OBJECTIVE

Endoscopic injection therapy improves outcome in bleeding peptic ulcer, but the optimum regimen is unknown. The aim of this study was to compare the efficacy of endoscopic therapy with dilute adrenaline alone vs. adrenaline plus human thrombin in the treatment of patients with major peptic ulcer hemorrhage.

METHODS

One hundred forty patients with significant peptic ulcer hemorrhage and active arterial bleeding or a nonbleeding visible vessel were randomized to endoscopic injection with 1:100,000 adrenaline (70 patients; group 1) or to adrenaline plus 600-1000 IU of human thrombin (70 patients; group 2). The two groups were well matched for age, shock, hemoglobin concentration, comorbid disease, endoscopic findings, and consumption of nonsteroidal anti-inflammatory drugs.

RESULTS

Fourteen patients from group 1 (20%) and 3 patients from group 2 (4.5%) rebled (P < 0.005). Seven patients from group 1 (10%) but no patients from group 2 died within 30 days of admission (P < 0.013). Patients from group 1 were administered a total of 297 units of blood compared with 219 units in group 2 (P < 0.041).

CONCLUSIONS

Endoscopic injection using adrenaline plus human thrombin is superior to injection with dilute adrenaline alone and may represent the best treatment for bleeding peptic ulcers.

Interrelations among blood pressure, circulatory volume, plasma renin activity (PRA) and urinary catecholamine excretion rates were studied in normal subjects and in patients with benign essential hypertension. Mean plasma or blood volumes related to lean body mass, products of blood volume and the logarithm of PRA, and catecholamine excretion rates did not differ significantly between normal and hypertensive subjects. In both normal subjects and hypertensive patients, blood pressure levels correlated positively with the noradrenaline excretion rate (r = 0.40 and 0.36, respectively; p less than 0.025) but not with adrenaline excretion, circulatory volume or the volume-renin product. The logarithm of PRA correlated inversely with mean blood pressure in normal subjects (r = 0.40; p less than 0.001) but not in hypertensive patients; however, there was no convincing evidence for an inappropriate blood pressure-PRA relationship as a prominent feature in the hypertensive patients. PRA did not correlate with blood volume. Patients with low PRA relative to sodium excretion (21 per cent of hypertensive population) were consistently normovolemic, but they tended to be older and excreted less (p less than 0.025) adrenaline than patients with normal or high PRA. The patient subgroup with high PRA relative to sodium excretion (11 per cent of population) was hypovolemic (p less than 0.02); despite this, urinary sodium output was high (172 +/- 64 meq/24 hours). These data reveal no evidence for major roles of PRA, circulatory volume and free peripheral catecholamines in the maintenance of benign essential hypertension. Essential hypertension with low PRA is usually not a hypervolemic state, but it may reflect diminished adrenergic activity, factors associated with aging and effects of a high systemic pressure. High PRA in benign essential hypertension may be at least partly a consequence of hypovolemia resulting from high blood pressure-induced sodium diuresis.

1. The structure of catechol O-methyltransferase (COMT) has been recently characterized and a series of new and selective COMT inhibitors developed. 2. Entacapone, nitecapone and tolcapone are nitrocatechol-type potent COMT inhibitors in vitro (Ki in nanomolar range). They are also very selective for COMT and active in vivo even after oral administration. CGP 28014 is a pyridine derivative that is active only in vivo. 3. In animal studies, these compounds inhibit effectively the O-methylation of L-dopa, thus improving its bioavailability and brain penetration and potentiating its behavioural effects. 4. Entacapone and nitecapone have mainly a peripheral effect whereas tolcapone and CGP 28014 also inhibit O-methylation in the brain. 5. In man, entacapone, nitecapone and tolcapone all inhibit dose dependently the COMT activity in erythrocytes. These COMT inhibitors also decrease the amount of COMT dependent metabolites of adrenaline and noradrenaline in plasma. 6. In human volunteers, entacapone, tolcapone and CGP 28014 improve the bioavailability of L-dopa and inhibit the formation of 3-O-methyldopa. 7. In the first clinical studies in patients with Parkinson's disease, both entacapone and tolcapone potentiate and prolong the therapeutic effect of L-dopa.

Fifteen patients with hypertension due to phaeochromocytoma and 35 controls with essential hypertension were studied to assess the diagnostic value of urinary and plasma biochemical determinations in phaeochromocytoma. In every case of phaeochromocytoma the urinary concentration of vanillylmandelate, metanephrines, or adrenaline plus noradrenaline was diagnostic of the disease irrespective of whether the patient was normotensive or hypertensive at the time. Plasma determinations of adrenaline and noradrenaline, however, gave falsely negative results on three occasions. These findings suggest that urinary biochemical determinations--particularly of metanephrines--are more reliable than plasma catecholamine measurements as a test for phaeochromocytoma. The test is particularly useful in patients with intermittent hypertension.

