New Mechanism of Extractive Electrospray Ionization Mass Spectrometry for Heterogeneous Solid Particles.

Real-time in situ mass spectrometry analysis of airborne particles is important in several applications, including exposure studies in ambient air, industrial settings, and assessing impacts on visibility and climate. However, obtaining molecular and 3D structural information is more challenging, especially for heterogeneous solid or semisolid particles. We report a study of extractive electrospray ionization mass spectrometry (EESI-MS) for the analysis of solid particles with an organic coating. The goal is to elucidate how much of the overall particle content is sampled, and determine the sensitivity of this technique to the surface layers. It is shown that, for NaNO3 particles coated with glutaric acid (GA), very little of the solid NaNO3 core is sampled compared to the GA coating, whereas for GA particles coated with malonic acid (MA), significant signals from both the MA coating and the GA core are observed. However, conventional ESI-MS of the same samples collected on a Teflon filter (and then extracted) detects much more core material compared to EESI-MS in both cases. These results show that, for the experimental conditions used here, EESI-MS does not sample the entire particle but, instead, is more sensitive to surface layers. Separate experiments on single-component particles of NaNO3, GA, or citric acid show that there must be a kinetics limitation to dissolution that is important in determining EESI-MS sensitivity. We propose a new mechanism of EESI solvent droplet interaction with solid particles that is consistent with the experimental observations. In conjunction with previous EESI-MS studies of organic particles, these results suggest that EESI does not necessarily sample the entire particle when solid, and that not only solubility but also surface energies and the kinetics of dissolution play an important role.

The activities of the international precipitation working group.

The International Precipitation Working Group (IPWG) is a permanent International Science Working Group (ISWG) of the Coordination Group for Meteorological Satellites (CGMS), co-sponsored by CGMS and the World Meteorological Organization (WMO). The IPWG provides a focal point and forum for the international scientific community to address the issues and challenges of satellite-based quantitative precipitation retrievals, and for the operational agencies to access and make use of precipitation products. Through partnerships and biennial meetings, the group supports the exchange of information on techniques for retrieving and measuring precipitation and for enhancing the impact of space-borne precipitation retrievals in numerical weather and hydrometeorological prediction and climate studies. The group furthers the refinement of current estimation techniques and the development of new methodologies for improved global precipitation measurements, together with the validation of the derived precipitation products with ground-based precipitation measurements. The IPWG identifies critical issues, provides recommendations to the CGMS and supports upcoming precipitation-oriented missions. Training activities on precipitation retrieval from space are also part of the IPWG mandate in cooperation with WMO and other bodies.

Multicentre, randomised clinical trial evaluating the efficacy and safety of alfaxalone administered to bitches for induction of anaesthesia prior to caesarean section.

OBJECTIVE: To determine the clinical safety and efficacy of alfaxalone in bitches undergoing caesarean section (CS) and their puppies when it is administered for induction of anaesthesia followed by maintenance with isoflurane and oxygen and in conjunction with perioperative pharmaceuticals. DESIGN: A multicentre, randomised, positive-controlled clinical study. METHODS: A total of 74 bitches were enrolled in the study with 48/74 (65%) and 26/74 (35%) receiving alfaxalone and propofol, respectively, for induction of anaesthesia. Bitches were examined prior to induction and monitored during induction, surgery and recovery. Assessments were made for quality of induction, maintenance and recovery from anaesthesia. Assessments were made on pup viability for suction, dorsal flexion, withdrawal and anogenital reflexes. RESULTS: Of the 48 bitches receiving alfaxalone, 47 (98%) and 39 (81%) scored a top score of excellent for induction and anaesthesia effectiveness, respectively. For the same parameters with propofol in 26 bitches, 23 (88%) and 17 (65%) scored excellent. Average scores for recovery were not different between the two treatment groups with alfaxalone 46/48 (96%) and 25/26 (96%) of propofol induced bitches scoring a good or excellent rating. Bitches tolerated a number of concurrent medications throughout the peri-operative period. No bitch fatalities were observed in this study. There were no statistically significant differences between treatment groups for the puppy variables. Live puppies born by CS to bitches having been administered alfaxalone or propofol had similar survival rates 24 h after birth (i.e. 205/213 (96%) and 124/131 (95%), respectively). CONCLUSION: This study confirms the safety and efficacy of alfaxalone for the purpose of anaesthetic induction for CS in the bitch. In addition, alfaxalone had a negligible effect on the neonate with >95% of puppies alive 24 h after the bitch had recovered from anaesthesia with alfaxalone induction.

