1. The effects of adrenaline on Ca distribution in isolated rat liver parenchymal cells were studied using a (45)Ca exchange technique under steady-state conditions with respect to the net movement of Ca. (45)Ca was initially introduced into the extracellular medium. The amount of cellular (45)Ca was determined after separation of the cells from the medium by centrifugation through a solution which contained LaCl(3) (to displace (45)Ca bound to sites on the outside of the cell membrane) and silicon oil. At 1.3 and 2.4 mm-extracellular Ca, a stimulation of the initial rate of (45)Ca exchange was observed in the presence of 10(-7)m-adrenaline (or 10(-6)m-phenylephrine) with a 7% decrease, and no change, respectively, in the plateau of the exchange curve. The same degree of stimulation was observed when (45)Ca was added at 1, 15, 30 or 45 min after the adrenaline.2. No stimulation of the initial rate of exchange was observed at 0.1 mm-extracellular Ca, or at 2.4 mm-extracellular Ca in the presence of antimycin A and oligomycin. At 0.1 mm-Ca, a 60% decrease in the plateau of the exchange curve was observed in the presence of adrenaline. The concentration of adrenaline (10(-7)m) which caused half-maximal stimulation of the initial rate of (45)Ca exchange at 1.3 mm-Ca was similar to that (2 x 10(-7)m) which caused half-maximal decrease in the plateau at 0.1 mm-Ca.3. The addition of adrenaline to cells equilibrated with (45)Ca at either 2.4 or 1.3 mm-Ca caused a transient loss of (45)Ca followed by a return to a new steady state after 1 or 10 min, respectively. A loss of (45)Ca was also observed at 0.1 mm-Ca, but the (45)Ca content of the cells remained maximally depressed for at least 30 min.4. A non-linear least-squares iterative curve-fitting technique was used to demonstrate that (a) an equation which includes two exponential terms and (b) a parallel or series arrangement of three compartments of exchangeable Ca (the medium and two compartments associated with the cell) are consistent with each set of data obtained at 1.3 or 2.4 mm-Ca in the presence or absence of adrenaline (or phenylephrine). At 1.3 mm-Ca, the quantities of exchangeable Ca in the two kinetically defined cellular compartments were 0.04-0.07 and 0.34-0.37 nmol per mg wet weight with rate constants for Ca outflow of 1.2-1.5 and 0.06-0.08 min(-1), respectively.5. Analysis of the changes induced by adrenaline or phenylephrine showed that at 1.3 and 2.4 mm-extracellular Ca these agents caused a 75-150% increase in the quantity of exchangeable Ca in the small kinetically defined compartment and a 20% decrease in the quantity of exchangeable Ca in the large kinetically defined compartment. These changes were mediated by an 80-160% increase in the rate constant for the inflow of Ca from the medium to the small kinetically defined compartment, and either a 20-60% decrease in the rate constant for inflow to, or a 20% increase in the rate constant for outflow from, the large compartment.6. Replacement of the LaCl(3) in the solution used to separate the cells from the incubation medium with either 5 mm-EGTA or 5 mm-CaCl(2) did not alter the kinetics of (45)Ca exchange or the stimulation by adrenaline. This, together with the observation that at 1.3 mm-extracellular Ca, adrenaline increases the initial rate of exchange in the absence, but not in the presence, of antimycin A plus oligomycin, indicates that both cellular compartments of exchangeable Ca are intracellular.7. The addition of antimycin A plus oligomycin to cells equilibrated with (45)Ca at 2.4 mm-extracellular Ca in the presence or absence of adrenaline displaced 0.09 and 0.14 nmol (45)Ca. mg(-1), respectively.8. Subcellular fractionation of cells equilibrated with (45)Ca at 0.1 mm-extracellular Ca revealed that the mitochondria and microsomes contained significant amounts of (45)Ca. The amounts of (45)Ca in these fractions decreased by 50 and 40%, respectively, in the presence of adrenaline.9. In (45)Ca exchange experiments conducted with isolated mitochondria at 37 degrees C at 1.5 x 10(-7)m and 0.9 x 10(-7)m free Ca in the presence of 2 mm-Mg(2+), one kinetically defined compartment of exchangeable mitochondrial Ca was detected. The rate constants for Ca outflow were found to be 0.15+/-0.03 and 0.12+/-0.04 min(-1), respectively, in reasonable agreement with the value obtained for the rate constant for the outflow of Ca from the large kinetically defined compartment of exchangeable Ca observed in cells.10. It is concluded that adrenaline has two effects on Ca movement in the liver cell. These are to cause a loss of Ca from an intracellular compartment, which includes the mitochondria and microsomes, and to increase the transport of Ca from the extracellular medium to an intracellular site. This results in an increase in the amount of Ca in a small intracellular compartment which may represent cytoplasmic Ca, or Ca bound to sites on the inside of the plasma membrane.

