BACKGROUND

The successful interaction of bacterial pathogens with host tissues requires the sensing of specific chemical and physical cues. The human gut contains a huge number of neurons involved in the secretion and sensing of a class of neuroendocrine hormones called catecholamines. Recently, in Escherichia coli O157:H7, the catecholamines adrenaline and noradrenaline were shown to act synergistically with a bacterial quorum sensing molecule, autoinducer 3 (AI-3), to affect bacterial virulence and motility. We wished to investigate the impact of adrenaline on the biology of Salmonella spp.

RESULTS

We have determined the effect of adrenaline on the transcriptome of the gut pathogen Salmonella enterica serovar Typhimurium. Addition of adrenaline led to an induction of key metal transport systems within 30 minutes of treatment. The oxidative stress responses employing manganese internalisation were also elicited. Cells lacking the key oxidative stress regulator OxyR showed reduced survival in the presence of adrenaline and complete restoration of growth upon addition of manganese. A significant reduction in the expression of the pmrHFIJKLM antimicrobial peptide resistance operon reduced the ability of Salmonella to survive polymyxin B following addition of adrenaline. Notably, both phenotypes were reversed by the addition of the beta-adrenergic blocker propranolol. Our data suggest that the BasSR two component signal transduction system is the likely adrenaline sensor mediating the antimicrobial peptide response.

CONCLUSIONS

Salmonella are able to sense adrenaline and downregulate the antimicrobial peptide resistance pmr locus through the BasSR two component signalling system. Through iron transport, adrenaline may affect the oxidative stress balance of the cell requiring OxyR for normal growth. Both adrenaline effects can be inhibited by the addition of the beta-adrenergic blocker propranolol. Adrenaline sensing may provide an environmental cue for the induction of the Salmonella stress response in anticipation of imminent host-derived oxidative stress. However, adrenaline may also serve in favour of the host defences by lowering antimicrobial peptide resistance and hence documenting for the first time such a function for a hormone.

BACKGROUND

Medical texts continue to perpetuate the belief that epinephrine should not be injected in fingers. Little attention has been paid to analyze the evidence that created this belief to see whether it is valid. The significance is that elective epinephrine finger injection has been shown to remove the need for a tourniquet, and therefore delete sedation and general anesthesia for much of hand surgery.

METHODS

All of the evidence for the antiadrenaline dogma comes from 21 mostly pre-1950 case reports of finger ischemia associated with procaine and cocaine injection with epinephrine. The authors performed an in-depth analysis of those 21 cases to determine their validity as evidence. They also examined in detail all of the other evidence in the literature surrounding issues of safety with procaine, lidocaine, and epinephrine injection in the finger.

RESULTS

The adrenaline digital infarction cases that created the dogma are invalid evidence because they were also injected with either procaine or cocaine, which were both known to cause digital infarction on their own at that time, and none of the 21 adrenaline infarction cases had an attempt at phentolamine rescue.

CONCLUSIONS

The evidence that created the dogma that adrenaline should not be injected into the fingers is clearly not valid. However, there is considerable valid evidence in the literature that supports the tenet that properly used adrenaline in the fingers is safe, and that it removes the need for a tourniquet and therefore removes the need for sedation and general anesthesia for many hand operations.

BACKGROUND

Low birth weight is associated with cardiovascular disease. The underlying mechanisms are unknown. We hypothesized that perinatal stress alters autonomic regulation of the cardiovascular system. In this study, catecholamines, heart rate (HR) and blood pressure (BP) were measured in healthy children with low birth weight.

METHODS

This clinical study included 105 children (mean age 9.6 years) in three groups; born at term with normal birth weight (controls, n=37), born at term but small for gestational age (SGA, n=29) and born preterm (Preterm, n=39). Dopamine, adrenaline and noradrenaline were determined in urine. HR and BP were measured at rest, during an orthostatic test and after a mathematical mental stress test.

RESULTS

Children in the Preterm and SGA groups excreted higher levels of catecholamines when compared with controls. HR (mean [SD] values) were higher at rest and after mental stress in Preterm (at rest 76 [9] and after mental stress 82 [12] min(-1)) and in SGA (79 [8] and 82 [10]) when compared with controls (70 [9] and 75 [9]). HR correlated with urinary catecholamines (r=0.24-0.27, P<0.05). Blood pressures measured at rest, during orthostatic testing and after mental stress did not differ between the groups.

