Is walking netball an effective, acceptable and feasible method to increase physical activity and improve health in middle- to older age women?: A RE-AIM evaluation.

BACKGROUND: Physical activity is a modifiable risk factor for health and wellbeing, all-cause mortality and healthy aging. However, for middle- to older-age females less is known about the benefits of sports participation on these outcomes. Further, the acceptability and feasibility of setting-up, implementing and maintaining sports-based programmes for an aging population is an understudied area of inquiry. The current study used the RE-AIM framework to investigate a nationwide Walking Netball (WN) programme. METHODS: The evaluation used a mixed-methods approach incorporating a multiple-baseline study, quasi-experimental study, programme monitoring data and qualitative studies to evaluate the programme in the Women's Institutes (WI) in England. Data were analysed using multilevel growth modelling, mixed-design ANOVAs, multilevel regression, t-testing, and thematic analysis. Data were triangulated to address each dimension of the RE-AIM framework. FINDINGS: The programme reached 1.4% (n = 3148) of the WI population across 82.0% of WI regions in England and attracted inactive members at risk of ill-health. WN contributed to adaptations in physical function, mental health and wellbeing, social isolation, quality of life and increased physical activity. The adoption of the programme was successful with 87.7% WN groups' maintaining participation beyond the 20-session initial delivery phase. Adoption was effective because of its set-up, peer-mentorship and long-term delivery; these factors likewise shaped implementation. Adapting and tailoring WN to the varying characteristics of participants within the WI and the facilities available, along with training delivery staff and providing resources are key programme components. The Walking Netball programme can be maintained through promotion within the local community, sustainable funding, inter-WI competitions, festivals and networks, multiple-hosts and continued host development. CONCLUSIONS: WN was found to be an acceptable, feasible and effective intervention to increase physical activity and improve health in middle- to older- aged women. Future programmes may consider adapted styles of set-up and delivery. These include adapting to people, places and spaces through personalised support and providing a range of resources. Future designs may seek to understand how participation can contribute to healthy aging through longitudinal research beyond 12-months. STUDY REGISTRATION: The evaluation protocol was published in Open Science Framework in December 2018 prior to follow-up data collection being collected ( https://www.osf.io/dcekz ). Date of registration: 17 December 2018.

Acute and chronic effects of hot water immersion on inflammation and metabolism in sedentary, overweight adults.

Regular exercise-induced acute inflammatory responses are suggested to improve the inflammatory profile and insulin sensitivity. As body temperature elevations partly mediate this response, passive heating might be a viable tool to improve the inflammatory profile. This study investigated the acute and chronic effects of hot water immersion on inflammatory and metabolic markers. Ten sedentary, overweight men [body mass index (BMI): 31.0 ± 4.2 kg/m2, mean ± SD] were immersed in water set at 39°C for 1 h (HWI) or rested for 1 h at ambient temperature (AMB). Venous blood was obtained before the session, immediately postsession, and 2 h postsession for assessment of monocyte intracellular heat shock protein-72 (iHsp72) and plasma concentrations of extracellular Hsp72 (eHsp72), interleukin-6 (IL-6), fasting glucose, insulin, and nitrite. Thereafter, participants underwent a 2-wk intervention period, consisting of 10 hot water immersion sessions (INT). Eight BMI-matched participants (BMI: 30.0 ± 2.5 kg/m2) were included as control (CON). Plasma IL-6 and nitrite concentrations were higher immediately following HWI compared with AMB (IL-6 P < 0.001, HWI: 1.37 ± 0.94 to 2.51 ± 1.49 pg/ml; nitrite P = 0.04, HWI: 271 ± 52 to 391 ± 72 nM), whereas iHsp72 expression was unchanged ( P = 0.57). In contrast to resting iHsp72 expression ( P = 0.59), fasting glucose ( P = 0.04; INT: 4.44 ± 0.93 to 3.98 ± 0.98 mmol/l), insulin ( P = 0.04; INT: 68.1 ± 44.6 to 55.0 ± 29.9 pmol/l), and eHsp72 ( P = 0.03; INT: 17 ± 41% reduction) concentrations were lowered after INT compared with CON. HWI induced an acute inflammatory response and increased nitric oxide bioavailability. The reductions in fasting glucose and insulin concentrations following the chronic intervention suggest that hot water immersion may serve as a tool to improve glucose metabolism. NEW & NOTEWORTHY A single hot water immersion (HWI) session induces an acute increase in plasma interleukin-6 and nitrite concentrations but does not acutely elevate heat shock protein-72 expression in monocytes [intracellular Hsp72 (iHsp72)]. A chronic HWI intervention reduces fasting glucose and insulin concentrations in the absence of changes in resting iHsp72. Therefore, HWI shows potential as a strategy to combat chronic low-grade inflammation and improve glucose metabolism in individuals without the physical capacity to do so using exercise.