Valoración no invasiva de la sobrecarga hepática de hierro en pacientes con hemocromatosis

Nuestro objetivo es analizar el metabolismo y la fisiopatología del depósito de hierro, describir la utilidad de la resonancia magnética (RM) con el empleo de secuencias específicas en la estimación de la sobrecarga hepática de hierro y evaluar las diferentes patologías que la generan en el abdomen, señalando también sus formas de presentación en la RM. La sobrecarga de hierro en el hígado puede ser consecuencia de un trastorno genético (hemocromatosis primaria) o estar relacionada con múltiples transfusiones o enfermedades crónicas, como aumento de la absorción, mielodisplasia, talasemia, etc. (hemocromatosis secundaria). La RM es un método no invasivo que permite detectar la sobrecarga de hierro y monitorear el tratamiento luego del diagnóstico, evitando la repetición de biopsias. Esto se debe a las propiedades paramagnéticas del hierro, cuya acumulación en los tejidos provoca distorsión local en los campos magnéticos, con disminución de la señal en los órganos afectados de forma proporcional a la cantidad de hierro depositado. La RM convencional con secuencias en fase y fuera de fase detecta el depósito de hierro en el hígado, bazo y páncreas, aunque las formas leves pueden pasar inadvertidas si no se utilizan secuencias más sensibles, como las de eco de gradiente. Estas, según la técnica de Gandon et al., permiten estimar cuantitativamente la severidad. El depósito de hierro puede tener un patrón retículo-endotelial (secundario a múltiples transfusiones con depósito en hígado, bazo y médula ósea sin daño tisular), parenquimatoso (hígado y páncreas) o mixto. La RM es fundamental en el diagnóstico de la hemocromatosis, especialmente en la fase subclínica. Contribuye a definir la severidad de la sobrecarga de hierro hepático y a valorar la respuesta al tratamiento, evitando procedimientos invasivos.(AU)

Our purpose is to analyze the metabolism and pathophysiology of iron deposition, to describe the usefulness of magnetic resonance imaging (MRI) in the estimation of hepatic iron overload using specific sequences, and to review the different pathologies leading to iron overload of the abdominal organs and its presentation in MRI. Iron overload in the liver may be due to a genetic condition (primary hemo chromatosis), or due to multiple blood transfusions and chronic diseases like increased absorption, myelodysplasia, thalassemia, etc. (secondary hemochromatosis). MRI is a noninvasive method to detect the presence of iron overload and to monitor treatment after diagnosis, avoiding repeated biopsies. This is due to the paramagnetic properties of iron accumulation in the tissues causing local distortion in the magnetic field. This phenomena is seen as a reduction of the MRI signal in the affected organs, being directly proportional to the amount of iron deposited. The conventional in phase and out of phase MRI sequences can show iron deposition in liver, spleen and pancreas, although milder forms may go undetected if more sensitive sequences, like gradient echo sequence, are not used, according to the technique proposed by Gandon et al., which can estimate quantitatively the severity of iron deposition. Iron deposition can show a reticuloendothelial type pattern (secondary to multiple transfusions where iron deposits in the liver, spleen and bone marrow without tissue damage), a parenchymal pattern (involving the liver and pancreas) and a mixed pattern. MRI has a fundamental role in the diagnosis of hemochromatosis, especially in subclinical phase. It helps to stratify the severity of hepatic iron overload and assess response to treatment, avoiding invasive procedures.(AU)

Valoración no invasiva de la sobrecarga hepática de hierro en pacientes con hemocromatosis / Noninvasive assessment of hepatic iron overload in patients with hemochromatosis