CONCLUSIONS

Preterm birth and fetal growth restriction are associated with increased sympathoadrenal activity in childhood, as indicated by stress-induced increases in HR and urinary catecholamines. These findings suggest that the cardiovascular control is differently programmed in these children with possibly higher risk of developing hypertension in adulthood.

Inhaled beta(2)-adrenoceptor agonists are by far the most effective and safe bronchodilators currently available. They have not been surpassed by any other bronchodilating principle. The way to this position has been long and started with the first successful treatment of acute, severe asthma with s.c. injections of adrenaline 100 years ago. Over the years, synthetic congeners of adrenaline have been produced and tested for their pharmacological properties. During the first decades, little attention was given airway smooth muscle. The discovery of isoprenaline in 1940 was the first major step towards selective bronchodilation. This compound became a key tool for the classification of adrenoceptors into alpha and beta. Salbutamol and terbutaline were the first to show a significant attenuation of the cardiostimulant effect and confirmed the subdivision of beta-adrenoceptors into beta(1) and beta(2). Much effort was made to eliminate the next dose-limiting side effect, skeletal muscle tremor but in vain. Prolonged duration of action was achieved in three ways: with bambuterol, an orally active carbamate ester prodrug of terbutaline, salmeterol, an inhaled beta(2)-adrenoceptor agonist emerging from a purposeful research project, and formoterol which was found, accidentally, to have a long duration of action when inhaled. Throughout the 20th century, beta-adrenoceptor agonists have been developed and marketed as racemates. The pharmacological activity usually resides in the (R)-enantiomer. Despite claims for the opposite, there is so far no compelling evidence that the presence of the less active (S)-enantiomer is of any harm to the patient. One hundred years of experience of structural modifications of adrenaline has shown that the possibilities to modify the properties of this endogenous prototype appear to be unlimited.

1. Using a gastric barostat to quantify variations in gastric tone, we had previously demonstrated that food ingestion or intestinal nutrient perfusion induces gastric relaxation. These data suggested a basal tonic contraction of the stomach during fasting. 2. To determine the role of vagal input in maintaining fasting gastric tone, we prepared two chronic canine models, either isolating both cervical vagal trunks in a cutaneous tunnel or including the supradiaphragmatic vagi within an implanted cooling jacket. In the fasted conscious dogs, we then studied the effect, on gastric tone, of acute and reversible vagal blockade by cooling. 3. Cervical vagal cooling produced a reversible gastric relaxation and increased the heart rate. Supradiaphragmatic vagal cooling produced a similar gastric relaxation without the cardiac effect. 4. Adrenergic blockade did not change either the base-line gastric tone or the cooling-induced relaxation. Adrenaline decreased gastric tone, but vagal cooling still produced a significant relaxation. 5. Atropine alone or combined with adrenergic antagonists produced a gastric relaxation that was not further increased by vagal cooling. Bethanechol increased gastric tone, an effect unchanged by vagal cooling. 6. We conclude that gastric tone during fasting is maintained by a cholinergic input, which is vagally mediated at both the cervical and the supradiaphragmatic levels.

OBJECTIVE

Nine elite canoeists were investigated concerning changes in performance, heart rate variability (HRV), and blood-chemical parameters over a 6-d training camp. The training regimen consisted of cross-country skiing and strength training, in total 13.0+/-1.6 h, corresponding to a 50% increase in training load.

RESULTS

Time to exhaustion (RunT) decreased from 19.1+/-1.0 to 18.0+/-1.2 min (P < 0.05). VO2max and max lactate (La(max)) both decreased significantly (P < 0.05) over the training period (4.99+/-0.97 to 4.74+/-0.98 L x min(-1) and from 10.08+/-1.25 to 8.98+/-1.03 mmol x L(-1) respectively). Heart rates (HR) decreased significantly at all workloads. Plasma volume increased by 7+/-7% (P < 0.05). Resting cortisol, decreased from 677+/-244 to 492+/-222 nmol x L(-1) (P < 0.05), whereas resting levels of adrenaline and noradrenaline remained unchanged. The change between tests in RunT correlated significantly with the change in HRmax (r = 0.79; P = 0.01). There were no group changes in high or low frequency HRV, neither at rest nor following a tilt.

CONCLUSIONS

The reduced maximal performance indicates a state of fatigue/overreaching and peripheral factors are suggested to limit performance even though HRmax and La(max) both were reduced. The reduced submaximal heart rates are probably a result of increased plasma volume. HRV in this group didn't seem to be affected by short-term overtraining.

