Alpha 1-adrenoceptors mediate some of the main actions of the natural catecholamines, adrenaline, and noradrenaline. They participate in many essential physiological processes, such as sympathetic neurotransmission, modulation of hepatic metabolism, control of vascular tone, cardiac contraction, and the regulation of smooth muscle activity in the genitourinary system. It is now clear that alpha 1-adrenoceptors mediate, in addition to immediate effects, longer term actions of catecholamines such as cell growth and proliferation. In fact, adrenoceptor genes can be considered as protooncogenes. Over the past years, considerable progress has been achieved in the molecular characterization of different alpha 1-adrenoceptor subtypes. Three main subtypes have been characterized pharmacologically and in molecular terms. Splice variants, truncated isoforms, and polymorphisms have also been detected. Similarly, it is now clear that these receptors are coupled to several classes of G proteins that, therefore, are capable of modulating different signaling pathways. In the present article, some of these aspects are reviewed, together with the distribution of the subtypes in different tissues and some of the known roles of these receptors in health and disease.

1. The administration of glucagon, cAMP [adenosine 3',5'-(cyclic)-monophosphate], BcAMP [6-N-2'-O-dibutyryladenosine 3',5'-(cyclic)-monophosphate] or adrenaline to foetal rats during the last 2 days of gestation evoked the appearance of tyrosine aminotransferase and enhanced the accumulation of glucose 6-phosphatase in the liver. In foetuses 1-2 days younger only BcAMP was effective. After birth liver glucose 6-phosphatase no longer responds to glucagon or BcAMP. Tyrosine aminotransferase is still inducible by these agents in 2-day-old rats, but not in 50-day-old rats. After adrenalectomy of adults glucagon or BcAMP can enhance the induction of the enzyme by hydrocortisone. The results indicate that the ability to synthesize tyrosine aminotransferase and glucose 6-phosphatase when exposed to cAMP develops sooner than the ability to respond to glucagon with an increase in the concentration of cAMP; the responsiveness of enzymes to different hormones changes with age. A scheme illustrating the sequential development of competence in regulating the level of an enzyme is presented. 2. Actinomycin inhibited the effects of glucagon and BcAMP on liver tyrosine aminotransferase and glucose 6-phosphatase in foetal rats. Growth hormone, insulin and hydrocortisone did not enhance the formation of these enzymes. 3. The time-course of accumulation of glucose 6-phosphatase in the kidney is different from that in the liver. Hormones that increase the accumulation in foetal liver do not do so in the kidney of the same foetus or in the livers of postnatal rats.

In an attempt to clarify whether circulating insulin per se exerts an inhibitory effect on the hormonal responses to hypoglycemia, with special emphasis on glucagon secretion, nine healthy volunteers were exposed to low dose (244 pmol/kg.h) and high dose (1034 pmol/kg.h) iv insulin infusions for 3 h on two separate occasions. A close to identical arterial hypoglycemia of about 3.4 mmo/L was obtained in both tests by glucose clamping during the high dose test. The corresponding glucose concentration in the venous blood was significantly lower in the high dose test (2.5 +/- 0.1 vs. 3.0 +/- 0.1 mmol/L; P less than 0.01), while the plasma free insulin level was 4 times higher in the high dose test (897 +/- 50 vs. 208 +/- 14 pmol/L). Plasma glucagon was elevated in both experiments, but its rise was reduced during the high dose test after 1 h, yielding an incremental area under the glucagon curve that was significantly smaller than that obtained during the low dose test (213 +/- 70 vs. 348 +/- 81 ng/L.h; P less than 0.05). The plasma adrenaline, noradrenaline, GH, C-peptide, pancreatic polypeptide, and somatostatin profiles were similar in the two tests. We conclude that an inhibitory effect of circulating insulin on the glucagon response to hypoglycemia can be demonstrated in normal man during an infusion of insulin yielding a plasma concentration of about 900 pmol/L. The responses of other hormones studied are not significantly influenced by the circulating insulin level.

OBJECTIVE

To assess the effectiveness of the ILCOR Advisory Statements on Advanced Life Support adopted by the Resuscitation Council (UK), as the standard for resuscitation following cardiac arrest.

METHODS

Over the period May to November 1997, data on the process and outcome of cardiopulmonary resuscitation following in-hospital cardiac arrest were collected from 49 hospitals throughout the UK.

RESULTS

Of 2074 audit forms submitted, 1368 were included in the final analysis. The initial rhythm monitored was ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) in 429 patients, of whom 181 (42.2%) were discharged alive, compared to 6. 2% when the initial rhythm was non-VF/VT. Overall, 240 (17.6%) patients were discharged alive. At 6 months after discharge 195 (82. 3%) of 237 patients were still alive. Successful initial resuscitation, defined as return of spontaneous circulation lasting longer than 20 min (ROSC>20 min), was significantly associated with VF/VT as the initial arrest rhythm, return of circulation in less than 3 min, age less than 70 years and the use of an advanced airway (P<0.01). There was a significant increased likelihood of survival to discharge when the circulation was restored in less than 3 min and age was less than 70 years (P<0.05). The administration of any adrenaline (epinephrine) was significantly associated with a reduced likelihood of ROSC>20 min or alive discharge (P<0.0001).

