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PurposeAMB-FUBINACA is a synthetic cannabinoid receptor agonist (SCRA) which is primarily metabolised by hepatic enzymes producing AMB-FUBINACA carboxylic acid. The metabolising enzymes associated with this biotransformation remain unknown. This study aimed to determine if AMB-FUBINACA metabolism could be reduced in the presence of carboxylesterase (CES) inhibitors and recreational drugs commonly consumed with it. The affinity and activity of the AMB-FUBINACA acid metabolite at the cannabinoid type-1 receptor (CB1) was investigated to determine the activity of the metabolite.MethodsThe effect of CES1 and CES2 inhibitors, and delta-9-tetrahydrocannabinol (Δ9-THC) on AMB-FUBINACA metabolism were determined using both human liver microsomes (HLM) and recombinant carboxylesterases. Radioligand binding and cAMP assays comparing AMB-FUBINACA and AMB-FUBINACA acid were carried out in HEK293 cells expressing human CB1.ResultsAMB-FUBINACA was rapidly metabolised by HLM in the presence and absence of NADPH. Additionally, CES1 and CES2 inhibitors both significantly reduced AMB-FUBINACA metabolism. Furthermore, digitonin (100 µM) significantly inhibited CES1-mediated metabolism of AMB-FUBINACA by ~ 56%, while the effects elicited by Δ9-THC were not statistically significant. AMB-FUBINACA acid produced only 26% radioligand displacement consistent with low affinity binding. In cAMP assays, the potency of AMB-FUBINACA was ~ 3000-fold greater at CB1as compared to the acid metabolite.ConclusionsCES1A1 was identified as the main hepatic enzyme responsible for the metabolism of AMB-FUBINACA to its less potent carboxylic acid metabolite. This biotransformation was significantly inhibited by digitonin. Since other xenobiotics may also inhibit similar SCRA metabolic pathways, understanding these interactions may elucidate why some users experience high levels of harm following SCRA use.

The Atlantic meridional overturning circulation (AMOC) plays a key role in determining the distribution of heat and nutrients in the global ocean. Climate models suggest that Southern Ocean winds will strengthen and shift poleward in the future, which could have implications for future AMOC trends. Using a coupled global-ocean sea-ice model at 1/4°horizontal resolution, we study the response of the North Atlantic overturning to two anomalous Southern Ocean wind-forcing (τ+15%), and a poleward intensification(). In both scenarios a strengthening in the North Atlantic overturning develops within a decade, with a much stronger response in the case. In , we find that the primary link between the North Atlantic response and the Southern Ocean forcing is via the propagation of baroclinic waves. In fact, due to the rapid northward propagation of these waves, changes in the AMOC in the case appear to originate in the North Atlantic and propagate southward, whereas in the τ+15% case AMOC anomalies propagate northward from the Southern Ocean. We find the difference to be predominately caused by the sign of the baroclinic waves propagating from the forcing region into the North Atlantic; downwelling in the τ+15% case, versus upwelling in the case. In the case, upwelling waves propagating into the NADW formation regions along shelf-slope topography bringing dense water to the surface. This reduces vertical density gradients leading to deeper wintertime convective overturn of surface waters, and an intensification of the AMOC.

Two active learning physics courses were taught and compared. The “concepts first” course was organized to teach only concepts in the first part of the class, the ultimate goal being to increase students' problem-solving abilities much later in the class. The other course was taught in the same quarter by the same instructor using the same curricular materials, but covered material in the standard (chapter-by-chapter) order. After accounting for incoming student characteristics, students from the concepts-first course scored significantly better in two outcome measures: their grade on the final exam and the grade received in their subsequent physics course. Moreover, in the concepts-first class course, students from groups underrepresented in physics had final exam scores and class grades that were indistinguishable from other students. Finally, students who took at least one concepts-first course in introductory physics were found to have significantly higher rates of graduation with a STEM major than st...

A rare terminal cadmium hydride complex [(BDI)CdH] (BDI = [{N(2,6-iPr2C6H3)C(Me)}2CH]) has been synthesised from [(BDI)CdCl] and LiEt3BH. The hydride can be reduced to the cadmium(i) dimer, [(BDI)CdCd(BDI)] upon treatment with a catalytic amount of diisopropyl- or dicyclohexylcarbodiimide.

