptors.     

Acute effects of morphine on rat intestinal motility

The cumulative urinary excretion over 24 h of pentazocine, under conditions of acidic urinary pH, has been measured in smokers and non-smokers using both male and female subjects (seventy subjects in total). A restricted urban population was studied. An overall three-fold inter-subject variation in elimination was observed. The cumulative urinary excretion of pentazocine was normally distributed in both smokers and non-smokers. Smokers metabolize 40% more pentazocine than non-smokers. It is concluded that induction is principally responsible for the observed subject variability.     

Inhibitory effects of catecholamines and maternal stress on aromatase activity in the fetal rat brain

OBJECTIVES: To describe the extent of pain relief two weeks after an epidural steroid injection in patients with herniated disks and lumbar spinal stenosis, and to identify predictors of changes in pain ratings in each population. METHODS: The study design was a prospective evaluation of patients with lumbar spinal stenosis (LSS) and herniated disks (HDs) referred to a hospital-based pain clinic for an epidural steroid injection (ESI). A complete history, detailed physical examination, comprehensive pain questionnaire, and Brief Symptom Inventory were obtained for all patients. Pain was assessed at baseline and two weeks following a single ESI using a visual analog scale. RESULTS: Two hundred twelve patients (mean age 54 years) were enrolled, and 78 of these provided pain ratings before and two weeks after the injection. LSS patients improved less two weeks following the ESI than HD patients (P = 0.04). Just 38% of LSS patients reported improvement in pain score compared with 61% of HD patients. In analyses that combined LSS and HD patients, predictors of worse response included a report of health problems and a diagnosis of LSS. CONCLUSIONS: LSS patients have worse response to ESIs than HD patients. The poor response to ESI in patients with LSS underscores the need for randomized controlled trials of ESI in this population.     

Acute effects of cocaine on ornithine decarboxylase activity in fetal and neonatal rat heart: evidence for cardiotoxicity

Fetal exposure to cocaine is associated with increased perinatal cardiac risk. In the current study, we examined the effects of acute cocaine administration on ornithine decarboxylase (ODC) activity in fetal and neonatal rat heart. ODC is a key regulatory enzyme in the control of cell differentiation and growth, and rapid changes in ODC are associated with the response to cell injury. Administration of 30 mg/kg s.c. of cocaine to pregnant rats on the 20th day of gestation caused acute elevation of fetal cardiac ODC that persisted throughout the ensuing 24 h. In contrast, the same dose given directly to neonatal rats the day after birth evoked only a short-term (1-h) stimulation of ODC that was reversed by 4 h after treatment. By 4 days of age and subsequently, cocaine was unable to elicit acute stimulation of heart ODC and only evoked inhibition of enzyme activity. Elevated progesterone levels during pregnancy have been shown to sensitize the maternal myocardium to cocaine-induced catecholaminergic effects; the greater sensitivity of fetal heart ODC to cocaine, as compared to neonatal heart, supports the hypothesis that similar enhancement of fetal cardiac irritability can contribute to cocaine-induced cell damage.     

Comparison of the effects of ORG 30029, dobutamine and high perfusate calcium on function and metabolism in rat heart

Cardiac contractility may be enhanced via multiple cellular mechanisms resulting in varied effects on cardiac energetics. The mechanisms that account for the varied energetic responses are not well understood. The purpose of this investigation was to compare the effects of the calcium sensitizing agent ORG 30029 (N-hydroxy-5,6-dimethoxy-benzo[b]thiophene-2-carboximidamide hydrochloride, a calcium sensitizing agent which increases contractility without increasing calcium transients significantly), dobutamine and high perfusate calcium on contractility and energetics. Langendorff-perfused rat hearts were stimulated with ORG 30029, dobutamine and high perfusate calcium in graduated concentrations while myocardial oxygen consumption (MVO2) and force-time integral were measured. ORG 30029, dobutamine and high perfusate calcium increased contractility in a dose-dependent manner. Despite an increase of 50% in systolic pressure and a 17% increase in force-time integral from control, ORG 30029 had no significant effect on MVO2 at the lower concentrations (n = 6). However, dobutamine (n = 4) and high perfusate calcium (n = 4) caused a 65% increase in systolic pressure and a 17% increase in force-time integral and a 50% and 41% increase in MVO2 respectively (P < 0.05). High energy phosphates (by 31P NMR), and lactate production were unaltered by these agents, suggesting that metabolism was steady state. Basal metabolism tended to increase slightly with dobutamine but not with ORG 30029 or high perfusate calcium. ORG 30029, dobutamine, and high perfusate calcium increase contractility in perfused rat hearts with disparate effects on energetics. These differences may be accounted for, in part, by differences in energy expenditure for calcium handling.     