CONCLUSIONS

Compared to the last major multiple hospital study published in 1992, the results of this study suggest that there appears to have been an improvement in survival of in-hospital patients in the UK who have a VF/VT cardiac arrest. How much of this is directly attributable to the adoption of the latest guidelines is uncertain.

The influence of epidural neural blockade on postoperative insulin resistance was studied using the euglycaemic insulin clamp technique. Eighteen patients undergoing elective upper abdominal surgery of moderate severity were allocated to two groups: group G patients underwent operation under general anaesthesia, and postoperative pain was relieved by systemic administration of analgesia; and group E patients received epidural analgesia during surgery and epidural morphine postoperatively. In each patient the euglycaemic insulin clamp test was performed twice: several days before surgery and on postoperative day 1. Peroperative catecholamine and cortisol responses were also measured to investigate possible endocrine mechanisms of the insulin resistance. Glucose disposal (M) decreased in both groups on postoperative day 1 at plasma insulin concentrations ranging from 1.2 to 10.0 milliunits ml-1, resulting in the downward shift of dose-response curves. However, this downward shift was significantly smaller in group E than in group G patients. Urinary adrenaline excretion increased markedly on the day of operation in group G, but was significantly inhibited in group E. Urinary noradrenaline excretion increased mainly on postoperative day 1 in group G, but was significantly inhibited in group E. Plasma cortisol response was lower in group E than in group G during and shortly after operation, and was significantly inhibited in group E on postoperative day 1. These results indicate that insulin resistance after elective abdominal surgery is due to a postreceptor deficit in glucose utilization, as indicated by the downward shift of the dose-response curves. This disturbance in glucose metabolism was reduced by epidural analgesia, the results being associated with inhibited catecholamine and cortisol responses.

OBJECTIVE

Adrenal-sparing adrenalectomy is considered the treatment of choice for hereditary bilateral pheochromocytoma in patients with multiple endocrine neoplasia type 2A (MEN 2A).

METHODS

Retrospective analysis of prospectively documented data with a mean +/- SD follow-up of 81.5 +/- 85.3 months. The PubMed database was searched for articles published between 1975 and 2004 to identify published series and/or case reports.

METHODS

University hospital referral center.

METHODS

In 17 (22%) of 77 patients with various mutations of the RET proto-oncogene, unilateral (n = 12) or bilateral (n = 5) pheochromocytomas were documented at the time of diagnosis or during the course of MEN 2A. Adrenal-sparing surgery was performed in 13 patients (group 1), synchronous bilateral total adrenalectomy in 4 patients (group 2A), and metachronous bilateral total adrenalectomy in 5 patients after adrenal-sparing adrenalectomy (group 2B).

METHODS

Measurement of 24-hour urinary catecholamine levels (noradrenaline, adrenaline, and dopamine) and, in case of high catecholamine levels, imaging studies to localize the tumors in 1 or both adrenal glands to determine the size and exclude extra-adrenal tumors and distant metastasis.

RESULTS

The mean+/-SD estimated 5- and 10-year cumulative risk of developing recurrence in both groups was 38.5% +/- 15.7%. Five (38%) of 13 patients in group 1 developed recurrence in the contralateral gland. Two (22%) of 9 patients in groups 2A and 2B developed several episodes of an addisonian crisis, 1 of whom died.

CONCLUSIONS

Substantial morbidity and mortality are associated with addisonian crisis after bilateral adrenalectomy. Adrenal-sparing adrenalectomy and close monitoring of the remnant may be the treatment of choice for hereditary bilateral pheochromocytoma in MEN 2A, since overall recurrence is low.

The hormonal response to a standardized bicycle exercise test was studied in 11 male cadets exposed to a course of 107 h of continuous activity with less than 2 h sleep. The subjects expended only about 8,600-11,000 kcal/24 h whereas their daily food intake contained only about 1,500 kcal. The exercise test was performed once 12 days before the course (control experiment) and on day 3 and day 5 during the course, always between 0700-0900 h. A two to six fold increase was seen in the resting levels of noradrenaline, adrenaline, dopamine, and growth hormone during the course whereas a decrease was observed for thyroxine, triiodothyronine, and prolactin. Cortisol increased on day 3 and then decreased to precourse levels on day 5. The response to the exercise test during the course for all catecholamines was a further increase above and proportional to the raisted resting levels. Growth hormone increased by about 6-8 microgram/l both before and during the course. During the exercise test, cortisol decreased before the course whereas it increased during the course. All plasma levels of cortisol were higher on day 3 than on day 5 and in the control experiment. The post-exercise insulin increase was reduced during the course corresponding to a reduction in blood glucose levels. Prolactin decreased during and after exercise in the control experiment, whereas on day 5 the opposite response was seen. No changes in the disappearance rate of different hormones were observed during the course. The present investigation has demonstrated that prolonged strain severely affects the resting plasma levels of different hormones as well as the endocrine response to a short-term physical exercise.