Stress responses are elicited by a variety of stimuli and are aimed at counteracting direct or perceived threats to the well-being of an organism. In the mammalian central and peripheral nervous systems, specific cell groups constitute signaling circuits that indicate the presence of a stressor and elaborate an adequate response. Pituitary adenylate cyclase-activating polypeptide (PACAP) is expressed in central and peripheral parts of these circuits and has recently been identified as a candidate for regulation of the stress axis. In the present experiments, we tested the involvement of PACAP in the response to a psychological stressor in vivo. We used a restraint paradigm and compared PACAP-deficient mice (PACAP-/-) to wild-type controls (PACAP+/+). Acute secretion of corticosterone elicited by 1 h of restraint was found to be identical between genotypes, whereas sustained secretion provoked by 6 h of unrelieved restraint was 48% lower in PACAP-/-mice. Within the latter time frame, expression of messenger RNA (mRNA) encoding corticotropin-releasing hormone (CRH) was increased in the hypothalamus of wild type, but not PACAP-deficient mice. Expression of the activity-regulated transcription factors Egr1 (early growth response 1) and Fos (FBJ osteosarcoma oncogene) in the hypothalamus was rapidly and transiently induced by restraint in a PACAP-dependent fashion, a pattern that was also found in the adrenal glands. Here, abundance of transcripts encoding enzymes required for adrenomedullary catecholamine biosynthesis, namely TH (tyrosine hydroxylase) and PNMT (phenylethanolamine N-methyltransferase), was higher in PACAP+/+ mice after 6 h of unrelieved restraint. Our results suggest that sustained corticosterone secretion, synthesis of the hypophysiotropic hormone CRH in the hypothalamus, and synthesis of the enzymes producing the hormone adrenaline in the adrenal medulla, are controlled by PACAP signaling in the mouse. These findings identify PACAP as a major contributor to the stimulus-secretion-synthesis coupling that supports stress responses in vivo.

1. Foetal and maternal plasma catecholamine concentrations were measured during and after hypoxia (mean maternal Pa,02 44mmHg) in chronically catheterized sheep, 118-141 days pregnant. 2. In most foetuses the initial plasma catecholamines were smaller than 0.07 ng/ml. During hypoxia plasma adrenaline and noradrenaline always rose; there was a rise in arterial pressure and a fall in heart rate. 3. The initial catecholamine concentration in the ewes was smaller than 0.05-2.3 ng/ml. During hypoxia there was no consistent change; the maternal plasma concentrations were less than the foetal. 4. Infusion of adrenaline at 0.3 mug kg(-1) min(-1) to the ewe resulted in plasma catecholamine concentrations higher than those observed during hypoxia. There was a rise in heart rate but no consistent change in arterial pressure. 5. Infusion of adrenaline 0.4 mug kg(-1) min(-1) into the foetal jugular vein caused a rise in plasma concentration similar to that seen during hypoxia. There was a rise in heart rate but no significant change in arterial pressure. 6. The half-life of adrenaline and of noradrenaline in the maternal and foetal circulation was 0.25-1 min. There was no evidence of transfer of labelled catecholamine across the placenta.