Nuestro objetivo es analizar el metabolismo y la fisiopatología del depósito de hierro, describir la utilidad de la resonancia magnética (RM) con el empleo de secuencias específicas en la estimación de la sobrecarga hepática de hierro y evaluar las diferentes patologías que la generan en el abdomen, señalando también sus formas de presentación en la RM. La sobrecarga de hierro en el hígado puede ser consecuencia de un trastorno genético (hemocromatosisprimaria) o estar relacionada con múltiples transfusiones o enfermedades crónicas, como aumento de la absorción, mielodisplasia, talasemia, etc. (hemocromatosis secundaria). La RM es un método no invasivo que permite detectar la sobrecarga de hierro y monitorear el tratamiento luego del diagnóstico, evitando la repetición de biopsias. Esto se debe a las propiedades paramagnéticas del hierro, cuya acumulación en los tejidos provoca distorsión local en los campos magnéticos, con disminución de la señal en los órganos afectados de forma proporciona la la cantidad de hierro depositado. La RM convencional con secuencias en fase y fuera de fase detecta el depósito de hierro en el hígado, bazo y páncreas, aunque las formas leves pueden pasar inadvertidas si no se utilizan secuencias más sensibles, como las de eco de gradiente. Estas, según la técnica de Gandon et al., permiten estimar cuantitativamente la severidad. El depósito de hierro puede tener un patrón retículo-endotelial (secundario a múltiples transfusiones con depósito en hígado, bazo y médula ósea sin daño tisular), parenquimatoso (hígado y páncreas) o mixto. La RM es fundamental en el diagnóstico de la hemocromatosis, especialmente en la fase subclínica.Contribuye a definir la severidad de la sobrecarga de hierro hepático y a valorar la respuesta al tratamiento, evitando procedimientos invasivos.

Our purpose is to analyze the metabolism and pathophysiology of iron deposition, to describe the usefulness of magnetic resonance imaging (MRI) in the estimation of hepatic iron overload using specific sequences, and to review the different pathologies leading to iron overload of the abdominal organs and its presentation in MRI.Iron overload in the liver may be due to a genetic condition (primary hemo chromatosis), or due to multiple blood transfusions and chronic diseases like increased absorption, myelodysplasia, thalassemia, etc. (secondary hemochromatosis).MRI is a noninvasive method to detect the presence of iron overload and to monitor treatment after diagnosis, avoiding repeated biopsies. This is due to the paramagnetic properties of iron accumulation in the tissues causing local distortion in the magnetic field. This phenomena is seen as a reduction of the MRI signal in the affected organs, being directly proportional to the amount of iron deposited.The conventional in phase and out of phase MRI sequences can show iron deposition in liver, spleen and pancreas, although milder forms may go undetected if more sensitive sequences, like gradient echo sequence, are not used, according to the technique proposed by Gandon et al., which can estimate quantitatively the severity of iron deposition.Iron deposition can show a reticuloendothelial type pattern (secondary to multiple transfusions where iron deposits in the liver, spleen and bone marrow without tissue damage), a parenchymal pattern (involving the liver and pancreas) and a mixed pattern.MRI has a fundamental role in the diagnosis of hemochromatosis, especially in subclinical phase. It helps to stratify the severity of hepatic iron overload and assess response to treatment, avoiding invasive procedures.

Predictors of outcome in fungal keratitis.