Plasma noradrenaline, adrenaline, and cyclic 3'5' AMP (cAMP) were measured in seven asthmatic patients with known exercise-induced bronchospasm and six matched non-atopic control subjects during a standard treadmill exercise test and then during matched isocapnic hyperventilation. Normal subjects showed a 5.5 fold rise in noradrenaline and a 3.2 fold rise in adrenaline during exercise compared with a 2.1 fold rise in noradrenaline and no significant rise in adrenaline in asthmatics who all developed bronchoconstriction after exercise (mean fall in peak flow rate 28.4 +/- 5.8%). Plasma cAMP rose 1.4 fold in controls but showed no significant rise in asthmatics. This reduced sympatho-adrenal response to exercise in asthmatics is difficult to explain. The failure of circulating catecholamines to rise and stimulate beta adrenoceptors on the mast cell may facilitate the release of bronchoconstrictor mediators. Matched hyperventilation produced bronchospasm in asthmatics (mean fall in peak flow rate 29.0 +/- 4.4%) but no change in catecholamines in either group suggesting that circulating catecholamines have no direct role in exercise-induced bronchospasm but may play a permissive role via the mast cell.

1. The effects on phosphatidylinositol metabolism of three Ca(2+)-mobilizing glycogenolytic hormones, namely angiotensin, vasopressin and adrenaline, have been investigated by using rat hepatocytes. 2. All three hormones stimulate both phosphatidylinositol breakdown and the labelling of this lipid with (32)P. 3. The response to angiotensin occurs quickly, requires a high concentration of the hormone and is prevented by [1-sarcosine, 8-isoleucine]angiotensin, a specific angiotensin antagonist that does not prevent the responses to vasopressin and to adrenaline. This response therefore seems to be mediated by angiotensin-specific receptors. 4. [1-Deaminocysteine,2-phenylalanine,7-(3,4-didehydroproline),8-arginine] vasopressin, a vasopressin analogue with enhanced antidiuretic potency, is relatively ineffective at stimulating phosphatidylinositol metabolism. This suggests that the hepatic vasopressin receptors that stimulate phosphatidylinositol breakdown are different in their ligand selectivity from the antidiuretic vasopressin receptors that activate renal adenylate cyclase. 5. Incubation of hepatocytes with ionophore A23187, a bivalent-cation ionophore, neither mimicked nor appreciably changed the effects of vasopressin on phosphatidylinositol metabolism, suggesting that phosphatidylinositol breakdown is not controlled by changes in the cytosol Ca(2+) concentration. This conclusion was supported by the observation that hormonal stimulation of phosphatidylinositol breakdown and resynthesis persists in cells incubated for a substantial period in EGTA, although this treatment somewhat decreased the phosphatidylinositol response of the hepatocyte. The phosphatidylinositol response of the hepatocyte therefore appears not to be controlled by changes in cytosol [Ca(2+)], despite the fact that this ion is thought to be the second messenger by which the same hormones control glycogenolysis. 6. These results may be an indication that phosphatidylinositol breakdown is an integral reaction in the stimulus-response coupling sequence(s) that link(s) activation of alpha-adrenergic, vasopressin and angiotensin receptors to mobilization of Ca(2+) in the rat hepatocyte.

1. 0.5mm-Palmitate stimulated incorporation of [U-(14)C]glucose into glyceride glycerol and fatty acids in normal fat cells in a manner dependent upon the glucose concentration. 2. In the presence of insulin the incorporation of 5mm-glucose into glyceride fatty acids was increased by concentrations of palmitate, adrenaline and 6-N-2'-O-dibutyryladenosine 3':5'-cyclic monophosphate up to 0.5mm, 0.5mum and 0.5mm respectively. Higher concentrations of these agents produced progressive decreases in the rate of glucose incorporation into fatty acids. 3. The effects of palmitate and lipolytic agents upon the measured parameters of glucose utilization were similar, suggesting that the effects of lipolytic agents are mediated through increased concentrations of free fatty acids. 4. In fat cells from 24h-starved rats, maximal stimulation of glucose incorporation into fatty acids was achieved with 0.25mm-palmitate. Higher concentrations of palmitate were inhibitory. In fat cells from 72h-starved rats, palmitate only stimulated glucose incorporation into fatty acids at high concentrations of palmitate (1mm and above). 5. The ability of fat cells to incorporate glucose into glyceride glycerol in the presence of palmitate decreased with increasing periods of starvation. 6. It is suggested that low concentrations of free fatty acids stimulate fatty acid synthesis from glucose by increasing the utilization of ATP and cytoplasmic NADH for esterification of these free fatty acids. When esterification of free fatty acids does not keep pace with their provision, inhibition of fatty acid synthesis occurs. Provision of free fatty acids far in excess of the esterification capacity of the cells leads to uncoupling of oxidative phosphorylation and a secondary stimulation of fatty acid synthesis from glucose.