The drag force on a racing shell increases with the square of velocity corresponding to a 3.2 power increase in energy expenditure. However, the metabolic cost increases with only an approximately 2.4 power function of shell velocity. During international races the metabolic cost corresponds to an oxygen uptake of 6.7 to 7.0 L/min over 6.5 min. The relative anaerobic contribution to 6.5 min of 'all-out' rowing has not been determined but is estimated to range from 21 to 30%. Because of the large muscle mass involved in rowing, blood variables reach extreme values: adrenaline 19 nmol/L; noradrenaline 74 nmol/L; pH 7.1; and bicarbonate 9.8 mmol/L. Because of the static component of the rowing stroke at the catch, blood pressure increases to near 200mm Hg, and the heart of oarsmen has adapted to this load by increasing wall thickness and internal diameters. The maximal oxygen uptake of oarsmen may reach 6.6 L/min and ventilation 243 L/min. Arterial oxygen tension decreases by 20mm Hg during 'all-out' rowing corresponding to a decrease in pulmonary diffusion capacity. A force of approximately 800 to 900N is developed on the oar. Force generation during rowing is relatively slow, 0.3 to 0.4 sec. Oarsmen are strongest in low velocity movement with 70 to 75% slow twitch fibres in skeletal muscle. Data indicate that rowing technique and training may improve explaining why results become approximately 0.7 sec faster per year.

Projections from the nucleus tractus solitarii (NTS) to autonomic control regions of the ventrolateral medulla, particularly the nucleus reticularis rostroventrolateralis (RVL), which serves as a tonic vasomotor center, were analyzed in rat by anterograde, retrograde, and combined axonal transport techniques. Autonomic portions of the NTS, including its commissural, dorsal, intermediate, interstitial, ventral, and ventrolateral subnuclei directly project to RVL as well as to other regions of the ventrolateral medulla. The projections are organized topographically. Rostrally, a small cluster of neurons in the intermediate third of NTS, the subnucleus centralis, and neurons in proximity to the solitary tract selectively innervate neurons in the retrofacial nucleus and nucleus ambiguus. Neurons generally located in more caudal and lateral sites in the NTS innervate the caudal ventrolateral medulla (CVL). The RVL, CVL, and nucleus retroambiguus are interconnected. A combined retrograde and anterograde transport technique was developed so as to prove that projections from the NTS to the ventrolateral medulla specifically innervate the region of RVL containing neurons projecting to the thoracic spinal cord or the region of the nucleus containing vagal preganglionic neurons. When the retrograde tracer, fast blue, was injected into the thoracic spinal cord, and wheat germ agglutinin-conjugate horseradish peroxidase (HRP) was injected into the NTS, anterogradely labeled terminals from the NTS surrounded the retrogradely labeled neurons in the RVL and in the nucleus retroambiguus in the caudal medulla. Among the bulbospinal neurons in the RVL innervated by the NTS were adrenaline-synthesizing neurons of the C1 group. When fast blue was applied to the cervical vagus, and HRP was injected into the NTS, anterogradely labeled terminals from the NTS surrounded retrogradely labeled neurons in the rostral dorsal motor nucleus of the vagus, the region of the nucleus ambiguus, the retrofacial nucleus, and the dorsal portion of the RVL, a region previously shown to contain cardiac vagal preganglionic neurons. This combined anterograde and retrograde transport technique provides a useful method for tracing disynaptic connections in the brain. These data suggest that the RVL is part of a complex of visceral output regions in the ventrolateral medulla, all of which receive afferent projections from autonomic portions of the NTS. Bulbospinal neurons in the RVL, in particular the C1 adrenaline neurons, may provide a portion of the anatomic substrate of the baroreceptor and other visceral reflexes.