PURPOSE: To analyse predictors of clinical outcome in fungal keratitis. METHODS: Data was collected during a prospective, randomized, controlled, double-masked clinical trial of treatment for fungal keratitis. Clinical features at presentation and demographics were collected at the enrollment visit for all patients. Pre-specified clinical outcomes included 3-month visual acuity and infiltrate/scar size, time to re-epithelialization, and corneal perforation. A separate multivariable model with each outcome as the dependent variable included all predictor variables. RESULTS: Predictors for worse 3-month visual acuity include older age (P=0.024), worse presentation visual acuity (P<0.001), larger infiltrate size at presentation (P<0.001), and pigmented ulcer (P=0.030). Larger infiltrate size at presentation was a significant predictor of worse 3-month infiltrate/scar size (P<0.001). Larger epithelial defect size was a significant predictor of perforation (P=0.0013). Predictors of longer time to re-epithelialization include infiltrate size at presentation (P<0.001) and older age (P=0.025). CONCLUSION: Ulcer severity at presentation is highly predictive of worse outcomes. Presentation of clinical characteristics such as baseline acuity and infiltrate scar can provide important information to clinicians about prognosis, and may help guide management and treatment decisions. Prevention of corneal ulcer remains important, as it is difficult to change the course of the ulcer once it has begun.

Serotonergic modulation of startle-escape plasticity in an African cichlid fish: a single-cell molecular and physiological analysis of a vital neural circuit.

Social life affects brain function at all levels, including gene expression, neurochemical balance, and neural circuits. We have previously shown that in the cichlid fish Astatotilapia burtoni brightly colored, socially dominant (DOM) males face a trade-off between reproductive opportunities and increased predation risk. Compared with camouflaged subordinate (SUB) males, DOMs exposed to a loud sound pip display higher startle responsiveness and increased excitability of the Mauthner cell (M-cell) circuit that governs this behavior. Using behavioral tests, intracellular recordings, and single-cell molecular analysis, we show here that serotonin (5-HT) modulates this socially regulated plasticity via the 5-HT receptor subtype 2 (5-HTR(2)). Specifically, SUBs display increased sensitivity to pharmacological manipulation of 5-HTR(2) compared with DOMs in both startle-escape behavior and electrophysiological properties of the M-cell. Immunohistochemistry showed serotonergic varicosities around the M-cells, further suggesting that 5-HT impinges directly onto the startle-escape circuitry. To determine whether the effects of 5-HTR(2) are pre- or postsynaptic, and whether other 5-HTR subtypes are involved, we harvested the mRNA from single M-cells via cytoplasmic aspiration and found that 5-HTR subtypes 5A and 6 are expressed in the M-cell. 5-HTR(2), however, was absent, suggesting that it affects M-cell excitability through a presynaptic mechanism. These results are consistent with a role for 5-HT in modulating startle plasticity and increase our understanding of the neural and molecular basis of a trade-off between reproduction and predation.

Slaughterfloor decontamination of pork carcases with hot water or acidified sodium chlorite - a comparison in two Australian abattoirs.

A decontamination trial on the effectiveness of hot water or acidified sodium chlorite (SANOVA) treatment on Salmonella spp., Escherichia coli and Total Viable Count (TVC) was undertaken on pork carcases prior to primary chilling in two large pork abattoirs in Australia using belly-strip excision sampling. A total of 123 samples from Abattoir A and 400 samples from Abattoir B were cultured and analysed. Test pigs were selected from herds with a known high level of on-farm Salmonella infection. At Abattoir A, Salmonella spp. were not isolated from carcases. The prevalence of E. coli on control carcases was 92.9% compared with 9.8% for hot water and 12.5% for SANOVA treated carcases. The mean log(10) E. coli concentration for control carcases was 0.89 cfu/gram, compared with -0.83 cfu/gram from hot water and -0.75 cfu/gram from SANOVA treated carcases. The mean log(10) TVC for control carcases was 4.06 compared with 1.81 cfu/gram for hot water and 2.76 cfu/gram for SANOVA treated carcases. At Abattoir B, the prevalence of Salmonella on control carcases was 16% compared with 2.7% for hot water and 7.0% for SANOVA treated carcases. The prevalence of E. coli on control carcases was 69.3% compared with 22% for hot water and 30% for SANOVA treated carcases. The mean log(10) E. coli concentration for control carcases was 0.45 cfu/gram, compared with -0.65 cfu/gram from hot water and -0.60 cfu/gram from SANOVA treated carcases. The mean log(10) TVC for control carcases was 3.00 cfu/gram compared with 2.10 cfu/gram for hot water and 2.53 cfu/gram for SANOVA treated carcases. The reductions in prevalence and mean log(10) concentrations in the present trial were all found to be statistically significant and indicate that carcases decontamination with either hot water or SANOVA are effective risk management options immediately available to the pork industry.