The aggregating effects of adenosine diphosphate, thrombin, 5-hydroxytryptamine, tryptamine, adrenaline and noradrenaline, and tri-ethyl tin have been carefully compared. The first three compounds in some circumstances produce remarkably similar effects although there are important differences. The kinetics of aggregation induced by adrenaline (and noradrenaline) are quite different and the tri-ethyl tin effects are different again. Anti-serotonins specifically inhibit 5-hydroxytryptamine and the anti-adrenaline drug phentolamine specifically inhibits the effects of the catecholamines. Experiments presented suggest but do not prove that aggregation produced by all these compounds is accompanied by the liberation of diphosphate from the platelets and that platelet triphosphate may be converted to diphosphate. How these different compounds all produce this effect is discussed. Either the presence of diphosphate or the action of a triphosphatase might be the immediate cause of aggregation if there is a single final common cause. The anti-adrenaline phentolamine prolongs the bleeding time, so adrenaline or noradrenaline may be involved in platelet phenomena in haemostasis.

Apamin (10(-7) M), a substance extracted from bee venom (apis mellifica) causes stimulation of the taenia caeci as seen from an increase in spike activity. The inhibitory effect of ATP or adrenaline (Adr) was reflected by hyperpolarization of the muscle cell, cessation of spike activity and relaxation of the muscle. The 42K efflux and the membrane conductance were enhanced in the presence of these substances. Apamin converted the hyperpolarization caused by ATP or Adr into a transient depolarization which produced contraction of the muscle cells. The changes in membrane conductance and 42K efflux were diminished by the bee toxin. Furthermore, the potassium-dependent phase of the action potential was lengthened by apamin. Reduction of the extracellular chloride or sodium concentration, blockade of the nervous system by TTX (3 x 10(-7) M) or inhibition of spike activity by D600 (3 x 19(-6) M) did not affect the excitatory and blocking action of apamin. A high concentration of the calcium antagonist D600 (10(-4) M) or omission of extracellular calcium was needed to reduce the transient depolarization evoked by ATP or Adr in the presence of apamin. It is concluded that apamin prevents the opening of the ATP- and Adr-sensitive and voltage-dependent potassium channels in guinea-pig taenia caeci.

1. In the avian brain, a high concentration of dopamine was found in a sharply contoured region of the nucleus basalis which may or may not have included the nucleus entopeduncularis, and therefore lay within the palaeostriatum of the nomenclature of Crosby and Huber. This was thus the only region which may be considered biochemically homologous to the mammalian corpus striatum. For purposes of macroscopic identification only, the region is described here as the ;anterior part of the nucleus basalis'. The concentration of dopamine was 3 mug/g in the pigeon, about the same in the duck and chicken, and 7.5 mug/g in the finch. In the pigeon this region also contained some noradrenaline; the quantity of 5-hydroxytryptamine (1.4 mug/g) and 5-hydroxyindolylacetic acid (0.6 mug/g) was larger than in any other part of the brain.2. In the brain of the pigeon and the chicken, the highest concentrations of noradrenaline (1.5 and 1.4 mug/g) were found in the hypothalamus.3. The concentration of adrenaline was higher in the avian than in the mammalian brain. In the hypothalamus, it ranged from 0.4 mug/g in the pigeon to 1 mug/g in the chicken.4. Fluorescence microscopy, using the formaldehyde condensation method, showed, in the anterior part of the nucleus basalis, a large area of diffuse green-yellow fluorescence, similar in appearance to the fluorescence of the striatum of the rat. In addition this part of the brain contained a small region of fluorescent fibres and varicosities. It is suggested that the diffuse fluorescence was produced by dopamine. It was absent from brains of reserpine-treated pigeons.5. In the pigeon, reserpine, tetrabenazine and prenylamine produced a decrease in the concentration of brain monoamines, an effect which was comparable to that seen in mammals. Yet, none of these drugs raised the concentration of homovanillic acid, but they increased that of 5-hydroxyindolylacetic acid; these drugs raise the concentration of both acids in mammalian brain.6. In the pigeon beta-tetrahydronaphthylamine decreased the concentration of all monoamines and their metabolites, an action quite different from that produced in the mammalian brain.7. The main effect of morphine and of M 99 (6,14-endoetheno-7-(2-hydroxy-2-pentyl)-tetrahydro-oripavine hydrochloride) was a lowering of the noradrenaline concentration.8. As in mammals, chlorpromazine affected only the dopamine metabolism.9. In the guinea-pig and the pigeon, the administration of alpha-methyl-DOPA led to a substitution of much of the cerebral noradrenaline by alpha-methyl-noradrenaline, sometimes in excess of the lost noradrenaline. However, although the loss of dopamine was severe in both pigeon and guinea-pig, only little alpha-methyl-dopamine accumulated in the pigeon brain, so that it did not consitute a replacement for the lost dopamine; in the guinea-pig, alpha-methyl-dopamine was found in quantities similar to, or exceeding those, of the lost dopamine.