Plasma adrenaline and noradrenaline concentrations were measured in 24 patients during the induction of anaesthesia and the subsequent tracheal intubation. The patients received either suxamethonium 1 mg kg-1 or pancuronium 0.1 mg kg-1 to facilitate tracheal intubation. Mean arterial pressure (MAP) increased in both groups following laryngoscopy and tracheal intubation and there were concomitant increases in the plasma catecholamine concentrations, the changes being more marked in the suxamethonium group. There was a significant correlation between MAP and plasma catecholamine concentrations in the suxamethonium group. Measurement of plasma catecholamine concentrations in samples obtained simultaneously from central venous, peripheral venous and arterial sites were in broad agreement; the greatest changes occurred in central venous samples.

This paper describes a technique for selectively extracting catecholamines from body fluids prior to quantification by high-performance liquid chromatography with electrochemical detection. The technique is a two-stage process, the first stage involves the extraction of cations from the sample whilst the second stage is a liquid-liquid extraction involving the complexation of the cationic catecholamines with diphenylborate. This technique provides a very specific extraction procedure which results in chromatograms with no interfering compounds, and gives absolute recoveries of 70-80% for noradrenaline (NA), adrenaline (A) and dihydroxybenzylamine (internal standard), with similar relative recoveries of the 3 compounds. The intra-assay coefficients of variation for the measurement of catecholamines in venous plasma taken from resting subjects, are 8-9% for both NA and A, whilst the inter-assay values are 8% for NA and 20% for A.

1. Insulin secretion was studied in isolated islets of Langerhans obtained by collagenase digestion of rat pancreas. In addition to responding to glucose and mannose as do whole pancreas and pancreas slices in vitro, isolated rat islets also secrete insulin in response to xylitol, ribitol and ribose, but not to sorbitol, mannitol, arabitol, xylose or arabinose. 2. Xylitol and ribitol readily reduce NAD(+) when added to a preparation of ultrasonically treated islets. 3. Adrenaline (1mum) inhibits the effects of glucose and xylitol on insulin release. Mannoheptulose and 2-deoxy-glucose, however, inhibit the response to glucose but not that to xylitol. 4. The intracellular concentration of glucose 6-phosphate is increased when islets are incubated with glucose but not with xylitol, suggesting that xylitol does not promote insulin release by conversion into glucose 6-phosphate. 5. Theophylline (5mm) potentiates the effect of 20mm-glucose on insulin release from isolated rat islets of Langerhans, but has no effect on xylitol-mediated release. These results indicate that xylitol does not stimulate insulin release by alterations in the intracellular concentrations of cyclic AMP. 6. A possible role for the metabolism of hexoses via the pentose phosphate pathway in the stimulation of insulin release is discussed.

OBJECTIVE

There has been a revolution in cardiovascular neuroscience in recent years with, in some cases, translation into clinical practice of the knowledge of pathophysiology gained through application of sympathetic nerve recording and catecholamine isotope dilution methodology. OBESITY-RELATED HYPERTENSION: An earlier hypothesis, based on findings in most models, was that weight gain in obesity is due in part to sympathetic nervous underactivity reducing thermogenesis. Microneurography and regional noradrenaline spillover measurements in human obesity have disproven this hypothesis, weakening the case for the use of beta3-adrenergic agonists to stimulate thermogenesis. Sympathetic nerve firing rates in post-ganglionic fibres directed to the skeletal muscle vasculature are increased, as is renal sympathetic tone, with a doubling of the spillover rate of noradrenaline from the kidneys. Given these findings, antiadrenergic antihypertensive drugs may be the preferred agents for obesity-related hypertension, but this has not been adequately tested.

UNASSIGNED

Whether stress causes high blood pressure, previously hotly debated, has been under recent review by an Australian Government body, the Specialist Medical Review Council. Despite medicolegal implications, the ruling was that stress is one proven cause of hypertension. The judgment was reached after consideration of the epidemiological evidence, but in particular the described neural pathophysiology of essential hypertension: (a) persistent sympathetic nervous stimulation is commonly present, (b) suprabulbar projections of noradrenergic brainstem neurones are activated and (c) adrenaline is released as a cotransmitter in sympathetic nerves. These were taken to be biological markers of stress.