Rheumatoid arthritis-associated necrotizing scleritis and peripheral ulcerative keratitis treated successfully with infliximab.

In patients with rheumatoid arthritis (RA), necrotizing scleritis, an ocular manifestation of a systemic vasculitic process, is associated with significant ocular morbidity and high mortality. We present a 60-year-old man with RA who developed necrotizing scleritis and peripheral ulcerative keratitis. The scleritis was refractory to local measures, systemic corticosteroids, and cyclophosphamide but responded rapidly to infliximab. Our case illustrates that biologic agents may be considered in refractory cases of sight- and life-threatening scleritis.

Hybridization and contemporary evolution in an introduced cichlid fish from Lake Malawi National Park.

Rapidly evolving systems offer the chance to observe genetic and phenotypic change in real time. We exploit a well-characterized introduction of cichlid fish into Lake Malawi National Park to document a short history of habitat colonization and the evolution of genes and colour pattern. In the early 1960s, a fish exporter introduced individuals of Cynotilapia afra to a single site (Mitande Point) of Thumbi West Island and, as late as 1983, the species was confined to this location. In 2001, C. afra had colonized the entire perimeter of Thumbi West. In July of that year, we sampled C. afra individuals from six sites around the island and scored variation in dorsal fin colour as well as allelic diversity at six microsatellite loci. We found that, in two decades, C. afra had diverged into genetically distinct, phenotypically different northern and southern populations. We observed a high proportion of hybrids between the introduced C. afra and the native Metriaclima zebra on the southern coast of Thumbi West, and speculate that hybridization is facilitated by low water clarity at these windward sites. The short history of C. afra at Thumbi West is a microcosm of contemporary evolutionary divergence and may provide the opportunity to study the process from start to finish in genetic detail.

Work organization and patient care staff injuries: the impact of different care models for "alternate level of care" patients.

BACKGROUND: The number of elderly patients who do not have acute-care needs has increased in many North American hospitals. These alternate level care (ALC) patients are often cognitively impaired or physically dependent. The physical and psychosocial demands on caregivers may be growing with the increased presence of ALC patients leading to greater risk for injury among staff. METHODS: This prospective cohort study characterized several models for ALC care in four acute-care hospitals in British Columbia, Canada. A cohort of 2,854 patient care staff was identified and followed for 6 months. The association between ALC model of care and type and severity of injury was examined using multinomial and ordinal logistic regression. RESULTS: Regression models demonstrated that the workers on ALC/medical nursing units with "high" ALC patient loads and specialized geriatric assessment units had the greatest risk for injury and the greatest risk for incurring serious injury. Among staff caring for ALC patients, those on dedicated ALC units had the least risk for injury and the least risk for incurring serious injury. CONCLUSIONS: The way in which ALC care is organized in hospitals affects the risk and severity of injuries among patient care staff.

Nitric oxide facilitates vagal control of heart rate via actions in the cardiac parasympathetic ganglia of the anaesthetised dog.

The effects of neuronal inhibition of nitric oxide (NO) production on the bradycardia resulting from stimulation of preganglionic and postganglionic parasympathetic fibres were investigated in an anaesthetised dog preparation following transection of the cervical vagi and in the presence of a beta-adrenoreceptor antagonist. Injection of 1-(2-trifluoromethylphenyl) imidazole (TRIM), an inhibitor of neuronally released NO, into the sinus node artery reduced the bradycardia evoked by right cervical vagal stimulation. In contrast, when the response to preganglionic stimulation had been abolished by hexamethonium (10 mg kg(-1)), the bradycardia following stimulation of postganglionic parasympathetic fibres on the atrial epicardium was unaffected by TRIM. First, these results confirm the facilitatory actions of neuronally released NO on vagal heart responses in the dog. Second, they indicate that this modulatory and facilitatory role of NO is likely to be exerted at vagal preganglionic-postganglionic synaptic mechanisms in the cardiac parasympathetic ganglia and not at the postganglionic-sinoatrial node synapse.