Turner's syndrome is a disorder defined by an absent or structurally abnormal second X chromosome and affects around 1 in 2000 newborn females. The standardised mortality ratio in Turner's syndrome is around three-times higher than in the general female population, mainly as a result of cardiovascular disorders. Most striking is the early age at which Turner's syndrome patients develop the life-threatening complications of cardiovascular disorders compared to the general population. The cardiovascular risk stratification in Turner's syndrome is challenging and imaging is not systematically used. The aim of this article is to review cardiovascular risks in this group of patients and discuss a systematic imaging approach for early identification of cardiovascular disorders in these patients.

Data on sugar beet yields from a long-term experiment (1965–1993) at IACR Broom's Barn are used, in conjunction with long-term weather data, to assess the degree to which weather affects yield and how this effect is modified by nutrient availability. Mean temperatures and rainfall during July and August were strongly correlated with sugar beet yields, as well as mean temperature during April and the length of time between sowing and harvest. The data from July and August were entered into a factor analysis to generate two factors describing how hot and dry weather conditions are during July and August. These two factors, as well as April temperature and the length of the growing season, were entered into a multiple regression. The regressions revealed strong effects of the principal axis factors on sugar beet yields across treatments, as well as strong effects of the length of the growing season, but weaker effects of April temperatures. The strength of response to weather was dependent on the nutrient regime, and was, in particular, greater with increased application of nitrogen. There was, however, no effect of nutrient regime on the strength of response of yield to the length of the growing season. These results indicate that weather-induced year-to-year variability in sugar beet yields in unirrigated crops is primarily determined by conditions in July and August as well as the length of time between sowing and harvest, and imply that drought limits yields in well-fertilised crops. The practical implications of these results are that the risk of yield losses due to drought may be minimised by maximising the length of growing season, and that there is the potential for developing simple measures to forecast yields through monitoring of rainfall.

Parmi les facteurs abiotiques conditionnant la survie au cours de la vie embryonnaire et larvaire des poissons, le pH semble jouer un role primordial. La motivation de ce travail provient d'observations sur les importantes variations de ses valeurs au printemps, l'existence de pH tres acides en etangs forestiers et des mortalites importantes de brochetons au cours de la meme periode. L'experimentation s'est deroulee en aquariums avec une gamme de valeurs allant de 4,5 a 10,5 unites pH. Des tests en bains, continus ou momentanes (1 heure), sont effectues. Deux stades sont etudies : les oeufs fecondes suivis jusqu'apres l'eclosion ; les alevins incubes a pH neutre suivis jusqu'a la resorption de la vesicule vitelline. Les parametres suivants sont etudies : survie, deroulement de l'embryogenese, anomalies eventuelles, performances de nage. Le rythme cardiaque de l'embryon a ete mesure. Les resultats sont les suivants : - Les valeurs letales sont respectivement de 6 et 10 (alevins) et 4,5 et 10,5 (embryons). - L'action sur les oeufs est moins forte, meme si une mortalite importante (46,7 %) et de faibles performances de nage pour un pH inferieur a 6 semblent hypothequer la reussite du recrutement. La valeur de 10,5 provoque un developpement deficient des quelques individus survivants. - Sur les alevins, meme en bains d'une heure, la survie est faible : 42,6 % a pH 5, 29,3 % a pH 10. Le rythme cardiaque ne variait pas de facon notable entre les seuils de tolerance. Ces resultats permettent de recapituler pour une espece largement distribuee les conditions de recrutement liees a l'acidite du milieu. Il faut noter que les hausses brutales du pH au printemps dans des plans d'eau sur substrat cristallin rendent aleatoires la reussite des empoissonnements en brochetons des premiers stades.

The phytoplankton community, physical variables, and nutrient and chlorophyll a (Chl a) concentrations were monitored during the first two of six open-water seasons of hypolimnetic oxygenation in double-basined Amisk Lake, Alberta. Deep mixing of the water column in the treated basin (Zmax = 34 m) in spring was enhanced by hypolimnetic oxygenation. Oxygenation began in June 1988, when stratification was likely already established, but subsequent year-round treatment favoured an extended spring diatom bloom (Asterionella formosa and Cyclotella spp.), followed by a delay in the development of, and reduction in the severity of, cyanobacterial blooms (Aphanizomenon flos-aquae and Anabaena flos-aquae) in 1989. Historically, mean summer Chl a and total phosphorus (TP) concentrations in the euphotic zone (0-6 m) of the treated basin were 15.9 ± 1.6 and 33.5 ± 1.5 µg ·L-1, respectively, indicating a eutrophic lake. In 1988 and 1989, mean summer Chl a (10.0 ± 0.6 and 8.1 ± 0.7 µg ·L-1, respectively) and TP concentrations (29.0 ± 0.5 and 22.5 ± 0.9 µg ·L-1, respectively) in this stratum were lower than historic values (P < 0.05), indicating that the trophic status of Amisk Lake had shifted towards mesotrophy.