UNASSIGNED

At one time, the failing heart was thought to be sympathetically denervated. Longterm administration of inotropic adrenergic agonists, to provide the cardiac catecholamine stimulation thought to be lacking, increased mortality. Noradrenaline isotope dilution methodology subsequently demonstrated that the sympathetic outflow to the heart was preferentially activated, cardiac noradrenaline spillover being increased as much as 50-fold. The level of stimulation of the cardiac sympathetic nerves was the most powerful predictor of death. These observations provide the theoretical foundation for the very successful introduction of beta-adrenergic blockers for treatment of heart failure.

1. Secretagogues of pancreatic enzyme secretion: pancreozymin, carbamylcholine, gastrin I, the octapeptide of pancreozymin, caerulein and the Ca2+ ionophore A 23187 stimulate 45Ca uptake into isolated rat pancreatic cells, whereas adrenaline, isoproterenol, secretin, dibutyrylic cyclic adenosine 3',5'-monophosphate and dibutyrylic cyclic guanosine 3',5'-monophosphate have no effect on 45Ca uptake. 2. A graphical analysis of the Ca2+ uptake curves reveals at least two phases: a fast phase, probably due to binding of Ca2+ to the membrane and a slow phase representing Ca2+ transport into cells. Both phases are stimulated by pancreozymin and carbamylcholine. 3. The 45Ca-exchangeable pool size is increased by both carbamylcholine and pancreozymin, whereas a significant increase of total content of cell calcium was too small to be detected. 4. Atropine blocks the stimulatory effect of carbamylcholine completely but not that of pancreozymin. The Ca2+ antagonist D600 blocks the stimulatory effects of both carbamylcholine and pancreozymin only partially. 5. The data suggest that secretagogues of pancreatic enzyme secretion act by increasing the rate of Ca2+ transfer into the cell most probably through an increase of the cell membrane permeability for Ca2+.

1. Methods are described for the extraction and assay of ATP, ADP, AMP, glucose 6-phosphate, l-glycerol 3-phosphate and citrate in rat epididymal adipose tissue incubated in vitro for 1hr. At this time of incubation rates of glucose uptake and outputs of glycerol, free fatty acids, lactate and pyruvate were shown to be constant. 2. In fat pads incubated in medium containing glucose (3mg./ml.) and albumin (20mg./ml.) the concentrations (in mmumoles/g. wet wt.) were: ATP, 70; ADP, 36; AMP, 9.0; glucose 6-phosphate, 3.0; l-glycerol 3-phosphate, 3.3; citrate, 8.1. 3. The volume of intracellular water calculated from ([(3)H]water space-[(14)C]sorbitol space), ([(14)C]urea space-inulin space) and (weight loss on drying-[(14)C]sorbitol space) was 1.4ml./100g. wet wt. of tissue. The intracellular volume was not changed by insulin, alloxan-diabetes or adrenaline. 4. When compared in terms of mumoles/ml. of intracellular water the concentration of ATP in adipose tissue was less than in heart and diaphragm muscles. The concentrations of ADP and AMP were greater both in absolute terms and relative to ATP. Insulin, alloxan-diabetes and adrenaline had no significant effects on the concentrations of the adenine nucleotides in adipose tissue. 5. The concentration of glucose 6-phosphate was increased by insulin and lowered by alloxan-diabetes and adrenaline. The concentration of l-glycerol 3-phosphate was increased by insulin, unchanged by alloxan-diabetes and lowered by adrenaline. The concentration of citrate was increased by adrenaline and alloxan-diabetes and unchanged by insulin. 6. The effect of glucose concentration in the medium on rates of glucose uptake in adipose tissue from normal rats and alloxan-diabetic rats was investigated. The K(u) of glucose uptake was 29-44mg./100ml. and the V(max.) was 0.77mg./g. wet wt. of tissue/hr. Insulin increased the V(max.) and alloxan-diabetes diminished it, but neither agent significantly altered the K(u). 7. The significance of these results in relation to control of metabolism of adipose tissue is discussed.