Anesthesia with spinal cord stimulation--II). The effects on the cardiovascular function and the level of the plasma catecholamines

In 78 patients who underwent general anesthesia and surgery with nitrous oxide (50-60%) and SCS, SCS decreased heart rate and blood pressure. Both the skin temperature and the amplitude of plethysmographic wave of a left finger increased with SCS. Among plasma catecholamines, only epinephrine level rose significantly with SCS. These results suggest that in addition to the analgesic action, SCS may have sympathetic blocking action, but not suppressive action on release of epinephrine from adrenal gland.     

A 31P-NMR study of the effects of reflow on the ischaemic rat heart

The movement of neutral amino acids across the blood-brain barrier is bidirectional, however, blood to brain transport is much better characterized than brain to blood transport. Available evidence points to the existence of a single transport system (system L) at the luminal capillary surface. The properties of this system place constraints on possible mechanisms of regulating blood-brain neutral amino acid transport activity. One property, mediation of exchange transport, suggests that amino acid influx is coupled to efflux, particularly efflux of glutamine, synthesized in glial astrocytes from ammonia and glutamic acid. Such a coupling could account for increased blood-brain neutral amino acid transport in liver disease and decreased transport activity after treatment with methionine sulfoximine, a glutamine synthetase inhibitor.     

Thrombus formation of the right heart

We investigated the alteration of esophageal pressure (Pes) in 10 patients with upper-airway sleep-disordered breathing (UASDB) and the relationship among Pes, breathing patterns and EEG arousals. Increased negative Pes without apnea or hypopnea, appeared not only in upper airway resistance syndrome but also in obstructive sleep apnea syndrome. This phenomenon produced frequent EEG microarousals leading to sleep fragmentation and daytime sleepiness. Moreover, increased negative Pes occasionally continued for more than 20 min without an EEG arousal, which might be considered to be one of the factors to cause complications of UASDB.     

Pulmonary hypertension after transjugular intrahepatic portosystemic shunt: effects on right ventricular function

The short- and mid-term hemodynamic effects of transjugular intrahepatic portosystemic shunt (TIPS) were studied in 16 sedated cirrhotic patients. Indications included relapsing variceal bleeding (n = 10) and refractory ascites (n = 6). The decrease of porto-atrial pressure gradient (from 20.4 +/- 4.2 mm Hg to 10.1 +/- 2.4 mmHg; P < .05) was associated with an increase of mean pulmonary artery pressure (MPAP) (from 12.3 +/- 3.0 mm Hg to 20.3 +/- 5.3 mm Hg; P < .05) and of right atrial pressure (RAP) from 3.4 +/- 2.6 mm Hg to 8.3 +/- 3.7 mm Hg; P < .05), whereas right ventricular end-diastolic volume (RVEDVI) remained unchanged. The significant increase of cardiac index (CI) (from 4.5 +/- 1.2 L/min/m2 to 5.0 +/- 1.1 L/min/m2; P < .05) was essentially attributable to an increase of heart rate (HR) (from 81 +/- 11 to 88 +/- 10 beats/min; P < .05). Systemic vascular resistance (SVR) decreased (from 812 +/- 281 to 666 +/- 191 dynes/sec/cm5; P < .05), whereas pulmonary vascular resistance (PVR) increased (from 60.6 +/- 29.6 to 82.0 +/- 34.6 dynes/sec/cm5; P < .05). After transient shunt occlusion with a balloon catheter, all of the hemodynamic parameters returned to baseline values, except pulmonary artery pressure, which also decreased but remained significantly increased. One month after TIPS, pulmonary pressure remained elevated, and CI further increased. It is concluded that increased PVR is the major hemodynamic alteration occurring after TIPS placement. It correlates with the decrease of porto-atrial gradient and is probably mediated by both mechanical and neurohumoral factors.     