Activin A is a member of the transforming growth factor-beta family of growth factors and a potent regulator of cellular activity. A number of binding proteins for activin A have been identified, including alpha 2-macroglobulin (alpha 2M). Alpha 2M has several conformational states that are known to have different growth factor-binding properties. The effect of alpha 2M conformation on activin A binding has not been characterized. The aims of this study were to determine 1) whether activin A binds preferentially to the native (alpha 2M-N) or "activated" (alpha 2M*) conformation of alpha 2M, 2) the affinity of different alpha 2M conformations for activin A, and 3) the fate of activin A complexed with alpha 2M-N or alpha 2M* in vivo. [125I]Activin A associated with alpha 2M in plasma and follicular fluid and with purified alpha 2Ms. In this qualitative assay, more activin A was associated with alpha 2M* than with alpha 2M-N. The affinity of the activin A-alpha 2M interaction was determined. The Kd values for activin A-alpha 2M* and activin A-alpha 2M-N were 190 +/- 30 and 510 +/- 60 nM, respectively. The plasma clearance profiles and tissue distribution of uncomplexed activin A and purified alpha 2M*-activin A complex were determined. Radiolabeled activin A cleared in a biphasic manner, with rapid clearance over the initial 10 min and substantially slower clearance over the subsequent 20 min. During the slow phase of clearance, activin A formed a complex with circulating alpha 2M-N. In contrast, radiolabeled activin A-alpha 2M* complexes were rapidly cleared from plasma with a half-life of approximately 5 min and were specifically targeted to alpha 2M receptors in vivo. These studies reveal that alpha 2M can maintain activin A in the circulation or rapidly target the hormone for plasma clearance depending on the conformational state of the carrier protein in vivo.

The temperature of shock compressed iron has been measured to 340 GPa, using well characterized iron films sputtered on transparent diamond substrates and a 1 ns time-resolved optical method. We find a knee on the (P,T) iron Hugoniot indicating melting at 6350 K and 235 GPa and at 6720 K and 300 GPa. An extrapolation yields an iron melting temperature of 6830 (\ifmmode\pm\else\textpm\fi{} 500) K at 330 GPa, the pressure of the Earth inner-outer core boundary. Implication of the melting data for the iron phase diagram is also discussed.

Inactivation of endothelin B receptors (ETB), either through selective pharmacological antagonism or genetic mutation, increases the circulating concentration of endothelin-1 (ET-1), suggesting ETB plays an important role in clearance of this peptide. However, the cellular site of ETB-mediated clearance has not yet been determined. We have used a novel mouse model of endothelial cell-specific knockout (KO) of ETB (EC ETB(-/-)) to evaluate the relative contribution of EC-ETB to the clearance of ET-1. Phenotypic evidence of EC-specific ETB KO was confirmed by immunocytochemistry and autoradiography. Binding of the radiolabelled selective ETB ligand BQ3020 was significantly and selectively decreased in EC-rich tissues of EC ETB(-/-) mice, including the lung, liver, and kidney. By contrast, ETA binding was unaltered. RT-PCR confirmed equal expression of ET-1 in tissue from EC ETB(-/-) mice and controls, despite increased concentration of plasma ET-1 in EC ETB(-/-). Clearance of an intravenous bolus of [(125)I]ET-1 was impaired in EC ETB(-/-) mice. Pretreatment with the selective ETB antagonist A192621 impaired [(125)I]ET-1 clearance in control animals to a similar extent, but did not further impair clearance in EC ETB(-/-) mice. These studies suggest that EC-ETB are largely responsible for the clearance of ET-1 from the circulation.