Effects of montmorency tart cherry (L. Prunus Cerasus) consumption on nitric oxide biomarkers and exercise performance.

The purpose of this study was to investigate the effects of Montmorency tart cherry juice (MC) on nitric oxide (NO) biomarkers, vascular function, and exercise performance. In a randomized, double-blind, placebo (PLA)-controlled, crossover study, 10 trained cyclists (mean ± SD; V˙O2peak 59.0 ± 7.0 mL/kg/min) acutely ingested 30 mL of either MC or PLA following dietary restrictions of polyphenol-rich compounds and completed 6-minutes moderate- and severe-intensity cycling bouts 1.5 hour post-ingestion on 2 occasions for each experimental condition. The severe-intensity cycling test was continued to exhaustion on 1 occasion and immediately followed by a 60-seconds all-out sprint on the other occasion. Blood pressure, pulse wave measures, tissue oxygenation index, and plasma nitrite concentration were assessed pre- and 1.5 hour post-ingestion. Time to exhaustion was not different between conditions (P > .05), but peak power over the first 20 seconds (363 ± 42 vs 330 ± 26 W) and total work completed during the 60-seconds all-out sprint (21 ± 3 vs 19 ± 3 kJ) were 10% higher in the MC trial compared to the PLA trial (P < .05). Systolic blood pressure was 5 ± 2 mm Hg lower 1.5 hour post-MC supplementation compared to PLA supplementation (P < .05). There were no differences in pulse wave measures, plasma nitrite concentration, or tissue oxygenation between the MC and PLA trials (P > .05). These results suggest that acute supplementation with MC can lower blood pressure and improve some aspects of exercise performance, specifically end-sprint performance, in trained cyclists.

Evaluation of a fast, objective tool for assessing body condition of budgerigars (Melopsittacus undulatus).

There is currently no suitable system available for the assessment of budgerigar body condition. A tool has been developed that uses an algorithmic decision tree of yes-no answers based on physical examination to objectively guide the assessor to a body condition score. The aim of this work was to evaluate the guide. Repeatability and reproducibility were measured by four assessors on three sequential days, using 38 budgerigars of mixed sex, age and weight. Data were analysed using a 3-factor anova, with Person and Bird as variable factors and occasion as a fixed factor. The association between body condition score and body fat was measured using three assessors and 63 dead budgerigars, which were chemically analysed for fat content after assessment. Data were statistically analysed to determine correlation using Spearman's Rank Coefficient. Occasion and person had no significant effect on body condition score (p = 0.988 and 0.347 respectively). Body condition score and percentage body fat were highly significantly correlated (R(2) = 0.768): percentage fat increased with increasing body condition score. The guide would appear to be a repeatable measure of body condition in budgerigars, suitable for use during physical examinations.

A 'new' method to normalise exercise intensity.

Exercise intensity has traditionally been described, prescribed and normalised as a fraction (%) of the maximal oxygen uptake ( V˙O (2max)). We hypothesised that the extent of inter-subject variability in the physiological responses to exercise would be greater when work rates were prescribed using % V˙O (2max) as compared to % 'delta' (Δ), a method of normalising exercise intensity in which both the gas exchange threshold (GET) and the V˙O (2max) are considered. 9 men completed a ramp incremental test on a cycle ergometer to establish the GET and V˙O (2max). Subsequently, subjects completed 6 constant-work-rate exercise bouts at intensities corresponding to: 50%, 70% and 90% V˙O (2max); and 60% GET, 40% Δ (that is, 40% of the difference between the GET and V˙O (2max)) and 80% Δ. For all bouts, exercise was continued for 20 min or until task failure if this occurred sooner. When exercise was prescribed using the % Δ concept, there were significant reductions in the inter-subject variability in pulmonary gas exchange, blood lactate accumulation, heart rate, and ratings of perceived exertion (all P < 0.05). In conclusion, the % Δ concept resulted in more consistent inter-subject physiological responses to constant-work-rate exercise and should be used in preference to % V˙O (2max) to more effectively normalise exercise intensity.