Inhibition of neuronal nitric oxide reduces heart rate variability in the anaesthetised dog.

In the vagally intact anaesthetised dog, we have investigated the role of nitric oxide (NO) on a normal sinus arrhythmia using an inhibitor of neuronally released NO, 1-(2-trifluoromethylphenyl) imidazole (TRIM). The mean and S.D. of the R-R interval was used to describe mean heart rate and heart rate variability, respectively. TRIM (0.8 mg I.C.) injected into the sinus node artery increased the mean heart rate slightly but reduced heart rate variability 3-fold from a control of 790 +/- 124 ms (mean +/- S.D.; n = 5) to 666 +/- 36 ms (P < 0.01 Student's paired t test, n = 5). These results suggest that neuronally released NO may have a vagal facilitatory role in the maintenance of sinus arrhythmia in the normal heart.

Dehydration, hydration behavior, and structural analysis of fenoprofen calcium.

Fenoprofen calcium (FC) is a nonsteroidal, anti-inflammatory, analgesic, and antipyretic agent. The dehydration behavior of FC dihydrate and the rehydration of the dried FC were investigated using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and powder X-ray diffractometry (PXRD). The stoichiometry, the crystal packing arrangement, and water environments in FC dihydrate were determined using single-crystal X-ray diffraction (XRD) analysis. The Arrhenius plot (natural logarithm of the dehydration rate constant versus the reciprocal of absolute temperature) for FC dihydrate from isothermal TGA is not linear. The activation energy of dehydration was 309 kJ/mol in the 50-60 degrees C range and 123 kJ/mol in the 60-80 degrees C range. The difference in activation energy can be explained from the crystal structure data where one water molecule is sandwiched between repeating polar carboxylate groups and the other water is in a slightly less polar region of the crystal. Single-crystal XRD analysis also indicated each calcium ion is coordinated to six oxygens. Two coordinating oxygens are provided by two water molecules and the other four oxygens are provided by the carboxylate group of four separate fenoprofen anions. Each fenoprofen anion, which can provide two oxygens for coordination, is associated with two different calcium ions. Hot-stage PXRD suggested that only a loss of 1 mole of water per mole of FC dihydrate (forming a monohydrate) was required to convert the material to a partially crystalline state. The monohydrate is not completely disordered as evidenced by a strong diffraction peak as well as some weaker peaks in the PXRD pattern. The rehydration of the anhydrous form of FC follows a solution-mediated transformation, prior to crystallizing as the dihydrate.

A randomised controlled trial of epidural compared with non-epidural analgesia in labour.

OBJECTIVES: To investigate possible short and long term side effects of epidural analgesia, compared with non-epidural analgesia for pain relief in labour. DESIGN: Randomised controlled study, with long term follow up by questionnaire. Analysis by intention-to-treat. SETTING: Busy maternity unit within a district general hospital in England. PARTICIPANTS: Three hundred and sixty nine primigravid women in labour were included (randomised allocation: epidural n = 184, non-epidural n = 185). MAIN OUTCOME MEASURES: Backache at three and twelve months after delivery, instrumental delivery rates and maternal opinion of pain relief in labour. RESULTS: No significant differences were found in the reported incidence of backache between the groups at three months: middle backache [22% vs 20%, chi2 = 0.057, P = 0.81; odds ratio (95% CI) 1.4(0.9-2.3)]; low backache [35% vs 34%, chi2 = 0.009, P = 0.92; odds ratio (95% CI) 1.0(0.6-1.6)]. Nor were there significant differences at 12 months: [middle backache 16% vs 16%, chi2 = 0.013, P = 0.91; odds ratio (95% CI) 1.0(0.5-1.8)]; or low backache [35% vs 27%, chi2 = 1.91, P = 0.17; odds ratio (95% CI) 1.4(0.9-2.3)]. The incidence of instrumental delivery was somewhat higher in the epidural group [30% vs 19%, odds ratio (95% CI) 1.77(1.09-2.86)]. Maternal satisfaction was not significantly different between the groups. CONCLUSIONS: This study provided no evidence to support the suggestion of a direct association between the use of epidural anaesthesia in labour and the incidence of long term backache. Despite a significant proportion of women in each group not receiving their allocated analgesia, a significant difference in terms of instrumental delivery rates remained. Satisfaction in both groups of women was high.