Wounds within the oral mucosa, similarly to fetal wounds, exhibit rapid healing with reduced scarring. We hypothesized that a progenitor population resident within the oral mucosal lamina propria (OMLP) contributes to this preferential healing. Progenitor cells (PC) were reliably isolated from the OMLP by differential adhesion to fibronectin. Isolated colonies originating from a single cell demonstrated a rapid initial phase of proliferation, completing in excess of 50 population doublings (PDs) before entering cellular senescence. These data were supported by the expression of active telomerase within both developing colonies and expanded clones as assessed by immunocytochemistry (ICC) and the quantitative telomeric repeat amplification protocol. FACS analysis confirmed expression of the stem cell markers CD44, CD90, CD105, and CD166, but negative expression of CD34 and CD45 ruling out a hematopoietic or fibrocyte origin for these progenitors. A neural crest origin was confirmed by increased colony-forming efficiency (CFE) in the presence of Jagged 1 and the expression of a number of neural crest markers within the developing colonies by ICC and serially passaged clones by Western blotting. The multipotency of this novel PC population was demonstrated by differentiation of the cells down both mesenchymal (chondrogenic, osteoblastic, and adipogenic) and neuronal (neuron and Schwann-like cells) cell lineages. This article reports for the first time, the isolation and characterization of a novel, clonally derived PC population resident within the OMLP. The attributes of this adult stem cell (ASC) population and its accessibility lends itself to future therapeutic applications.

Chlorophyll a (Chl a) in water samples from three mesotrophic to eutrophic lakes in north-central Alberta was extracted with one of three solvents (95% ethanol, 90% ethanol, or a 2:3 mixture of dimethyl sulfoxide and 90% acetone (DMSO/acetone)) and analyzed by two techniques (spectrophotometry and high pressure liquid chromatography (HPLC). The dominant phytoplankton were blue-green algae and diatoms. Total Chl a concentrations (i.e. no correction for phaeopigments (Pha)) were not significantly different among solvents (P > 0.5). Total Chl a concentrations from spectrophotometric analyses were significantly higher than those from HPLC analyses (4.2 ± 0.88 and 2.6 ± 0.50 μg∙L−1 respectively, P −1 respectively, P

The feasibility of analysing and presenting global wave climate by fitting annual and semi-annual harmonics to monthly mean values of significant wave height in 2° x 2° bins is investigated using one year's data from Geosat (November 1986 to November 1987). Stringent checks on the data result in 16 percent being discarded. Nevertheless, the analysis is found to give a generally coherent and realistic picture. The annual component dominates in most areas, but in places the semi-annual harmonic is significant, either by itself or in conjunction with the annual cycle.

BACKGROUND Exercise hypotension has been documented in hypertrophic cardiomyopathy. It is not the result of an inability to augment cardiac output but instead relates to an inappropriate and exaggerated decrease in systemic vascular resistance at high work loads. METHODS AND RESULTS To enable us to examine the behavior of the peripheral vasculature during exercise, 103 consecutive patients underwent maximal symptom-limited supine bicycle exercise with measurement of forearm blood flow. A minimum reduction of 12% from the basal value was defined as a normal response based on the study of 25 normal controls. In the patients, two patterns of forearm blood flow were observed. Sixty-four patients had an appropriate reduction in forearm blood flow of 40 +/- 16% from resting flow. In 39 patients, the forearm blood flow either failed to decrease or increased with exercise by 45 +/- 105% of the resting value. Patients with an abnormal forearm vasodilator response were younger (31 +/- 13 versus 46 +/- 14 years), and more of them had a family history of hypertrophic cardiomyopathy and sudden death than did those with a normal vasoconstrictor response (16 of 39 versus eight of 64). Left ventricular end-diastolic cavity dimensions were smaller in those with an abnormal forearm blood flow response, but other clinical, echocardiographic, and arrhythmic variables were similar. To assess the relation of abnormal peripheral vascular responses to erect exercise blood pressure response, patients underwent treadmill exercise testing with careful monitoring of systolic blood pressure response. Thirty-eight patients had significant exercise hypotension with failure of the systolic blood pressure to increase during progressive exercise (n = 6) or an abrupt decrease in systolic blood pressure (20-60 mm Hg) from the peak value (n = 32); 65 patients had a normal exercise blood pressure response, but 18 of these patients had an oscillation in systolic blood pressure of 10 mm Hg or more early in the recovery phase. Thirty-one of 39 patients with an abnormal forearm blood flow response demonstrated exercise hypotension during the erect exercise testing, and the remaining eight patients had a normal exercise blood pressure response; however, five of these eight had abnormal oscillations in blood pressure during recovery (r = 0.61, p less than 0.001). CONCLUSIONS The relation of abnormal peripheral vascular responses to exercise hypotension confirms the observation of hemodynamic instability in patients with hypertrophic cardiomyopathy. The finding of abnormal vascular responses in patients known to be at increased risk (young age and a family history of hypertrophic cardiomyopathy and sudden death) suggests that hemodynamic mechanisms may be important in the occurrence of sudden death in hypertrophic cardiomyopathy.