1. The effect of native low-density lipoproteins (LDL) and oxidized LDL (OXLDL) on the relaxations to endothelium-derived relaxing factor (EDRF) in isolated, intact aortic rings of the rabbit were investigated. 2. Native LDL induced a concentration-dependent reversible inhibition of the relaxations elicited by acetylcholine (ACh) or A23187, in rings pre-contracted by noradrenaline (NA), adrenaline (Ad) and 5-hydroxytryptamine (5-HT), but not phenylephrine (PE), which was not influenced by indomethacin. 3. The inhibition was surmountable in the rings pre-contracted with NA and Ad and only partially in those pre-contracted with 5-HT. 4. OXLDL induced an inhibition of the relaxations elicited by ACh and A23187 which was independent of the contractile agonist. The extent of inhibition and its reversibility varied with the LDL from individual donors, but was unaffected by indomethacin. 5. Native and oxidized LDL inhibited relaxations evoked by exogenous nitric oxide (NO) to the same extent. Higher concentrations of NO overcame the inhibition. The inhibition was independent of the contractile agonist and the preparation of LDL from individual donors. 6. Only OXLDL inhibited reversibly relaxations evoked by glyceryl trinitrate (GTN) and the inhibition was independent of the LDL preparation from individual donors. 7. This study demonstrates that native and OXLDL influence the response to EDRF in isolated aorta. We suggest that these lipoproteins may contribute to the attenuation of responses to EDRF found in isolated arteries from hypercholesterolaemic and atherosclerotic animals.

Corticotropin releasing factor (CRF), a neuropeptide synthesized in the parvocellular subnuclei of the hypothalamic paraventricular nucleus (PVN), takes part in the regulation of different stress evoked responses of the organism. In order to elucidate the role of the central adrenergic system in the regulation of these CRF-synthesizing neurons, a novel ultrastructural immunocytochemical dual localization technique was utilized. Phenylethanolamine-N-methyltransferase (PNMT), a specific enzyme marker for the central adrenaline system, and CRF-immunoreactive elements were simultaneously visualized in hypothalamic sections. PNMT-immunoreactive axon terminals established synaptic connections with somata, dendrites and spinous structures of CRF-producing neurons. This morphological finding indicates that the central adrenergic system directly influences CRF-synthesizing neurons in the PVN and provides basis for a more definitive pharmacological manipulation of this system.

1. The total calcium concentration in rat hepatocytes was 7.9 microgram-atoms/g dry wt.; 77% of this was mitochondrial. Approx. 20% of cell calcium exchanged with 45Ca within 2 min. Thereafter incorporation proceeded at a low rate to reach 28% of total calcium after 60 min. Incorporation into mitochondria showed a similar time course and accounted for 20% of mitochondrial total calcium after 60 min. 2. The alpha-adrenergic agonists phenylephrine and adrenaline + propranolol stimulated incorporation of 45Ca into hepatocytes. Phenylephrine was shown to increase total calcium in hepatocytes. Phenylephrine inhibited efflux fo 45Ca from hepatocytes perifused with calcium-free medium. 3. Glucagon, dibutryl cyclic AMP and beta-adrenergic agonists adrenaline and 3-isobutyl-1-methyl-xanthine stimulated calcium efflux from hepatocytes perifused with calcium-free medium. The effect of glucagon was blocked by insulin. Insulin itself had no effect on calcium efflux and it did not affect the response to dibutyryl cyclic AMP. 4. Incorporation of 45Ca into mitochondria in hepatocytes was stimulated by phenylephrine and inhibited by glucagon and by carbonyl cyanide p-trifluoromethoxyphenylhydrazone. The effect of glucagon was blocked by insulin. 5. Ionophore A23187 stimulated hepatocyte uptake of 45Ca, uptake of 45Ca into mitochondria in hepatocytes and efflux of 45Ca into a calcium-free medium.