Chromaffin, small granule-containing (SGC)-cells, neurons and the innervation of these cells was studied in the adrenal gland of three species of reptiles (Testudo graeca, Lacerta dugesi, Natrix natrix). 1. After fixation with glutaraldehyde and osmium-tetroxide adrenaline (A)- and noradrenaline (NA)-storing cells can be distinguished by means of the different electron density of their granules: A-granules are moderately electron-dense, while NA-granules show a core of high electron density. The unusually high electron density of a few A-granules in Testudo occasionally required viewing of unstained sections which facilitated the discrimination of the two cell types in this species. In all species studied NA-granules display a remarkable polymorphism which is most pronounced in the tortoise. In this species A-granules are polymorphic, too. Both types of granules show wide variations in size, which are particularly great in the tortoise. This species also exhibits the largest average sizes for A-granules (285 nm), and NA-granules (354 nm). The corresponding parameters for Lacerta and Natrix, are 255 and 179 nm for A- and 323 and 304 nm for NA-granules, respectively. The rough ER in A-cells of the tortoise regularly occurs in the form of circular dilations ('ergastosomes', Kanerva and Hervonen, 1973). Mitochondria sometimes contain longitudinal cristae with a crystalloid internal pattern. Large dense bodies which incorporate granules are abundant in NA-cells. Smaller dense bodies containing a few dense patches and membranes are present in both A- and NA-cells. Intermediate stages between dense bodies and what appear to be A- or NA-granules (if the latter have lost some of their amine-content) are frequently observed.

Segments of mouse parotid were placed in a superfusion chamber. Surface acini were impaled by one or two micro-electrodes for measurement of membrane potential and resistance. The acinus under investigation was stimulated by micro-iontophoretic application of acetylcholine (ACh) or adrenaline. Neighbouring acinar cells were electrically coupled. Electrical coupling between acinar cells only occurred within restricted domains probably corresponding to an acinus or a group of acini. Passing direct current through one intracellular electrode, the resting potential of an acinus could be set at desired levels and the dependency of the ACh-evoked potential change on the resting potential investigated. The ACh null potential (initial effect) was about--60 mV. A delayed hyperpolarizing effect of ACh could not be reversed. The initial ACh-evoked potential change was sensitive to alterations in extracellular Na, K and Cl concentration. The delayed ACh-evoked hyperpolarization was blocked by ouabain, exposure to Na-free or K-free solutions. It is concluded that ACh increases mainly K and Na membrane conductance causing K efflux and Na influx with a subsequent Na activation of an electrogenic Na pump.

The uptake of 45Ca2+ by a lanthanum-non-displaceable pool in pancreatic islets was studied; Raising the extracellular D-glucose concentration from 3 to 20 mM stimulated the 45Ca2+ uptake in hand-dissected islets of ob/bo-mice as well as in collagenase-isolated islets of ob/ob or normal mice. The effect was dose-dependent in the range of 0-20 mM D-glucose and was seen throughout a wide range of extracellular calcium concentrations (16 mumol-2.56 mmol of Ca2+ added per litre of medium). The 45Ca2+ uptake was also enhanced by other known insulin secretagogues (D-mannose, L-leucine, tolbutamide) and was uninfluenced by compounds lacking insulin-releasing capacity (3-O-methyl-D-glucose, L-glucose, D-galactose, D-leucine). The stimulatory effect of D-glucose was blocked by inhibitors of glucose-induced insulin release (D-mannoheptulose, diazoxide, L-adrenaline). The results support the view that the lanthanum-nondisplaceable calcium pool is related to the insulin-releasing mechanism, although the exact nature of this relationship is still unclear.