We hypothesised that the potential protective effects of endothelial ET(B) are important in limiting pulmonary vascular muscularisation, vasoconstriction and the development of pulmonary arterial hypertension in response to hypoxia.EC-specific ET(B) knockout mice (EC ET(B)(-/-)) and control mice (ET(B)(f/f)) were subjected to hypobaric hypoxic (10% FiO2) or normoxic conditions for 14 days before assessment of right ventricular pressure and pulmonary vascular morphology and function.During normoxia, no difference in right ventricular pressure was detected between EC ET(B)(-/-) (23.7 +/- 1.7 mm Hg) and ET(B)(f/f) mice (20.2 +/- 1.5 mm Hg). Hypoxia induced an exaggerated increase in right ventricular pressure in EC ET(B)(-/-) mice (34.4 +/- 1.2 mm Hg vs. 24.6 +/- 1.4 mm Hg), accompanied by an increase in right ventricular mass. No effect was observed in ET(B)(f/f) mice. Endothelin-1 constricted pulmonary arteries from both groups, although maximum response was similar irrespective of inspired oxygen or genotype. Hypoxia increased the percentage of muscularised vessels in both groups of mice, but the percentage increase was significantly greater in EC ET(B)(-/-) mice.The potential protective effects of endothelial ET(B) are important in limiting pulmonary vascular muscularisation and the development of pulmonary arterial hypertension in response to hypoxia.

Wave height measurements made during the year November 1986 to November 1987 by the radar altimeter on the US Geosat satellite are used to map the seasonal variations in the global wave climate. The largest significant wave heights are found in winter in the Southern Ocean with only a slight reduction during the southern summer. In the North Atlantic and North Pacific the significant wave heights are lower and there is a larger variation between summer and winter.

Degradation studies with over 235 000 device hours have been performed on single‐quantum‐well AlGaAs lasers with uncoated and half‐wavelength Al2O3 ‐coated facets at stress levels ranging from below threshold up to optical power densities of 23 mW per μm facet width. The effectiveness of facet protection has been investigated with respect to gradual degradation and catastrophic failures. Facet protection is very important for obtaining long lifetimes and improved immunity to sudden catastrophic failures. With facet coatings, degradation rates as low as 0.18%/kh have been measured at 30 mW in single‐lateral‐mode operation and at 50 °C.

There is considerable evidence that the potent vasoconstrictor endothelin-1 (ET-1) contributes to the pathogenesis of a variety of cardiovascular diseases. As such, pharmacological manipulation of the ET system might represent a promising therapeutic goal. Many clinical trials have assessed the potential of ET receptor antagonists in cardiovascular disease, the most positive of which have resulted in the licensing of the mixed ET receptor antagonist bosentan, and the selective ET(A) receptor antagonists, sitaxsentan and ambrisentan, for the treatment of pulmonary arterial hypertension (PAH). In contrast, despite encouraging data from in vitro and animal studies, outcomes in human heart failure have been disappointing, perhaps illustrating the risk of extrapolating preclinical work to man. Many further potential applications of these compounds, including resistant hypertension, chronic kidney disease, connective tissue disease and sub-arachnoid haemorrhage are currently being investigated in the clinic. Furthermore, experience from previous studies should enable improved trial design and scope remains for development of improved compounds and alternative therapeutic strategies. Although ET-converting enzyme inhibitors may represent one such alternative, there have been relatively few suitable compounds developed, and consequently, clinical experience with these agents remains extremely limited. Recent advances, together with an increased understanding of the biology of the ET system provided by improved experimental tools (including cell-specific transgenic deletion of ET receptors), should allow further targeting of clinical trials to diseases in which ET is involved and allow the therapeutic potential for targeting the ET system in cardiovascular disease to be fully realized.

To determine whether acute insulin-induced hypoglycaemia provokes a detectable alteration in peripheral plasma endothelin (ET) concentrations in humans with Type 1 diabetes.Serial plasma concentrations of ET were measured in 20 patients with Type 1 diabetes during controlled hypoglycaemia induced by intravenous infusion of soluble insulin.A significant increase was observed in plasma ET concentrations, from 3.80 +/- 0.31 pg/ml at baseline to 6.72 +/- 1.47 pg/ml at 60 min after the onset of the hypoglycaemic reaction (P0.05).Acute insulin-induced hypoglycaemia induces a rise in plasma endothelin concentrations in people with Type 1 diabetes. This finding is consistent with a putative role for ET in the mediation of hypoglycaemia-induced vasoconstriction, and the possible precipitation of macrovascular or microvascular events.