Neuronal nitric oxide facilitates vagal chronotropic and dromotropic actions on the heart.

Previous studies, using non-specific nitric oxide synthase (NOS) inhibitors, have shown that nitric oxide (NO) has a significant facilitatory effect on the actions of the vagus nerve on several aspects of cardiac function. The present study aims to identify a potential neuronal site for the action of NO by using the n-NOS inhibitor, 1-(2-trifluoromethylphenyl) imidazole (TRIM) in the ferret and other mammals. The effects of TRIM on vagally evoked alterations in heart rate and atrio-ventricular (a-v) conduction in the anaesthetised ferret, rabbit and guinea pig are described. In ferrets with both vagi sectioned and repeated infusions of propranolol, the vagally evoked, frequency-dependent bradycardia was significantly attenuated by infusion of TRIM (10-30 mg kg(-1)). This effect was reversed by subsequent infusion of L-arginine (20-6 mg kg(-1)). TRIM also attenuated to a similar extent the vagally evoked bradycardia in similarly prepared guinea pigs, but NOS inhibition and the use of the NO donor, molsidimine, failed to alter the heart rate effects of vagal stimulation in the rabbit. In studies on a-v conduction (dromotropy) in the ferret, electrical stimulation of the left cervical vagus increased the a-v conduction time in a frequency-dependent manner. Administration of TRIM (30 mg kg(-1)) significantly attenuated this response. Again, L-arginine (60 mg kg(-1)) reversed it. Since an alteration in heart rate may have a concomitant action on a-v conduction time, the effects of vagal stimulation on a-v conduction were also carried out in ferrets with the heart paced at a constant rate electrically. There was no significant difference between the effects of vagal stimulation obtained from hearts which were paced and those which were unpaced. This implies that vagal stimulation had a direct effect on a-v delay and the changes were not secondary to alterations in cardiac rate. Based on other evidence that TRIM is a powerful reversible n-NOS inhibitor in vivo, our studies support strongly the hypothesis that NO liberated from neuronal sources has an important facilitatory action on the vagal control of the heart. In relation to vagal heart rate control, it has now been shown that, in line with other studies in the dog and the rat, NO exerts a powerful facilitatory action in the ferret and the guinea pig but not in the rabbit. It is to be expected that these effects of NO will also be demonstrable on other vagal cardiac actions.

The role of nitric oxide in the control by the vagal nerves of the heart of the ferret.

This study focuses on the potential role for nitric oxide on the actions of the parasympathetic innervation to the heart. Earlier, we showed that the nitric oxide synthase (NOS) inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) reduced the bradycardia induced by stimulation of vagal efferent motor fibres and that these effects are reversible through administration of the NOS substrate L-arginine. In the present study, we show that D-arginine does not reverse the effects of the inhibitors and confirm that they are reversed by L-arginine. Another NOS inhibitor, NG-nitro-L-arginine (L-NOARG), produced similar effects which were not reversed by L-arginine. In an examination of the effect of increasing NO availability with the NO donor sodium nitroprusside the vagally induced bradycardia was enhanced at all frequencies tested. In a separate series, the effects of NOS inhibitors and NO donors on the dromotropic actions of the vagus were examined. The NOS inhibitor L-NAME, reduced the increase in atrio-ventricular conduction delay normally induced by efferent vagal stimulation at all frequencies tested both in the 'paced' and 'unpaced' heart. Further, sodium nitroprusside enhanced this delay. Overall the study indicates that NO has an important facilitatory role on both the chronotropic and dromotropic actions of the vagus nerve on the heart and that NO may be a rate-limiting factor in the cardiac responses to vagal stimulation.