Further investigations about the role of the mitochondria-rich cell (MR cell) in hormone-mediated transport regulation in the epithelium of frog skin brought the following results: Unlike toad bladder, in frog skin the spontaneous potential difference cannot be reversed when Na transport is blocked. A similar situation is obtained when, in addition to transport-blockade, one applies a chemical gradient for chloride to the epithelium. Under these conditions we found that in the intact preparation as well as in the separated epithelium: (i) the reversed current (RC) is linearly related to the number of MR cells; (ii) RC is mainly carried by a passive, transcellular chloride flux inwards and (iii) RC is sensitive to nor-adrenaline (10(-7) M). The beta-blocker propranolol abolishes this effect. We propose that the MR cells are the sites of transepithelial shunt-path and that this chloride flux is transcellular. As it is hormone sensitive, it could be an important regulatory instrument for the regulation of overall salt transport (internal shorting).

Plasma noradrenaline (NA), adrenaline (A), corticosterone (CS) and glucose concentrations were determined in blood frequently sampled via a cardiac catheter from freely behaving rats exposed to five successive trials of water-immersion stress (WIS) with an interval between successive trials (interstressor interval; ISI) of either 24 hr or 72 hr. The first, acute exposure to WIS was accompanied by increased levels of plasma NA, A, CS and glucose which were substantially higher than those associated with handling or placement into a new cage. The magnitudes of the WIS-induced plasma NA, A, CS and glucose responses gradually declined across trials. However, five WIS exposures at a 24-hr ISI resulted in a faster and greater decrement of the plasma A, CS and glucose responses than five exposures at a 72-hr ISI. The data indicate that frequency of stressor presentation (i.e., length of interstressor interval) affects the adaptation pattern of neuroendocrine and metabolic responses to chronic intermittent stress. This finding supports the hypothesis that neuroendocrine adaptation to stress is (at least partly) similar to the process of behavioral or neurophysiological habituation to a sensory stimulus.

BACKGROUND

There are few data on the incidence, clinical features, and management of patients with acute anaphylaxis presenting to the emergency department. We investigated all presentations to one department during the course of a year to improve current awareness of this medical emergency.

OBJECTIVE

The purpose of the study was to describe the clinical features, management, and outcome of anaphylaxis presentations to a single Australian adult emergency department in a single year, 1998-1999.

METHODS

This was a retrospective, case-based study of adult patients >>or=13 years of age) attending a single emergency department in Brisbane, Australia, during the year 1998-1999. The medical records of 304 patients satisfying the relevant discharge diagnostic codes were studied. We determined incidence, sex ratio, age, clinical features, management, disposal, asthma prevalence, and causes in patients presenting with acute allergic reactions and anaphylaxis.

RESULTS

In all, 162 emergency department patients with acute allergic reactions and 142 emergency department patients with anaphylaxis, including 60 whose anaphylaxis was severe, were seen during the year, for an anaphylaxis presentation incidence of 1 in 439. One patient died; this gave a case fatality rate of 0.70%. Cutaneous features were present in 94% of the patients with anaphylaxis. Of those with severe anaphylaxis, 35% had dizziness/syncope before hospital presentation, 25% laryngeal edema, and 21.7% systolic hypotension on hospital presentation. A cause was recognized in 73% of the anaphylaxis cases; most commonly, the causative agent was a drug, insect venom, or food. Adrenaline was used in 57% of the severe cases before hospital presentation or in the hospital. The emergency department alone definitively cared for 94% of all patients, though only 43% severe anaphylaxis cases were referred for follow-up.

CONCLUSIONS

The emergency department anaphylaxis presentation incidence of 1 in 439 cases is greater than previously recognized, though death remains rare. In three fourths of cases, a precipitant was identified, a fact that emphasizes the need for a detailed initial history. Definitive management in the emergency department alone is possible in most cases, provided that the appropriate use of adrenaline and the need for allergy clinic follow-up are appreciated.