The effect of the interaction between the Ca2+-mobilizing hormone adrenaline, used as alpha-adrenergic agonist, and cyclic AMP-dependent hormones, including beta-adrenergic agonists and glucagon, on the initial 45Ca2+ uptake rate and polyphosphoinositide metabolism were investigated in isolated rat hepatocytes. Each hormone alone increased the initial 45Ca2+ uptake rate. When adrenaline was added without inhibitor, it induced a rise in the initial 45Ca2+ uptake rate larger than the sum of the rises elicited by its alpha and beta components singly. Similarly, when adrenaline was used as an alpha-agonist and added together with glucagon, it enhanced the initial 45Ca2+ uptake rate synergistically. Kinetic analysis of the initial 45Ca2+ uptake rate measured at different Ca2+ concentrations suggested that the increased influx elicited by the combination of adrenaline as alpha-adrenergic agonist and glucagon reflects an activation of the rate of Ca2+ transport via a homogeneous population of Ca2+ channels or carriers. Dose-response curves for the alpha-adrenergic action of adrenaline or glucagon applied in the presence of increasing doses of glucagon or adrenaline showed that each hormone increases the maximal response to the other without affecting its ED50. Measurement of polyphosphoinositide hydrolysis and of the inositol phosphates formed in the presence of adrenaline or vasopressin and/or glucagon showed that Ca2+-mobilizing hormones and glucagon had no synergistic effects on inositol 1,4,5-trisphosphate production. It is therefore proposed that the synergistic action of glucagon and Ca2+-mobilizing hormones on Ca2+ influx occurs at a step that takes place close to the Ca2+ channels or carriers themselves. The Ca2+ gating involved might be mainly controlled by two products, one of them arising from the polyphosphoinositide metabolism, and the other from the increase in internal cyclic AMP.

Catecholamines may stimulate ACTH secretion during stress. To investigate the nature and site of such an action, plasma ACTH was measured in four groups of unanesthetized adult female rats with an indwelling carotid cannula. Sequential 300-microliter blood samples were taken 60 min, 30 min, and immediately before an intracerebroventricular (icv) infusion of 2.5 microliter adrenaline or noradrenaline and 5, 15, 45, 60, and 120 min after the infusion. The four groups were: 1) intact rats; 2) rats infused 7 days after undergoing a discrete bilateral lesion of the ventral noradrenergic ascending bundle caused by 6-hydroxydopamine, which depleted their hypothalamic adrenaline and noradrenaline levels by 90% and 80%, respectively; 3) rats infused 30 min after pretreatment via the icv route with either prazosin or propranolol; and 4) rats infused 16 and 2 h after two successive intracarotid injections of an anti-rCRH-41 serum. In another group, the effects of icv catecholamine administration were compared with those of an intracerebral (ic) microinfusion close to a single paraventricular nucleus (PVN). Finally, in two additional groups blood was sampled at the above-mentioned times before and after a 2-min ether inhalation by intact rats or prazosin- and/or propranolol-pretreated rats. In the intact rats (group 1), a stress-like stimulatory dose response was noted after both adrenaline and noradrenaline infusions, with a half-maximal effect at concentrations of about 0.6 nmol and a maximal effect at 2.7 nmol or more. At maximally effective doses, adrenaline was significantly more active than noradrenaline. In the rats with ventral noradrenergic ascending bundle lesions (group 2), 2.7 nM adrenaline or noradrenaline stimulated ACTH release as in the controls without lesions. In group 3, prazosin blocked the ACTH responses to both adrenaline and noradrenaline, whereas propranolol only blocked the response to adrenaline. In group 4, i.e. rats pretreated with an anti-rCRH-41 serum, the amplitude of the ACTH surge after icv adrenaline or noradrenaline infusion was halved. A unilateral ic catecholamine microinfusion next to the PVN (half the icv dose given in group 1) led to a rapid ACTH release that peaked at half the response measured in the icv infused rats. Ether stress-induced ACTH release was decreased by 50-60% after icv pretreatment with 1 or 10 micrograms prazosin, 1 or 6.5 micrograms propranolol, or a combined dose comprising 1 microgram of both. The following conclusions were reached.(ABSTRACT TRUNCATED AT 400 WORDS)