The Indonesian Throughflow is analysed in two runs of the OCCAM 1/4 degree global ocean model, one using monthly climatological winds and one using ECMWF analysed six-hourly winds for the period 1993 to 1998. The long-term model throughflow agrees with observations and the value predicted by Godfrey's Island Rule. The Island Rule has some skill in predicting the annual signal each year but is poor at predicting year to year and shorter term variations in the total flow, especially in El Niño years. The spectra of transports in individual passages show significant differences between those connecting the region to the Pacific Ocean and those connecting with the Indian Ocean. On investigation we found that changes in the northern transports were strongly correlated with changes in the position of currents in the Celebes Sea and off Halmahera. Vertical profiles of transport are in reasonable agreement with observations but the model overestimates the near surface transport through the Lombok Strait and the dense overflow from the Pacific through the Lifamatola Strait into the deep Banda Sea. In both cases the crude representation of the passages by the model appears responsible. In the north the model shows, as expected, that the largest transport is via the Makassar Strait. However this is less than expected and instead there is significant flow via the Halmahera Sea. If Godfrey's Island Rule is correct and the throughflow is forced by the northward flow between Australia and South America, then the Halmahers Sea route should be important. It is the most southerly route around New Guinea to the Indian Ocean and there is no apparent reason why the flow should go further north in order to pass through the Makassar Strait. The model result thus raises the question of why in reality the Makassar Strait route appears to dominate the throughflow.

1. The effect on systemic haemodynamics of BQ-123, a selective endothelin A (ETA) receptor antagonist, was investigated in healthy men by giving, on separate occasions, ascending intravenous doses of 100, 300, 1000 and 3000 nmol min(-1) BQ-123, each for 15 min, in a randomized, placebo-controlled, double-blind study. The response of forearm blood flow to brachial artery infusion of endothelin-1 (ET-1; 5 pmol min(-1) for 90 min) was also studied using bilateral forearm plethysmography, after systemic pre-treatment, on separate occasions, with one of two doses of BQ-123 (300 and 1000 nmol min(-1) for 15 min) or placebo. 2. Systemic BQ-123 dose-dependently decreased systemic vascular resistance (P0.01 for all doses vs placebo) and mean arterial pressure (P0.05 for 300 nmol min(-1) and P0.01 for 1000 and 3000 nmol min(-1)) during the 60 min following infusion. There were concurrent increases in heart rate and cardiac index. BQ-123, when infused systemically for 15 min, appeared to reach a maximum effect at 1000 nmol min(-1). 3. Intra-brachial ET-1 infusion, after pre-treatment with placebo, caused a slow onset progressive forearm vasoconstriction without systemic effects. This vasoconstriction was attenuated by pre-treatment with BQ-123 at 300 nmol min(-1) and abolished by BQ-123 at 1000 nmol min(-1) (P0.01 vs placebo). 4. These effects occurred at concentrations of BQ-123 in the plasma (510+/-64 nmol l(-1)) that were ETA receptor selective, and were not accompanied by an increase in plasma ET-1 that would have indicated ETB receptor blockade. 5. We conclude that ETA-mediated vascular tone contributes to the maintenance of basal systemic vascular resistance and blood pressure in healthy men.

To compare the haemodynamic responses of proadrenomedullin N-terminal 20 peptide (PAMP) and adrenomedullin (ADM) in the forearm vascular bed of healthy male volunteers, and to investigate the role of neutral endopeptidase (NEP) in the metabolism of ADM.On two separate occasions, ADM (1-30 pmol x min(-1)) and PAMP (100-3000 pmol x min(-1)) were infused into the brachial artery of eight male subjects, and forearm blood flow (FBF) assessed using venous occlusion plethysmography. In a second study, eight male subjects received the same doses of ADM, co-infused with either the NEP inhibitor thiorphan (30 nmol x min(-1)) or the control vasoconstrictor noradrenaline (120 pmol x min(-1)), on separate occasions. Both studies were conducted in a double-blind, randomized manner.ADM and PAMP produced a dose-dependent increase in FBF (Por = 0.002). Based on the dose producing a 50% increase in FBF, ADM was approximately 60 times more potent than PAMP. Thiorphan and noradrenaline produced similar reductions in FBF of 14 +/- 4% (mean +/- s.e. mean) and 22 +/- 6%, respectively (P = 0.4). However, the area under the dose-response curve was significantly greater during co-infusion of ADM with thiorphan than with noradrenaline (P = 0.028), as was the maximum increase in FBF ratio (2.1 +/- 1.0 vs 1.2 +/- 0.2; P = 0.030).ADM and PAMP both produce a local dose-related vasodilatation in the human forearm, but PAMP is approximately 60 times less potent than ADM. In addition, NEP inhibition potentiates the haemodynamic effects of ADM. These findings suggest that PAMP may not play a role in the physiological regulation of blood flow. However, in pathophysiological conditions such as hypertension and heart failure, NEP inhibition may exert a beneficial effect by increasing the biological activity of ADM.