Experiments were carried out with hearts isolated from reserpine- and pargyline-pretreated rats; both noradrenaline-metabolizing enzymes and uptake1 were inhibited. Initial rates of extraneuronal uptake were measured after perfusion lasting for 2 min, either in the absence or in the presence of 100 mumol/l O-methyl-isoprenaline, a potent inhibitor of uptake2. The ID50 (i.e., the concentration of unlabelled substance that halves the rate of uptake of a tracer concentration of 3H-(+/-)-isoprenaline) was determined for a variety of agents. Two types of stereoselective preference of (-)-isomers were observed: for isoprenaline and adrenaline (but not for noradrenaline)--and also for dobutamine. The stereoselective preference for the (-)-isomers of isoprenaline and adrenaline is also evident from fluorimetric determination of initial rates of uptake of unlabelled isomers. Experiments with various tritiated compounds indicate that uptake2 has a broad substrate spectrum: uptake2 is not restricted to 3H-catecholamines and 3H-phenethylamines, but extends to resorcinols (3H-orciprenaline), imidazoline derivatives (3H-clonidine), 3H-histamine and 3H-5-hydroxytryptamine (3H-5-HT). Determinations of the Vmax of uptake2 revealed a correlation between the ID50 and the Vmax: the higher the ID50, the higher the Vmax. These results indicate that uptake2 is a carrier-mediated process.

BACKGROUND

Through-the-scope clips are commonly used for endoscopic hemostasis of gastrointestinal (GI) bleeding, but their efficacy can be suboptimal in patients with complex bleeding lesions. The over-the-scope clip (OTSC) could overcome the limitations of through-the-scope clips by allowing compression of larger amounts of tissue, allowing a more efficient hemostasis. We analyzed the use of OTSC in a consecutive case series of patients with acute GI bleeding unresponsive to conventional endoscopic treatment modalities.

METHODS

In a retrospective analysis of prospectively collected data in tertiary referral centers, patients undergoing emergency endoscopy for severe acute nonvariceal GI bleeding were treated with the OTSC after failure of conventional techniques. All patients underwent repeat endoscopy 2-4 days after the procedure. Data analysis included primary hemostasis, complications, and 1-month follow-up clinical outcome.

RESULTS

During a 10-month period, 30 patients entered the study consecutively. Bleeding lesions unresponsive to conventional endoscopic treatment (saline/adrenaline injection and through-the-scope clipping) were located in the upper and lower GI tract in 23 and 7 cases, respectively. Primary hemostasis was achieved in 29 of 30 cases (97 %). One patient with bleeding from duodenal bulb ulcer required emergent selective radiological embolization. Rebleeding occurred in two patients 12 and 24 h after the procedure; they were successfully treated with conventional saline/adrenaline endoscopic injection.

CONCLUSIONS

OTSC is an effective and safe therapeutic option for severe acute GI bleeding when conventional endoscopic treatment modalities fail.

1. The effects of some alpha- and beta-adrenoceptor agonists and antagonists were studied on isolated segments of rabbit intestine in an attempt to characterize the two types of inhibitory response produced by sympathomimetic amines.2. Phenylephrine, an alpha-adrenoceptor agonist, produced an inhibition of rapid onset, from which recovery occurred despite the continued presence of the drug. On washout there was an overshoot in contraction height. Isoprenaline, a beta-adrenoceptor agonist, produced an inhibition of slow onset which was maintained throughout the presence of the drug and there was no overshoot on washout.3. Adrenaline resembled phenylephrine more closely than it resembled isoprenaline, in that it showed more affinity for alpha-adrenoceptors, whereas noradrenaline, and the transmitter released on periarterial nerve stimulation, behaved more like isoprenaline, although both types of receptor were affected.4. Adenosine-5'-triphosphate produced an inhibition resembling that produced by an alpha-adrenoceptor agonist, whereas the dibutyryl analogue of cyclic adenosine 3',5'-monophosphate (cyclic 3',5'-AMP) produced an inhibition resembling that produced by a beta-adrenoceptor agonist.5. In critical concentrations theophylline augmented and imidazole inhibited beta-adrenoceptor mediated responses, as well as responses to dibutyryl cyclic AMP. However, additional actions of theophylline and imidazole were also demonstrated.6. Responses mediated by alpha-adrenoceptors, but not those mediated by beta-adrenoceptors, were blocked by membrane stabilizers, quinidine being the most potent of those studied.7. The results are discussed in relation to the possible mechanisms of action of alpha- and beta-adrenoceptor agonists.