The possible existence of a beta3-adrenergic receptor (beta3-AR) in the human detrusor muscle was investigated by in vitro functional studies and analysis of mRNA expression. Isoprenaline, noradrenaline and adrenaline each produced a concentration-dependent relaxation of the human detrusor. The rank order for their relaxing potencies was isoprenaline (pD2 6.37+/-0.07)>> or = noradrenaline (pD2 6.07+/-0.12)>> or = adrenaline (pD2 5.88< or =0.11). Neither dobutamine (beta1- and beta2-AR agonist) nor procaterol (beta2-AR agonist) produced any significant relaxation at concentrations up to 10(-5) M. BRL37344A, CL316243 and CGP-12177A (beta3-AR agonists), relaxed the preparations significantly at concentrations higher than 10(-6) M. The pD2 values for BRL37344A, CL316243 and CGP-12177A were 6.42+/-0.25, 5.53+/-0.09 and 5.74+/-0.14, respectively. CGP-20712A (10(-7) - 10(-5) M), a beta1-AR antagonist, did not affect the isoprenaline-induced relaxation. On the other hand, ICI-118,551, a beta2-AR antagonist, produced a rightward parallel shift of the concentration-relaxation curve for isoprenaline only at the highest concentration used (10(-5)>> M) and its pKB value was 5.71+/-0.19. Moreover, SR58894A (10(-7) - 10(-5) M), a beta3-AR antagonist, caused a rightward shift of the concentration-relaxation curve for isoprenaline in a concentration-dependent manner. The pA2 value and slope obtained from Schild plots were 6.24+/-0.20 and 0.68+/-0.31. The beta1-, beta2- and beta3-AR mRNAs were all positively expressed in detrusor smooth muscle preparations in a reverse transcription polymerase chain reaction assay. In conclusion, the present results provide the first evidence for the existence of the beta3-AR subtype in the human detrusor. They also suggest that the relaxation induced by adrenergic stimulation of the human detrusor is mediated mainly through beta3-AR activation.

The characteristics of oxygen uptake (VO2) kinetics differ with exercise intensity. When exercise is performed at a given work rate which is below lactate threshold (LT), VO2 increases exponentially to a steady-state level. Neither the slope of the increase in VO2 with respect to work rate nor the time constant of VO2 responses has been found to be a function of work rate within this domain, indicating a linear dynamic relationship between the VO2 and the work rate. However, some factors, such as physical training, age and pathological conditions can alter the VO2 kinetic responses at the onset of exercise. Regarding the control mechanism for exercise VO2 kinetics, 2 opposing hypotheses have been proposed. One of them suggests that the rate of the increase in VO2 at the onset of exercise is limited by the capacity of oxygen delivery to active muscle. The other suggests that the ability of the oxygen utilisation in exercising muscle acts as the rate-limiting step. This issue is still being debated. When exercise is performed at a work rate above LT, the VO2 kinetics become more complex. An additional component is developed after a few minutes of exercise. The slow component either delays the attainment of the steady-state VO2 or drives the VO2 to the maximum level, depending on exercise intensity. The magnitude of this slow component also depends on the duration of the exercise. The possible causes for the slow component of VO2 during heavy exercise include: (i) increases in blood lactate levels; (ii) increases in plasma epinephrine (adrenaline) levels; (iii) increased ventilatory work; (iv) elevation of body temperature; and (v) recruitment of type IIb fibres. Since 86% of the VO2 slow component is attributed to the exercising limbs, the major contributor is likely within the exercising muscle itself. During high intensity exercise an increase in the recruitment of low-efficiency type IIb fibres (the fibres involved in the slow component) can cause an increase in the oxygen cost of exercise. A change in the pattern of motor unit recruitment, and thus less activation of type IIb fibres, may also account for a large part of the reduction in the slow component of VO2 observed after physical training.

OBJECTIVE

To determine if earlier administration of epinephrine (adrenaline) in patients with non-shockable cardiac arrest rhythms is associated with increased return of spontaneous circulation, survival, and neurologically intact survival.

METHODS

Post hoc analysis of prospectively collected data in a large multicenter registry of in-hospital cardiac arrests (Get With The Guidelines-Resuscitation).