Acute effects of cell isolation on InsP profiles in adult rat cardiomyocytes

The isolation and culture of adult rat cardiomyocytes was shown to cause major changes in the contents of [3H]-labeled inositol phosphates and inositol phospholipids. Undigested heart tissue contained high levels of [3H]Ins(1,4,5)P3 (5364+/-800 ct/min/g tissue, 80+/-12 ct/min/mg protein) and mass content averaged 13.8 nmol/g tissue or 208+/-36 pmol/mg protein (mean+/-S.E.M., n=4). After collagenase digestion, [3H]Ins(1,4,5)P3 was undetectable and the mass content of Ins(1,4,5)P3 had decreased to 0.8+/-0.2 pmol/mg protein (mean+/-S.E.M., n=4, P<0.01). [3H]Ins(1,4)P2 was reduced by 80% and [3H]PtdIns(4,5)P2 by 90%. These profiles remained essentially unchanged when the isolated cells were maintained in culture for up to 24 h, even though the inositol phosphate response remained sensitive to norepinephrine. Similar to findings in intact tissue, the inositol phosphate response to norepinephrine in these cells was inhibited by neither U-73122 (5 microM) nor by neomycin (5 mM). By 48 h in culture, the relative levels of [3H]Ins(1,4,5)P3 and [3H]Ins(1,4)P2 had increased in relation to the total inositol phosphate content and responses appeared to better reflect intact tissue. However, while retaining insensitivity to neomycin, cells at 48 h were fully sensitive to U-73122 (5 microM). These data demonstrate that altered inositol phosphate responses are observed in adult cardiomyocytes from the time of isolation and that while the profiles change over time in culture, a pattern similar to that in intact heart is not re-established.     

Differential effects of nerve impulses on adrenergic storage vesicles in rat heart

The effects of increasing and decreasing activity in sympathetic neurons on light (D420 = 1.05) and heavy (D420 = 1.15) populations of adrenergic vesicles have been determined. Norepinephrine (NE) was used as a marker for the soluble contents of the vesicles, and dopamine beta-hydroxylase was used as a marker for the vesicle membranes. Cold exposure was used to increase activity in the sympathetic nervous system. A 40% decrease in the NE content of the rat heart with no change in the activity of dopamine beta-hydroxylase was observed after 70 minutes at 5 degrees C. The fall in NE content was completely blocked by pretreating the animals with chlorisondamine. Separation of light and heavy populations of vesicles was achieved with linear sucrose density gradients. Cold stress of 70 minutes duration led to a marked decrease in the NE content of the light vesicles. Blocking adrenergic nerve impulses with chlorisondamine resulted in an increase in total NE in the heart but had no effect on dopamine beta-hydroxylase activity. The initial effect of chlorisondamine was to increase the NE content of the light vesicles. The administration of alpha-methyl-p-tyrosine for 6 hours caused an approximately equal loss of NE from both vesicle populations. The decrease in total heart NE was about 25% and could be prevented by pretreating the animals with chlorisondamine. These results suggest that the light vesicle fraction is involved in the rapid or short-term responses to changes in nerve impulse frequency. Changes in the NE content of the heavy vesicles in rat heart were seen only after longer times, suggesting that these particles may function only as auxiliary storage sites for the neurotransmitter.     

The tocolytic effect of catecholamines in the gravid rat uterus

OBJECTIVE: The aim of the study was to determine the most cost-effective delivery management of vertex and nonvertex twin pair gestations. STUDY DESIGN: Two hundred sixty-six consecutive twin gestations were followed up prospectively in a special antepartum Twins Clinic directed by the Maternal-Fetal Medicine Division. Maternal demographic, obstetric, and neonatal data were compiled prospectively. Information regarding 84 vertex and nonvertex twin pair gestations was extracted for review. Comparison groups included 41 twin pairs managed by spontaneous vaginal delivery and breech extraction (group A), 19 twin pairs managed by spontaneous vaginal delivery and external cephalic version (group B), and 24 twin pairs managed by primary cesarean delivery (group C). In-hospital financial data were retrieved and adjusted for inflation to 1996 constant dollars (data from a single institution allow comparison of charges). The Kruskal-Wallis chi2 test, the Fisher exact test, and analysis of variance were used for statistical analysis. RESULTS: The 3 groups did not differ with respect to maternal demographics, medical complications, gestational age, birth weight, fetal sex, or intrauterine growth restriction. Maternal and neonatal hospital charges were both significantly lower (P = .01 and P = .0001, respectively) in the breech extraction group A ($5890 +/- $2304 and $3526 +/- $5017, respectively) than in either group B ($8638 +/- $4175 and $11,754 +/- $15,457, respectively) or group C ($7,608 +/- $3,256 and $36,994 +/- $54,318, respectively). Although maternal morbidity was similar among the 3 groups, length of stay was shorter for mothers in group A. The infants delivered by spontaneous vaginal delivery and breech extraction (group A) had significantly lower rates of pulmonary disease (7% vs 24% vs 31% for groups A, B, and C, respectively; P = .002) and neonatal infectious disease (1% vs 0% vs 16%; P = .0005). These infants required the use of a ventilator less frequently (5% vs 12% vs 24%; P = .01), were more likely to be admitted to the normal newborn nursery (71% vs 51% vs 50%; P = .0001), and had a significantly shorter length of hospitalization (4.8 vs 12.4 vs 17.8 days; P = .0001). CONCLUSIONS: There is no medical consensus regarding delivery management for vertex and nonvertex presenting twin pairs. When hospital charges are examined with clinical data, however, breech extraction of the nonvertex second twin is the most cost-effective delivery management strategy.     