Chronic administration of 13-cis-retinoic acid does not alter the number of serotoninergic neurons in the mouse raphe nuclei.

The synthetic retinoid 13-cis-retinoic acid (13-cis-RA), prescribed for the treatment of severe nodular acne, has been linked to an increased incidence of depression. Chronic treatment studies in rodents have shown that 13-cis-RA induces an increase in depression-related behaviours and a functional uncoupling of the hippocampus and dorsal raphe nucleus (DRN). Changes in the number of serotoninergic neurons in the DRN have been reported in depressed human patients. Given that retinoids have apoptotic effects, we hypothesized that a decrease in the number of serotoninergic neurons in the DRN or median raphe nucleus (MRN) would lead to decreased serotoninergic tone and in turn to the behavioural changes seen with 13-cis-RA administration. Here, we used immunolabelling and unbiased stereological methods to estimate the number of serotonin (5-hydroxytryptamine, 5-HT) neurons in the MRN and DRN of vehicle control and 13-cis-RA-treated adult mice. In the MRN, the number of 5-HT immunolabelled cells was 1815±194 in control, compared with 1954±111 in 13-cis-RA treated tissues. The number of 5-HT immunolabelled cells was much higher in the DRN, with 7148±377 cells in the control, compared with 7578±424 in the 13-cis-RA treated group. Further analysis of the DRN revealed that there were no changes in the number of 5-HT neurons within distinct subregions of the DRN. Similarly, changes in the density of serotoninergic neurons or in the volume of the MRN or DRN were not observed in 13-cis-RA treated animals. These data show that apoptotic actions of 13-cis-RA do not occur in vivo at drug concentrations that induce changes in depression-related behaviour and functional uncoupling of the DRN and hippocampus. The potential pro-depressant behavioural and molecular effects associated with chronic administration of 13-cis-RA may result from changes in serotoninergic activity rather than changes in the number of serotoninergic neurons.

Inhibition by glucose or leptin of hypothalamic neurons expressing neuropeptide Y requires changes in AMP-activated protein kinase activity.

AIMS/HYPOTHESIS: Changes in the activity of glucose-excited and glucose-inhibited neurons within the basomedial hypothalamus are key to the central regulation of satiety. However, the molecular mechanisms through which these cells respond to extracellular stimuli remain poorly understood. Here, we investigate the role of 5'-AMP-activated protein kinase (AMPK), a trimeric complex encoded by seven distinct genes of the PRKA family, in the responses to glucose and leptin of each cell type. METHODS: The activity of isolated rat basomedial hypothalamic neurons was assessed by: (1) recording cellular voltage responses under current clamp; (2) measuring intracellular free Ca(2+) with fluo-3 or fura-2; and (3) developing a neuropeptide Y (NPY) promoter-driven adenovirally produced ratiometric 'pericam' (a green fluorescent protein-based Ca(2+) sensor) to monitor [Ca(2+)] changes selectively in NPY-positive neurons. RESULTS: The stimulatory effects of decreased (0 or 1.0 vs 15 mmol/l) glucose on glucose-inhibited neurons were mimicked by the AMPK activator, 5-amino-imidazole-4-carboxamide riboside (AICAR) and blocked by the inhibitor Compound C. Similarly, AICAR reversed the inhibitory effects of leptin in the majority of glucose-inhibited neurons. The responses to glucose of Npy-expressing cells, which represented approximately 40 % of all glucose-inhibited neurons, were also sensitive to Compound C or AICAR. Forced changes in AMPK activity had no effect on glucose-excited and non-glucose-responsive neurons. CONCLUSIONS/INTERPRETATION: Changes in AMPK activity are involved in the responses of glucose-inhibited neurons to large fluctuations in glucose concentration, and possibly also to leptin. This mechanism may contribute to the acute reduction of electrical activity and Ca(2+) oscillation frequency in these, but not other neurons, in the basomedial hypothalamus.