In cats under chloralose anaesthesia the cerebral ventricles were perfused with Locke solution at a rate of 0.1 ml./min. from an indwelling cannula in the lateral ventricle. The effluent was collected from a cannula either inserted into the cisterna magna or pushed into the aqueduct. When collection was from the cisterna the perfusion included relatively large areas of the subarachnoidal spaces since in cats the foramina of Luschka form the only outlet from the fourth ventricle. Tubocurarine, histamine, and adrenaline injected intravenously caused great variations in outflow from the cisterna, but these changes did not occur when the collection was from the aqueduct. The changes in outflow from the cisterna were similar whether the injection produced a fall of arterial blood pressure as after tubocurarine and histamine, or a rise, as after adrenaline.

The ability of glucagon and of adrenaline to affect the concentration of fructose 2,6-bisphosphate in isolated hepatocytes was re-investigated because of important discrepancies existing in the literature. We were unable to detect a significant difference in the sensitivity of the hepatocytes with regard to the effect of glucagon to initiate the interconversion of phosphorylase, pyruvate kinase, 6-phosphofructo-2-kinase and fructose 2,6-bisphosphatase, and also to cause the disappearance of fructose 2,6-bisphosphate. In contrast, we have observed differences in the time-course of these various changes, since the interconversions of phosphorylase and of pyruvate kinase were at least twice as fast as those of 6-phosphofructo-2-kinase and of fructose 2,6-bisphosphatase. When measured in a cell-free system in the presence of MgATP, the cyclic AMP-dependent interconversion of pyruvate kinase was 5-10-fold more rapid than those of 6-phosphofructo-2-kinase and of fructose 2,6-bisphosphatase. These data indicate that 6-phosphofructo-2-kinase and fructose 2,6-bisphosphatase are relatively poor substrates for cyclic AMP-dependent protein kinase; they also support the hypothesis that the two catalytic activities belong to a single protein. Adrenaline had only a slight effect on the several parameters under investigation, except for the activation of phosphorylase. In the absence of Ca2+ ions from the incubation medium, however, adrenaline had an effect similar to that of glucagon.

1. Whole-cell recordings of voltage-gated Ca2+ current in single smooth muscle cells from rabbit ear artery were obtained with 110 mM-Ba2+ as charge carrier. 2. Noradrenaline (NA, 1-20 microM) produced a sustained increase in the dihydropyridine-sensitive L-type Ca2+ current, ranging up to 3-fold in some cells. The dihydropyridine-resistant T-type Ca2+ current was not affected. 3. The time and voltage dependence of activation and inactivation of the L-type current were not significantly changed during NA modulation. 4. The NA-induced increase in L-current was enhanced in magnitude and consistency by the inclusion of 200 microM-GTP in the pipette (internal) solution. 5. The effect of NA on L-current was not abolished by pre-treatment with prazosin, phentolamine or propranolol, suggesting that it is not mediated by alpha- or beta-adrenoceptors. 6. Phenylephrine (5 microM) was ineffective as an agonist, while adrenaline was approximately equipotent to NA. In these respects, the pharmacology of L-current modulation resembles that of 'gamma'-adrenergic receptors (Hirst & Nield, 1980). 7. NA modulation of L-type Ca2+ channels may be particularly important in promoting sympathetic vasoconstriction in resistance vessels where Ca2+ stores are relatively poorly developed and where NA-evoked contractions are very sensitive to organic Ca2+ channel antagonists.