Acute effects of nasal continuous positive airway pressure on 24-hour blood pressure and catecholamines in patients with obstructive sleep apnea

OBJECTIVE: To estimate the risk for spina bifida associated with the common mutation C677T of the MTHFR gene in a country with a relatively low prevalence of NTDs. DESIGN: Case-control study. SUBJECTS: Cases: 203 living patients affected with spina bifida (173 myelomeningocele and 30 lipomeningocele); controls: 583 subjects (306 young adults and 277 unselected newborns) from northern and central-southern Italy. SETTING: Cases: three spina bifida centres; young adult controls: DNA banks; newborn controls: regional neonatal screening centres. MAIN OUTCOME MEASURES: Prevalence of the C677T genotypes in cases and controls by place of birth; odds ratios for spina bifida and estimated attributable fraction. RESULTS: The prevalence of T/T, T/C, and C/C genotype was 16.6%, 53.7%, and 29.7% in controls and 25.6%, 43.8%, and 30.6% in cases, respectively. We found no differences between type of defect or place of birth. The odds ratio for spina bifida associated with the T/T genotype v C/C plus T/C was 1.73 (95% CI 1.15, 2.59) and the corresponding attributable fraction was 10.8%. No increased risk was found for heterozygous patients (OR=0.79, 95% CI 0.53-1.18). CONCLUSION: This study, as well as the meta-analysis we updated, shows that homozygosity for the MTHFR C677T mutation is a moderate risk factor in Europe, and even in Italy where there is a relatively low prevalence of spina bifida. The estimated attributable fraction associated with this risk factor explains only a small proportion of cases preventable by periconceptional folic acid supplementation. Thus, other genes involved in folate-homocysteine metabolism, their interaction, and the interaction between genetic and environmental factors should be investigated further.     

Influence of the estrous cycle on the sensitivity to catecholamines in right atria from rats submitted to foot-shock stress

We investigated the mechanisms of the alterations in sensitivity to catecholamines in right atria from female rats exhibiting regular 4-day estrous cycles after three foot-shock sessions at estrus, metestrus, and diestrus or at diestrus, proestrus, and estrus. Right atria from stressed rats sacrificed at diestrus showed subsensitivity to noradrenaline and adrenaline. After in vitro sympathetic denervation (38 microM 6-hydroxydopamine) plus inhibition of neuronal reuptake (0.1 microM desipramine) subsensitivity to noradrenaline was abolished, but it was again evident when extraneuronal uptake was also inhibited (10 microM phenoxybenzamine and 30 microM corticosterone). The same pretreatment abolished the subsensitivity to adrenaline. After addition of 1 microM butoxamine, a beta 2-adrenoceptor antagonist, the tissues from stressed rats were subsensitive to adrenaline. Right atria from stressed rats sacrificed at estrus did not show any alteration in sensitivity to catecholamines. We conclude that after foot-shock stress, right atria from female rats sacrificed at diestrus showed subsensitivity of the chronotropic response to catecholamines as a result of a conformational alteration of beta 1-adrenoceptors, simultaneously with an increase in beta 2-adrenoceptor-mediated response. The mechanisms seem to be similar to those which underlie stress-induced alterations in catecholamine sensitivity in right atria from male rats. However, during estrus there are some protective factors that prevent the effects of stress on right atria.