The Tabby cat locus maps to feline chromosome B1.

The Tabby markings of the domestic cat are unique coat patterns for which no causative candidate gene has been inferred from other mammals. In this study, a genome scan was performed on a large pedigree of cats that segregated for Tabby coat markings, specifically for the Abyssinian (Ta-) and blotched (tbtb) phenotypes. There was linkage between the Tabby locus and eight markers on cat chromosome B1. The most significant linkage was between marker FCA700 and Tabby (Z = 7.56, theta = 0.03). Two additional markers in the region supported linkage, although not with significant LOD scores. Pairwise analysis of the markers supported the published genetic map of the cat, although additional meioses are required to refine the region. The linked markers cover a 17-cM region and flank an evolutionary breakpoint, suggesting that the Tabby gene has a homologue on either human chromosome 4 or 8. Alternatively, Tabby could be a unique locus in cats.

Pre- and post-synaptic abnormalities associated with impaired neuromuscular transmission in a group of patients with 'limb-girdle myasthenia'.

The properties of neuromuscular junctions (NMJs) were studied in motor-point biopsy samples from eight patients with congenital myasthenic syndromes affecting primarily proximal limb muscles ['limb-girdle myasthenia' (LGM)]. All had moderate to severe weakness of the proximal muscles, without short-term clinical fatigability but with marked variation in strength over periods of weeks or months, with little or no facial weakness or ptosis and no ophthalmoplegia. Most had a characteristic gait and stance. All patients showed decrement of the compound muscle action potential (CMAP) on repetitive stimulation at 3 Hz, and increased jitter and blocking was detected by SFEMG, confirming the presence of impaired neuromuscular transmission. None of the patients had serum antibodies against acetylcholine receptors (AChRs). Two of the patients had similarly affected siblings. Intracellular recording from isolated nerve-muscle preparations revealed that the quantal content (the number of ACh quanta released per nerve impulse) was only approximately 50% of that in controls. However, the quantal size (amplitude of miniature end-plate currents) and the kinetic properties of synaptic potentials and currents were similar to control values. The area of synaptic contact and extent of post-synaptic folding were approximately 50% of control values. Thus, the quantal content per unit area of synaptic contact was normal. The number of AChRs per NMJ was also reduced to approximately 50% of normal, so the local AChR density was normal. Immunolabelling studies revealed qualitatively normal distributions and abundance of each of 14 proteins normally concentrated at the NMJ, including components of the basal lamina, post-synaptic membrane and post-synaptic cytoskeleton. DNA analysis failed to detect mutations in the genes encoding any of the following proteins: AChR subunits, rapsyn, ColQ, ChAT or muscle-specific kinase. Response of these patients to treatment was varied: few showed long-term improvement with pyridostigmine and some even deteriorated with treatments, while others had intolerable side-effects. Several patients showed improvement with 3,4-diaminopyridine, but this was generally only transient. Ephedrine was helpful in half of the patients. We conclude that impaired neuromuscular transmission in these LGM patients results from structural abnormalities of the NMJ, including reduced size and post-synaptic folding, rather from any abnormality in the immediate events of neuromuscular transmission.

White spotting in the domestic cat (Felis catus) maps near KIT on feline chromosome B1.

Five feline-derived microsatellite markers were genotyped in a large pedigree of cats that segregates for ventral white spotting. Both KIT and EDNRB cause similar white spotting phenotypes in other species. Thus, three of the five microsatellite markers chosen were on feline chromosome B1 in close proximity to KIT; the other two markers were on feline chromosome A1 near EDNRB. Pairwise linkage analysis supported linkage of the white spotting with the three chromosome B1 markers but not with the two chromosome A1 markers. This study indicates that KIT, or another gene within the linked region, is a candidate for white spotting in cats. Platelet-derived growth factor alpha (PDGFRA) is also a strong candidate, assuming that the KIT-PDGFRA linkage group, which is conserved in many mammalian species, is also conserved in the cat.

Localizing the X-linked orange colour phenotype using feline resource families.