1. Mitochondrial and microsomal fractions were prepared from rat parotid glands. Both fractions were able to take up (45)Ca. The mitochondrial (45)Ca-uptake system could be driven by ATP (energy-coupled Ca(2+) uptake) or by ADP+succinate (respiration-coupled Ca(2+) uptake). Energy-coupled Ca(2+) uptake was blocked by oligomycin but not by carbonyl cyanide m-chlorophenylhydrazone; respiration-coupled Ca(2+) uptake was blocked by carbonyl cyanide m-chlorophenylhydrazone but not by oligomycin. Microsomal Ca(2+) uptake was dependent on the presence of ATP; the ATP-dependent Ca(2+) uptake was not affected by oligomycin or carbonyl cyanide m-chlorophenylhydrazone. Ca(2+) uptake by both fractions was inhibited by Ni(2+). 2. Incubation of parotid pieces with adrenaline increased the rate of release of amylase and the uptake of (45)Ca. The adrenaline-stimulated release of amylase was not dependent on the presence of extracellular Ca(2+). 3. The effect of adrenaline on the subcellular distribution of (45)Ca in parotid pieces incubated with (45)Ca was studied. In parotid tissue incubated with (45)Ca, both mitochondrial and microsomal fractions contained (45)Ca. Incubation with adrenaline increased the amount of (45)Ca incorporated into the mitochondrial fraction but not the microsomal fraction. In parotid tissue preloaded with (45)Ca subsequent incubation with adrenaline caused a decrease in the amount of (45)Ca found in both the mitochondrial and microsomal fractions. 4. From these data we conclude that the regulation of the cytosolic Ca(2+) concentration in the parotid may involve both mitochondrial and microsomal Ca(2+)-uptake systems. We suggest that the action of adrenaline on the parotid may be to increase the movement of Ca(2+) to the cytosol by increasing the flux of Ca(2+) across mitochondrial, microsomal and plasma membranes.

1. Six male beagle dogs with carotid loops were infused with sodium chloride solution (150 mmol/l; saline) during control observations followed by dopamine infusion at various rates. Arterial blood samples were drawn during the control period and at the end of each period of dopamine infusion for the measurement of plasma dopamine, noradrenaline, adrenaline, renin, angiotensin II, aldosterone, vasopressin, electrolytes and packed cell volume. Blood pressure and pulse were recorded throughout. 2. The rate of infusion and plasma dopamine levels were closely correlated (r = 0.99, P less than 0.001). Plasma dopamine levels two to 20 times basal values produced no significant change in any of the other variables measured; levels 200 times basal values caused a significant increase (P less than 0.05) in plasma renin concentration; levels 2000 times basal values were associated with significant increases (P less than 0.05) in plasma renin and angiotensin II, packed cell volume and blood pressure, without significant changes in other measurements. 3. Circulating dopamine is unlikely to be important in the control of sodium and water metabolism.

1 The selectivity of alpha-adrenoceptors mediating the pro-aggregatory response of human and rabbit platelets to adrenaline and the conditions required to permit expression of an aggregatory response to partial agonists at these alpha-adrenoceptors have been studied.2 Yohimbine causes effective blockade of the pro-aggregatory responses whereas indoramin and prazosin are ineffective.3 The clonidine analogue, UK-14304, is nearly as effective as adrenaline in inducing an aggregatory response in human platelets and a pro-aggregatory response in rabbit platelets. Cross-tachyphylaxis between adrenaline and UK-14304 has been demonstrated.4 Clonidine is a weak agonist for the pro-aggregatory response of rabbit platelets and in some donors for the aggregatory response of human platelets.5 Methoxamine induces a pro-aggregatory response in human platelets which is blocked by indoramin or prazosin but not by yohimbine. No such response to methoxamine is observed in rabbit platelets.6 The divalent cation ionophore, A-23187, induces an aggregatory response to clonidine (in platelets from a non-responsive donor), phenylephrine and methoxamine in human platelets and to adrenaline, UK-14304 and clonidine in rabbit platelets. A secretory response to clonidine is also induced by A-23187 in human platelets.7 The adenylate cyclase inhibitor, SQ-22536, is ineffective in either inducing a response to the alpha-agonists or potentiating the effect of A-23187.8 The aggregatory responses to adrenaline and UK-14304 in rabbit platelets and to clonidine in human and rabbit platelets, which can be induced by A-23187, are blocked by yohimbine but not by prazosin or indoramin.9 From these studies we conclude that the pro-aggregatory responses of human and rabbit platelets to adrenaline are mediated primarily by alpha(2)-adrenoceptors. The presence of alpha(1)-adrenoceptors on human platelets is confirmed but these receptors do not appear to be present on rabbit platelets. The conditions required for expression of an aggregatory response to partial agonists at the human and rabbit platelet alpha-adrenoceptors implicate an increase in cytosolic Ca(2+) concentration as a key event in stimulus-response coupling but do not indicate such a role for depression of cyclic adenosine-3',5'-monophosphate concentration.