METHODS

We utilized the Get With The Guidelines-Resuscitation database (formerly National Registry of Cardiopulmonary Resuscitation, NRCPR). The database is sponsored by the American Heart Association (AHA) and contains prospective data from 570 American hospitals collected from 1 January 2000 to 19 November 2009.

METHODS

119,978 adults from 570 hospitals who had a cardiac arrest in hospital with asystole (55%) or pulseless electrical activity (45%) as the initial rhythm. Of these, 83,490 arrests were excluded because they took place in the emergency department, intensive care unit, or surgical or other specialty unit, 10,775 patients were excluded because of missing or incomplete data, 524 patients were excluded because they had a repeat cardiac arrest, and 85 patients were excluded as they received vasopressin before the first dose of epinephrine. The main study population therefore comprised 25,095 patients. The mean age was 72, and 57% were men.

METHODS

The primary outcome was survival to hospital discharge. Secondary outcomes included sustained return of spontaneous circulation, 24 hour survival, and survival with favorable neurologic status at hospital discharge.

RESULTS

25,095 adults had in-hospital cardiac arrest with non-shockable rhythms. Median time to administration of the first dose of epinephrine was 3 minutes (interquartile range 1-5 minutes). There was a stepwise decrease in survival with increasing interval of time to epinephrine (analyzed by three minute intervals): adjusted odds ratio 1.0 for 1-3 minutes (reference group); 0.91 (95% confidence interval 0.82 to 1.00; P=0.055) for 4-6 minutes; 0.74 (0.63 to 0.88; P<0.001) for 7-9 minutes; and 0.63 (0.52 to 0.76; P<0.001) for >9 minutes. A similar stepwise effect was observed across all outcome variables.

CONCLUSIONS

In patients with non-shockable cardiac arrest in hospital, earlier administration of epinephrine is associated with a higher probability of return of spontaneous circulation, survival in hospital, and neurologically intact survival.

We previously found that forest environments reduced stress hormones such as adrenaline and noradrenaline and showed the relaxing effect both in male and female subjects. In the present study, we investigated the effects of walking under forest environments on cardiovascular and metabolic parameters. Sixteen healthy male subjects (mean age 57.4 ± 11.6 years) were selected after obtaining informed consent. The subjects took day trips to a forest park in the suburbs of Tokyo and to an urban area of Tokyo as a control in September 2010. On both trips, they walked for 2 h in the morning and afternoon on a Sunday. Blood and urine were sampled on the morning before each trip and after each trip. Blood pressure was measured on the morning (0800) before each trip, at noon (1300), in the afternoon (1600) during each trip, and on the morning (0800) after each trip. The day trip to the forest park significantly reduced blood pressure and urinary noradrenaline and dopamine levels and significantly increased serum adiponectin and dehydroepiandrosterone sulfate (DHEA-S) levels. Walking exercise also reduced the levels of serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) and urinary dopamine. Taken together, habitual walking in forest environments may lower blood pressure by reducing sympathetic nerve activity and have beneficial effects on blood adiponectin and DHEA-S levels, and habitual walking exercise may have beneficial effects on blood NT-proBNP levels.

A pheochromocytoma that exclusively secretes dopamine (DA) rather than predominantly DA among a blend of catecholamines is as yet unreported. Of the 50 patients with pheochromocytoma who have undergone surgery, 32 underwent treatment within the last 5 years (when DA assay has been available). One half of these patients (15/32) exhibited DA secretion either in mixed catecholamines (12 patients) or exclusively (three patients). All three patients with exclusive DA-secreting tumors were normotensive. Without hypertension, the clinical investigation was a diagnostic challenge (unexplained cough or flank mass with inflammatory features). All three tumors were malignant and two were ectopic. Five of the 12 patients with mixed catecholamine-secreting tumors whose secretions included DA were hypertensive. Five other patients had flank mass and one had an unexplained cough. Tumors were rather large, and three of the tumors with mixed secretion were ectopic. Of the 12 patients, seven had tumors that were judged to be malignant. Three patients exhibited a dramatic decrease in blood pressure under alpha-blockade, which was not used in subsequent cases. Predominant or exclusive secretion of DA would explain the lack of hypertension due to its antiadrenergic action that inhibits the vasoconstrictive effects of other amines. Hypertension in patients with pheochromocytoma might depend on the ratio of DA/noradrenaline + adrenaline.