Many genes influencing mammalian coat colours are well conserved. While genes responsible for pelage phenotypes in one species provide strong evidence for a candidate gene in a different species, the X-linked orange phenotype of the domestic cat is unique within mammals. The orange locus (O) undergoes X-inactivation, producing females that express both wildtype black (wt) and orange (variant) phenotypes when heterozygous (tortoiseshell). The orange locus has not yet been localized on the X chromosome. Tortoiseshell male cats have been identified but have been shown to be sex chromosome trisomies (XXY). To localize the cat orange locus, 10 feline-derived X-linked microsatellites were analysed in two extended cat pedigrees consisting of 79 and 55 individuals, respectively, segregating for the orange phenotype. Linkage analyses excluded close association of orange in the vicinity of the nine informative X-linked microsatellites. One marker was not polymorphic within either family. Several markers suggested exclusion (Z < -2.0) at distances of 7.5-33 cM. Exclusion analyses suggested a possible location for orange a 14 cM region near Xcen. Recombination distances of markers in the segregating feline pedigrees were reduced as compared with the feline interspecies backcross family. Thus, the presented pedigrees may be useful as reference families for the domestic cat because more accurate recombination rates for domestic cats can be determined.

Effects of adenosine 5'-triphosphate, uridine 5'-triphosphate, adenosine 5'-tetraphosphate and diadenosine polyphosphates in guinea-pig taenia caeci and rat colon muscularis mucosae.

The functional effects of adenosine 5'-triphosphate (ATP), uridine 5'-triphosphate (UTP), adenosine 5'-tetraphosphate (AP4) and the diadenosine polyphosphates P1,P3-diadenosine triphosphate (Ap3A), P1,P4-diadenosine tetraphosphate (Ap4A) and P1,P5-diadenosine pentaphosphate (Ap5A) were studied in two isolated smooth muscle preparations thought to contain P2Y (P2Y1) receptors, the guinea-pig taenia caeci (which relaxes to ATP) and the rat colon muscularis mucosae (which contracts to ATP). In addition, the breakdown of these compounds by the rat colon muscularis mucosae was investigated by high pressure liquid chromatography. In the guinea-pig taenia caeci all the purine nucleotides caused relaxation with a potency order of Ap3A=Ap4A> ATP>AP4=Ap5A, and these relaxations were antagonised by suramin with apparent pA2 values in the region of 5, consistent with activation of a P2Y1 receptor. In the rat colon muscularis mucosae the nucleotides caused contraction with a potency order of Ap3A = Ap4A>ATP=AP4 =Ap5A >UTP. However, while suramin (100 microM) inhibited responses to ATP and UTP at all concentrations of agonist, it only inhibited contractions induced by the higher concentrations of AP4, Ap3A and Ap4A and had little effect on contractions induced by Ap5A. A higher concentration of suramin (1 mM) enhanced contractions induced by ATP but greatly inhibited those induced by UTP and had no effect on responses to the other agonists. The A1 adenosine receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 10 nM) had no effect on responses to ATP or UTP but inhibited responses to Ap3A, Ap4A, Ap5A and AP4. A combination of suramin (1 mM) and DPCPX (10 nM) almost abolished responses to all the agonists. ATP and UTP were rapidly degraded by the rat colon muscularis mucosae while AP4, Ap3A, Ap4A and Ap5A were degraded more slowly, and the major product detected after breakdown of the purine nucleotides was inosine rather than adenosine. The breakdown of all the nucleotides was inhibited by suramin (1 mM), although this inhibition did not achieve statistical significance in the case of ATP. These results show that while the diadenosine polyphosphates appear to act as P2 agonists in the taenia caeci, in the rat colon muscularis mucosae their major action is via adenosine A1 receptors rather than via P2 receptors. In addition, although they are more stable than ATP or UTP, their action in this tissue is clearly affected by their degradation which complicates the effects of suramin.

Neuroprotective effect of recombinant neutrophil inhibitory factor in transient focal cerebral ischaemia in the rat.