The thermohaline circulation of the ocean results primarily from downwelling at sites in the Nordic and Labrador Seas and upwelling throughout the rest of the ocean. The latter is often described as being due to breaking internal waves. Here we reconcile the difference between theoretical and observed estimates of vertical mixing in the deep ocean by presenting a revised view of the thermohaline circulation, which allows for additional upwelling in the Southern Ocean and the separation of the North Atlantic Deep Water cell from the Antarctic Bottom Water cell. The changes also mean that much less wind and tidal energy needs to be dissipated in the deep ocean than was originally thought.

To test the hypothesis that an increased plasma concentration of sialic acid, a marker of the acute-phase response, is related to the presence of diabetic micro- and macrovascular complications in type 1 diabetes.We investigated the relationship between plasma sialic acid concentration and nephropathy, retinopathy, neuropathy, and coronary heart disease (CHD) in a cross-sectional survey of 1,369 people with type 1 diabetes. Subjects were participants in the EURODIAB IDDM Complications Study, which involved 31 centers in 16 European countries.There was a significantly increasing trend of plasma sialic acid with severity of retinopathy (P0.001 in men) and with degree of urinary albumin excretion (P0.001 men, P0.01 women). Plasma sialic acid correlated with increasing plasma creatinine concentration (P0.009 men, P0.0002 women), and men with neuropathy had a higher plasma sialic acid concentration than those without (P0.006). There was no significant correlation between plasma sialic acid and CHD in either sex. Elevated plasma sialic acid concentrations were also associated with several risk factors for diabetic vascular disease: diabetes duration, HbA1c, plasma triglyceride and cholesterol concentrations, waist-to-hip ratio, hypertension and smoking (in men), and low physical exercise (in women). In multiple logistic regression analysis, plasma sialic acid was independently related to proliferative retinopathy and urinary albumin excretion rate in men.We conclude that an elevated plasma sialic concentration is strongly related to the presence of microvascular complications in type 1 diabetes, especially retinopathy and nephropathy. Further study of acute-phase response markers and mediators as indicators or predictors of diabetic microvascular complications is therefore justified.

We assessed forearm blood flow and plasma fibrinolytic factors in eight healthy males who received unilateral brachial artery infusions of the endothelium-dependent vasodilator, substance P, and the endothelium-independent vasodilator, sodium nitroprusside. These measurements, together with platelet aggregation studies, were performed on four occasions after double-blind randomized ingestion of placebo, methionine (0.1 mg/kg), vitamin C (2 g) and methionine plus vitamin C. Blood flow and platelet aggregation responses were unaffected by methionine loading. Substance P caused dose-dependent increases in plasma tissue plasminogen activator (t-PA) antigen (from 3.0+/-0.1 to 4.7+/-0.4 ng/ml; P0.001) and activity (from 1.2+/-0.2 to 4.2+/-0.4 i.u./ml; P0.001), which were augmented during acute methionine loading (4.7+/-0.4 to 5.6+/-0.5 ng/ml and 4.2+/-0.4 to 5.5+/-0.9 i.u./ml respectively; P/=0.05). Moreover, the estimated net release of t-PA was enhanced during methionine loading (two-way ANOVA; P=0.02), but this was unaffected by vitamin C supplementation. We conclude that, in the absence of alterations in endothelium-dependent vasomotion or platelet aggregation, substance P-induced t-PA release is enhanced following methionine loading. This suggests that the acute endogenous fibrinolytic capacity is augmented during acute hyperhomocysteinaemia in healthy humans via an oxidation-independent mechanism.

A number of endothelin (ET) receptor antagonists have been developed as research tools and as potential medicines (see Chap. 9). Some of these are selective for the ETA or ETB receptor while others are mixed ETA/B receptor antagonists. Peptide antagonists are inactive orally and, therefore, of limited use as long term treatments. However, these compounds have been useful as research tools and are currently being developed as short term therapeutic agents. Due to ease of administration, non-peptide, orally active antagonists are more promising candidates for the treatment of chronic conditions and several are at various stages of clinical evaluation.