Activation of both beta(1)- and beta(2)-adrenoceptors increases the contractility of human atrial myocardium through cyclic AMP-dependent pathways. Cyclic AMP is hydrolised by phosphodiesterases, but little is known about which isoenzymes catalyse inotropically relevant cyclic AMP accumulated upon stimulation of beta-adrenoceptor subtypes. We have compared the positive inotropic effects of (-)-noradrenaline and (-)-adrenaline, mediated through beta(1)- and beta(2)-adrenoceptors, respectively, in the absence and presence of the PDE3 inhibitor cilostamide (300 nM) or PDE4 inhibitor rolipram (1 muM) on human atrial trabeculae from non-failing hearts. Cilostamide, but not rolipram, potentiated the effects of both (-)-noradrenaline and (-)-adrenaline. Cilostamide increased the -logEC(50)M of (-)-adrenaline more than of (-)-noradrenaline (P < 0.05), regardless of whether or not the patients had been chronically treated with beta-blockers. The results are consistent with a greater PDE3-catalysed hydrolysis of inotropically relevant cyclic AMP produced through beta(2)-adrenoceptors than beta(1)-adrenoceptors in human atrium.

1. The venous outflow from the slow soleus muscle, at rest and during exercise, was compared with that of fast muscles. The blood flow through the soleus at rest was found to be, on average, 52 ml./100 g.min, which is about 4 times that of fast muscles.2. On stimulation of soleus through its motor nerve at low frequencies, up to 8/sec, hardly any increase in flow was observed, whereas fast muscles stimulated at the same rates showed a marked increase, the maximal functional hyperaemia being reached at 8/sec. Even when the soleus muscle was stimulated at frequencies of 40/sec the post-contraction hyperaemia was very small and sometimes absent.3. The relative absence of functional hyperaemia in the soleus does not appear to be due to low vascular tone, for small amounts of acetylcholine, injected close arterially, produced a considerable increase in blood flow. Further, in experiments in which the vascular tone was increased by lumbar sympathetic stimulation, no functional hyperaemia was seen. It is concluded that a contracting soleus does not release in adequate amounts the substance causing functional vasodilatation in fast muscles.4. No vasodilator effect of adrenaline could be demonstrated in soleus, and the vasodilator effect of isoprenaline was much smaller than that seen in fast muscles.5. The vasoconstrictor effect of lumbar sympathetic stimulation on the resistance vessels of soleus was much smaller than the effect seen in fast muscles. However, the responses of the resistance vessels in soleus to close arterial injections of noradrenaline were not very different from those of fast muscles, and it is suggested that the density of the terminal sympathetic innervation of the vessels of soleus differs from that of fast muscles.

1. This investigation was designed to determine the contribution of the exercise pressor reflex to the resetting of the carotid baroreflex during exercise. 2. Ten subjects performed 3.5 min of static one-legged exercise (20 % maximal voluntary contraction) and 7 min dynamic cycling (20 % maximal oxygen uptake) under two conditions: control (no intervention) and with the application of medical anti-shock (MAS) trousers inflated to 100 mmHg (to activate the exercise pressor reflex). Carotid baroreflex function was determined at rest and during exercise using a rapid neck pressure/neck suction technique. 3. During exercise, the application of MAS trousers (MAS condition) increased mean arterial pressure (MAP), plasma noradrenaline concentration (dynamic exercise only) and perceived exertion (dynamic exercise only) when compared to control (P < 0.05). No effect of the MAS condition was evident at rest. The MAS condition had no effect on heart rate (HR), plasma lactate and adrenaline concentrations or oxygen uptake at rest and during exercise. The carotid baroreflex stimulus-response curve was reset upward on the response arm and rightward to a higher operating pressure by control exercise without alterations in gain. Activation of the exercise pressor reflex by MAS trousers further reset carotid baroreflex control of MAP, as indicated by the upward and rightward relocation of the curve. However, carotid baroreflex control of HR was only shifted rightward to higher operating pressures by MAS trousers. The sensitivity of the carotid baroreflex was unaltered by exercise pressor reflex activation. 4. These findings suggest that during dynamic and static exercise the exercise pressor reflex is capable of actively resetting carotid baroreflex control of mean arterial pressure; however, it would appear only to modulate carotid baroreflex control of heart rate.

Neuropeptide Y (NPY) coexists with noradrenaline in postganglionic sympathetic neurons. In order to test the hypothesis that NPY may be released along with catecholamines by activation of the sympathoadrenal system we measured plasma NPY-like immunoreactivity (NPY-LI) concentrations during cold pressor test, head up tilt and bicycle exercise in healthy volunteers. All 3 manoeuvres resulted in elevation of blood pressure, heart rate and plasma noradrenaline and adrenaline concentrations. These were accompanied by increases in plasma NPY-LI concentrations on cold pressor test and exercise, but not with head up tilt. The increases in both NPY-LI and catecholamines were greatest with exercise. These findings suggest that NPY is released at the same time as noradrenaline when sympathetic noradrenergic nerves are activated.