The neuroprotective effects of recombinant neutrophil inhibitory factor (NIF) have been assessed with temporary (2 h) middle cerebral artery (MCA) occlusion in the rat using the intraluminal suture technique. Administration of NIF (1.5 mg/kg, i.v.) immediately after the onset of reperfusion and at 4 and 6 h post-MCA occlusion significantly reduced both hemispheric infarct volume (P < 0.001) and brain swelling (P < 0.001), and improved neurological outcome (P < 0.02) when assessed at 24 h. These results demonstrated the marked neuroprotective efficacy of NIF in a rat model of transient focal cerebral ischaemia.

Failure of isradipine to reduce infarct size in mouse, gerbil, and rat models of cerebral ischemia.

BACKGROUND AND PURPOSE: The dihydropyridine L-type calcium channel blocker isradipine has been reported to exhibit neuroprotective properties in some, but not all, studies performed in the rat middle cerebral artery occlusion (MCAO) model. In the present study, we examined isradipine in several other models of focal and global ischemia: rat rose bengal, mouse MCAO, and gerbil bilateral carotid artery occlusion (BCAO). For comparison, a novel calcium channel blocker, SB201823A, that we have previously shown to be neuroprotective in rat and gerbil models was also examined in the mouse. METHODS: In the gerbil BCAO model, isradipine was administered at 2.5 mg/kg i.p. as a single dose 60 minutes after ischemia (n = 10). Corresponding controls received vehicle (n = 10), and sham-operated animals received no treatment (n = 6). Locomotor activity and histological assessments were made at 4 days after ischemia. In the rat photothrombotic occlusion model, isradipine was administered at 2.5 mg/kg i.p. as a single dose 60 minutes after ischemia (n = 10), and corresponding controls (n = 10) received vehicle. Histological assessment was made at 7 days after ischemia. In the mouse MCAO model, isradipine was also administered at 2.5 mg/kg i.p. as a single dose 60 minutes after ischemia. Histological assessments were made at 1 (n = 13), 2 (n = 9), and 4 (n = 9) days after ischemia. Vehicle numbers were n = 10, n = 6, and n = 8, respectively. Isradipine and SB201823A were also examined using a combined preischemia and postischemia regimen. Isradipine was administered at 2.5 mg/kg i.p. before occlusion, 1.25 mg/kg i.p. 1 hour after occlusion, 1.25 mg/kg i.p. 2 hours after occlusion, and 2.5 mg/kg twice a day for 3 days after occlusion (n = 16). Corresponding controls received vehicle at the same time points (n = 14). SB201823A was administered 30 minutes before occlusion, 30 minutes after occlusion, and twice daily for 3 days (n = 12). Corresponding controls received vehicle (n = 9). Histological assessment was performed at 4 days after ischemia. RESULTS: When given after ischemia, isradipine failed to affect lesion volume in both the rat and mouse models. In the gerbil, locomotor hyperactivity and hippocampal cell loss were unaffected. Given before and after ischemia in the mouse, isradipine was also ineffective, whereas SB201823A produced a significant reduction in lesion volume. CONCLUSIONS: The L-type calcium channel blocker isradipine was devoid of neuroprotective activity in focal and global models of cerebral ischemia in three species of normotensive animals. These results were compared with data for the novel calcium channel blocker SB201823A, which exhibited a significant effect after pre- and postocclusion administration in the mouse model of permanent focal ischemia.

SB 201823-A antagonizes calcium currents in central neurons and reduces the effects of focal ischemia in rats and mice.