1. Reduced endothelial nitric oxide (NO) production in conduit vessels for coronary artery bypass grafting (CABG) has been implicated in post-operative complications, including spasm. 2. The brief effects of existing NO donors limits their applicability to improving patency of graft vessels. RIG200 is a novel S-nitrosothiol that might have advantages over conventional drugs because it has sustained effects in areas of endothelial damage. 3. Here we tested the hypothesis that RIG200 and S-nitrosoglutathione (GSNO) have prolonged, NO-mediated effects in human saphenous vein (SV) and internal mammary artery (IMA), compared with glyceryl trinitrate (GTN) and sodium nitroprusside (SNP). 4. 84 SV and 80 IMA rings from 64 patients undergoing CABG were studied in vitro. Rings were precontracted with phenylephrine (EC(80) concentration) and the functional integrity of the endothelium tested with acetylcholine (10 microM). 5. Relaxation of precontracted SV and IMA rings to GTN and SNP (0.01 - 10 microM) generally recovered fully on washout. In contrast, responses to RIG200 and GSNO were sustained during washout (30 min). Sustained relaxation was reversed by the NO scavenger, ferrohaemoglobin (10 microM) but not by the NO synthase inhibitor, N(omega)-nitro-L-arginine methyl ester (100 and 250 microM in SV and IMA respectively). 6. Pretreatment (30 min) of SV with both S-nitrosothiols (10 microM) inhibited phenylephrine-induced contraction for180 min, compared with90 min for GTN. In IMA, contractility was suppressed to 49+/-4% (GSNO) and 26+/-4% (RIG200) of baseline after 240 min washout. 7. Pretreatment of bypass conduits with S-nitrosothiols might improve their patency in the early post-operative period.

Endothelin-1 (ET-1) has been implicated as a mediator of increased vascular tone during development of heart failure post-myocardial infarction (MI). In the present study, expression and pharmacology of ET-1 and its receptors were studied in small mesenteric arteries from rats at 5 and 12 weeks after coronary artery ligation for induction of MI, or sham-operation. In vessels from sham-operated and 5 week post-MI rats preproET-1mRNA, immunoreactive (ir) ET-1, ET(B) receptor mRNA and irET(B) receptor were confined to the endothelium, while ET(A) receptor mRNA was distributed throughout the media. At 12 weeks post-MI, preproET-1 and irET(A) receptor localization was similar but ET(B) receptor mRNA and immunoreactivity were detectable in the media, as well as the endothelium. The ET-1 concentration-response curve (CRC) was progressively shifted to the right in pressurized third generation mesenteric arteries from 5 and 12 week post-MI rats relative to sham-operated rats, with no change in the maximum. The ET(A) receptor antagonist BQ-123 (10(-6) M) induced a rightward shift of the ET-1 CRC in all vessels. Desensitization of ET(B) receptors, by exposure to SRTX S6c (3x10(-8) M), had no effect on the ET-1 CRC in vessels from 5 week post-MI or sham-op rats but induced a leftward shift in vessels from 12 week post-MI rats. These results identify the endothelium as the primary site of ET-1 synthesis in small arteries and the ET(A) receptor as mediating the effects of ET-1 in these vessels. However, ET(B) receptor expression increases in vascular smooth muscle post-MI and is linked to mechanisms that inhibit the contractile response to ET-1.

The aim of the study was to examine the effects of the ETB receptor selective agonists sarafotoxin S6c (SFTX6c) and BQ-3020 on the forearm resistance and capacitance vessels in healthy subjects in vivo.The local response to intra-arterial or intravenous infusion of SFTX6c (5 pmol min-1) or BQ-3020 (50 pmol min-1) was assessed, on separate occasions, in eight healthy men (aged 20-28 years). Data (mean +/- s.e.mean) were examined by ANOVA. Results are expressed as percentage change from baseline at 90 min.SFTX6c and BQ-3020 reduced forearm blood flow, following local intra-arterial infusion (-25 +/- 7% and -27 +/- 7%, respectively; P0.001) and reduced hand vein diameter, following local intravenous infusion (-30 +/- 8% and -16 +/- 7%, respectively; P0.001).We have shown that locally active infusions of the selective ETB receptor agonists SFTX6c and BQ-3020 cause arterial constriction and venoconstriction in healthy human blood vessels in vivo. These results indicate that ETB receptor stimulation may mediate vasoconstriction in humans.