1. The smooth muscle of guinea-pig taenia coli was used to investigate the relation between metabolic and physiological effects of adrenaline. Electrical and mechanical activity was recorded with the sucrose gap technique and, in parallel experiments, the concentration of energy-rich phosphate compounds, adenosinetriphosphate and creatine phosphate, (ATP and CP) in the tissue was determined.2. Adrenaline (in concentrations from 2 x 10(-9) g/ml. to 5 x 10(-8) g/ml.) increased the tissue content of energy-rich phosphate compounds. This effect was coincident with the physiological, inhibitory effect on electrical and mechanical activity.3. After anaerobic exposure of the tissue to substrate-free medium, the biochemical and the physiological effects of adrenaline were both abolished; both recovered after readmission of oxygen and/or substrate.4. In muscles depleted of glycogen in substrate-free medium, either by anoxia or by high temperature, adrenaline produced its stabilizing effect on the cell membrane and the increase in ATP and CP content when beta-hydroxybutyrate was the substrate, i.e. in the complete absence of carbohydrate from the medium and from the tissue.5. When adrenaline was applied simultaneously with the readmission of substrate, the ATP and CP content of pieces treated with adrenaline was greater than of control pieces, though the tension of both was zero. This indicates that the effect was not secondary to the muscle relaxation but was the result of increased ATP synthesis.6. The physiological and biochemical effects of adrenaline were both abolished by the same concentration of imidazole (0.05 M).7. Low concentrations of ATP (1 x 10(6)-5 x 10(-6)M)-like adrenaline-inhibited electrical and mechanical activity of the taenia. This effect was also abolished by imidazole.

Hormone-sensitive lipase (HSL) catalyses the hydrolysis of myocellular triacylglycerol (MCTG), which is a potential energy source during exercise. Therefore, it is important to elucidate the regulation of HSL activity in human skeletal muscle during exercise. The main purpose of the present study was to investigate the role of 5'AMP-activated protein kinase (AMPK) in the regulation of muscle HSL activity and Ser565 phosphorylation (the presumed AMPK target site) in healthy, moderately trained men during 60 min bicycling (65%). Alpha2AMPK activity during exercise was manipulated by studying subjects with either low (LG) or high (HG) muscle glycogen content. HSL activity was distinguished from the activity of other neutral lipases by immunoinhibition of HSL using an anti-HSL antibody. During exercise a 62% higher (P < 0.01) alpha2AMPK activity in LG than in HG was paralleled by a similar difference (61%, P < 0.01) in HSL Ser565 phosphorylation but without any difference between trials in HSL activity or MCTG hydrolysis. HSL activity was increased (117%, P < 0.05) at 30 min of exercise but not at 60 min of exercise. In both trials, HSL phosphorylation on Ser563 (a presumed PKA target site) was not increased by exercise despite a fourfold increase (P < 0.001) in plasma adrenaline. ERK1/2 phosphorylation was increased by exercise in both trials (P < 0.001) and was higher in LG than in HG both at rest and during exercise (P = 0.06). In conclusion, the present study suggests that AMPK phosphorylates HSL on Ser565 in human skeletal muscle during exercise with reduced muscle glycogen. Apparently, HSL Ser565 phosphorylation by AMPK during exercise had no effect on HSL activity. Alternatively, other factors including ERK may have counterbalanced any effect of AMPK on HSL activity.

Sulfonation, like phosphorylation, can modify the activity of a variety of biological molecules. The sulfotransferase enzymes sulfonate neurotransmitters, drugs, steroid hormones, dietary carcinogens and proteins. SULT1A3 specifically sulfonates catecholamines such as dopamine, adrenaline and noradrenaline. The crystal structure of SULT1A3 with a sulfate bound at the active site, has been determined at 2.4 A resolution. Although the core alpha/beta fold is like that of estrogen and heparan sulfotransferases, major differences occur in and around the active site. Most notably, several regions surrounding the active site, including a section of 40 residues, are disordered in SULT1A3. Regions that are topologically equivalent to the disordered parts of SULT1A3 are involved in substrate and cofactor binding in estrogen and heparan sulfotransferase. Flexibility in these regions suggests that ligand binding elicits a disorder-order transition in and around the active site of sulfotransferases and might contribute to the broad substrate specificity of these enzymes.