BACKGROUND AND PURPOSE: Excessive calcium entry into depolarized neurons contributes significantly to cerebral tissue damage after ischemia. We evaluated the ability of a novel neuronal calcium channel blocker, SB 201823-A, to block central neuronal calcium influx in vitro and to reduce ischemic injury in two rodent models of focal stroke. METHODS: Patch-clamp electrophysiology and intracellular Ca2+ imaging in rat hippocampal and cerebellar neurons were used to determine effects on neuronal calcium channel activity. Middle cerebral artery occlusion was performed in Fisher 344 rats and CD-1 mice to determine the effects on rodent focal ischemic injury and neurological deficits. Cardiovascular monitoring in conscious rats was conducted to determine cardiovascular liabilities of the compound. RESULTS: In cultured rat hippocampal cells, calcium current measured at plateau was reduced by 36 +/- 8% and 89 +/- 4% after 5 and 20 mumol/L SB 201823-A, respectively. In cerebellar granule cells in culture, pretreatment with 2.5 mumol/L SB 201823-A totally prevented initial calcium influx and reduced later calcium influx by 50 +/- 2.5% after N-methyl-D-aspartate/glycine stimulation (P < .01). KCl depolarization-induced calcium influx also was reduced by more than 95%. In rats, a single treatment with 10 mg/kg IV SB 201823-A beginning 30 minutes after focal ischemia decreased (P < .05) hemispheric infarct by 30.4% and infarct volume by 29.3% and reduced (P < .05) forelimb deficits by 47.8% and hindlimb deficits by 36.3%. In mice, treatments with 10 mg/kg IP SB 201823-A beginning 30 minutes after focal ischemia significantly reduced infarct volume by 41.5% (P < .01). No blood pressure effects were observed with the therapeutic dose of the compound. CONCLUSIONS: These results indicate that the new neuronal calcium channel blocker SB 201823-A can block stimulated calcium influx into central neurons and can provide neuroprotection in two models of focal cerebral ischemia without affecting blood pressure. Data from several different studies now indicate that the neuronal calcium channel antagonists are a promising therapy for the postischemic treatment of stroke.

Effects of suramin on contractions of the guinea-pig vas deferens induced by analogues of adenosine 5'-triphosphate.

1. Adenosine 5'-triphosphate (ATP) and some of its analogues contract the guinea-pig vas deferens, acting via receptors which have been classified as P2X-purinoceptors. We have recently shown, however, that the effects of ATP are enhanced, rather than inhibited, by the non-selective P2 antagonist, suramin, and that this enhancement could not easily be explained in terms of inhibition by suramin of the breakdown of ATP. We therefore investigated the effects of suramin on contractions induced by ATP analogues, to define the structure-activity relationships of the suramin-resistant response. 2. In the absence of suramin, the order of potency for ATP analogues was adenosine 5'-(alpha,beta-methylene)triphosphonate (AMPCPP) = P1,P5-diadenosine pentaphosphate (Ap5A) = adenosine 5'-tetraphosphate (Ap4) > adenosine 5'-O-(3-thiotriphosphate) (ATP gamma S) = adenylyl 5'-(beta,gamma-methylene) diphosphonate (AMPPCP) > P1,P5-diadenosine tetraphosphate (Ap4A) > adenosine 5'-O-(2- thiodiphosphate) (ADP beta S) > 2-methylthioadenosine 5'-triphosphate (MeSATP) > or = ATP > adenosine 5'-diphosphate (ADP). This is generally in agreement with previously reported structure-activity relationships in this tissue. 3. In the presence of suramin (1 mM), responses to Ap5A, Ap4A, AMPPCP, ADP beta S and ADP were abolished or greatly reduced, and contractions induced by AMPCPP, Ap4 and ATP gamma S were inhibited. Contractions induced by MeSATP however, like those induced by ATP itself, were not reduced, but at concentrations above 100 microM were enhanced. In the presence of suramin (1 mM) the order of potency of analogues was therefore AMPCPP = Ap4> ATP = MeSATP> ATP gamma S, with all other analogues tested being essentially inactive at concentrations up to 500 microM.4. Contractile responses of the vas deferens to transmural nerve stimulation (1-50 Hz) in the presence of the alpha-adrenoceptor antagonist, phentolamine (10 microM), were abolished by suramin (1 mM). This is in agreement with previous reports that suramin inhibits the excitatory junction potential, a response thought to be mediated by P2 purinoceptors. It is however hard to reconcile the evidence implicating ATP as the non-adrenergic transmitter responsible for this response with the failure of suramin to inhibit the contractions induced by ATP itself while abolishing nerve-mediated contractions.5. In conclusion, these results confirm our previous findings of a suramin-resistant component to the ATP-induced contraction in the guinea-pig vas deferens, and show that the structure-activity relationships of this response are not identical to those of any known P2-purinoceptor subclass. Although the inhibition by suramin of the breakdown of ATP may contribute to the suramin-resistance of some of the ATP analogues, it does not appear to provide the full explanation.

Differential effects of suramin on P2-purinoceptors mediating contraction of the guinea-pig vas deferens and urinary bladder.

1. The effect of the P2-purinoceptor antagonist, suramin, was investigated on contractions of the guinea-pig vas deferens and urinary bladder induced by adenosine 5'-triphosphate (ATP) and by the other naturally occurring nucleoside triphosphates. 2. ATP, guanosine 5'-triphosphate (GTP), cytidine 5'-triphosphate (CTP), inosine 5'-triphosphate (ITP) and uridine 5'-triphosphate (UTP) (0.1-500 microM) each contracted both the guinea-pig bladder and the guinea-pig vas deferens. In the vas deferens the order of potency of the nucleotides was ATP >> CTP > GTP > or = UTP = ITP, and in the bladder it was ATP >> CTP = GTP > UTP = ITP, although maximal responses to these agonists were not achieved in either tissue. 3. Suramin (30 microM-1 mM) dose-dependently inhibited ATP-induced contractions of the bladder in an apparently non-competitive manner, causing a reduction in the slope of the concentration-response curve to ATP. In contrast, suramin (5 microM-1 mM) had little inhibitory effect on ATP-induced contractions of the vas deferens, and indeed at concentrations of 100 microM and above markedly potentiated high concentrations of ATP (100-500 microM). The contractions induced by CTP, GTP, UTP and ITP (1-500 microM) were, however, abolished by suramin (1 mM) in each tissue. 4. Desensitization of the P2X purinoceptors in the guinea-pig vas deferens with adenosine 5'-alpha,beta-methylenetriphosphonate (AMPCPP) (300 microM) abolished contractions induced by ATP (1 microM-1 mM) in the absence of suramin. However, the contractions induced in the presence of suramin were unaffected by prior desensitization, indicating that they were not mediated by P2X-purinoceptors.5. ATP (100 MicroM) was dephosphorylated by both isolated tissue preparations under the conditions of these experiments, breakdown products being detectable after 2 min, with the major breakdown product in the bladder being inosine whereas that in the vas deferens was adenosine. Approximately 35% of the ATP remained intact after incubation for 30 min with the bladder, and approximately 45% remained after incubation for 30 min with the vas deferens. In each tissue this degradation was inhibited by suramin (1 mM), so that after incubation of ATP (100 MicroM) in the presence of suramin for 30 min,approximately 50% remained in the case of the bladder and approximately 65% remained in the vas deferens. However, inhibition of the production of the inhibitory agonist, adenosine by suramin did not appear to be responsible for the potentiation observed in the vas deferens, as the PI-purinoceptor antagonist 8-sulphophenyltheophylline (100 MicroM) did not reduce this potentiation.6. Chelation of divalent cations did not appear to account for the enhancement by suramin of ATP-induced contractions of the vas deferens, as the enhancement was still observed when Mg2+ was omitted from the buffer or when its concentration (normally 1.2 mM) was increased ten fold to 12 mM,or when the concentration of Ca2+ (normally 2.5 mM) was reduced to 0.83 mM. Even in the absence of Mg2+ and with the Ca2+ concentration reduced to 0.83 mM, no inhibition by suramin (1 mM) of ATP-induced contractions was observed.7. The most likely explanation for the potentiation by suramin of the ATP-induced contractions of the vas deferens is the co-existence of inhibitory P2Y-purinoceptors. However, no consistent relaxations to ATP (1-100 MicroM) or to the more potent P2Y-purinoceptor agonist 2-methylthioadenosine 5'-triphosphate(2-MeSATP) (0.01-100 MicroM) could be detected in the vas deferens precontracted with KCl (35 mM), even after desensitization of P2x-purinoceptors with AMPCPP (300 MicroM). Similarly, ATP (1-100 MicroM) or 2-MeSATP (0.01-1100 MicroM) added before KCI (35 mM), carbachol (10 JM) or noradrenaline (10 MicroM) did not reduce subsequent contractions to these agents.8. The differential effect of suramin on the contractions induced by ATP in the bladder and the vas deferens was unexpected, and shows that the receptor populations by which ATP acts in these tissues may not be identical. The failure of suramin to inhibit responses to ATP in the vas deferens suggests that this tissue, in addition to possessing P2x-purinoceptors may also possess a suramin-insensitive contractile ATP receptor revealed in the presence of suramin.

High-volume obstetrics in a combined LDR/LDRP program.

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