Catechol-O-methyltransferase catalyses the O-methylation of biologically active or toxic catechols and is a major component of the metabolism of drugs and neurotransmitters such as L-dopa, noradrenaline, adrenaline, and dopamine. Human catechol-O-methyltransferase activity is an autosomal partially dominant trait and is strongly associated with a valine to methionine substitution at codon 158 of the protein. About 25% of Caucasians have low activity, 50% intermediate activity and 25% high activity as determined by either phenotypic or genotypic measurement. In black populations, the low activity allele (Met158; COMTL) is less frequent with about 7% being homozygous. Using a PCR based genotyping assay, we report that the Met158 allele is also less frequent in normal Han Chinese subjects with about 3% of the population being homozygous. Because of its role in catecholamine metabolism and several lines of evidence pointing to a locus for psychosis near the COMT gene on chromosome 22q11, we have analysed the COMT Val158Met polymorphism as a candidate susceptibility factor for bipolar affective disorder. We report an association between bipolar affective disorder and the Met158 allele (p = 0.004) and genotype (p = 0.01) in 93 affected Chinese subjects and 98 controls. We hypothesize that either the low activity allele of catechol-O-methyltransferase is a risk factor for bipolar affective disorder in Chinese populations or is in linkage disequilibrium with a nearby susceptibility gene or polymorphism.

The aim of the study was to quantitatively compare the relative affinities of noradrenaline, adrenaline, dopamine and isoprenaline for the, probably neural, receptors mediating feedback control of sympathetic neurotransmitter secretion. The experiments were carried out in isolated superfused field stimulated guinea-pig vas deferens, in which the noradrenaline stores had been labelled by preincubation with tritiated (-)-noradrenaline. Desipramine and normetanephrine were added to prevent rebinding of transmitter. Exogenous noradrenaline was found to cause a dose-dependent and reversible depression of the secretion of tracer noradrenaline evoked by field stimulation. Since the depressing effect was not affected by a ten-fold rise in the desipramine concentration, it seems likely that it was not due to uptake and preferential secretion of unlabelled exogenous noradrenaline, but was truly due to depression of the secretory mechanism. Adrenaline was significantly more potent than noradrenaline, as inhibitor of the secretion of tracer transmitter, while dopamine, at the same molar concentration, was without effect. The beta-agonist isoprenaline did not depress, but rather tended to enhance, the secretion of tracer noradrenaline. It is concluded that the receptors controlling the secretion of noradrenaline from the sympathetic nerves of guinea-pig vas deferens quantitatively-with regard to sensitivity-as well as qualitatively-with regard to order of preference for different catecholamines-resemble the "classical" alpha-receptors of e.g. smooth muscle in the same tissue.

BACKGROUND

Few prospective studies of the incidence and outcome of paediatric in-hospital cardiopulmonary arrest have been reported to enable quality assurance comparisons within and between institutions.

METHODS

All cardiac and respiratory arrests and their management over a 41-month period in children not subject to palliative treatment or to a 'do not resuscitate' order were recorded and analysed using the Utstein template.

RESULTS

Cardiac arrest occurred in a total of 111 of 104,780 admissions (1.06/1000) while respiratory arrest alone occurred in 36 (0.34/1000). Return of spontaneous circulation (ROSC) was achieved in 81 patients (73%) in cardiac arrest but only 40 (36%) were discharged from hospital and 38 (34%) survived for 1 year. The 1-year survival from respiratory arrest alone was 97%. Cardiac arrest was four times more common (89 versus 22) and approximately 90 times the incidence in the intensive care unit compared with wards but 1-year survival was similar (34% versus 36%). The initial heart rhythms were hypotensive-bradycardia in 73 (66%) with 38% survival; asystole in 17 (15%) with 12% survival; ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) in 10 (9%) with 40% survival; pulseless electrical activity (PEA) in 10 (9%) with 30% survival and SVT in 1 with survival. Secondary ventricular fibrillation occurred in 15 children given adrenaline (epinephrine) for treatment of asystole, hypotensive-bradycardia or PEA of whom 11 had received adrenaline in an initial dose of>> 15 mcg/kg and 4 had < 15 mcg/kg (P = 0.0013). Eleven of 15 patients (73%) in secondary VF never achieved ROSC.

CONCLUSIONS

In-patient paediatric cardiac arrest has a mediocre outcome with a better outlook if the initial rhythm is hypotensive-bradycardia, VF or pulsatile VT. Doses of adrenaline greater than 15 mcg/kg given for non-shockable rhythms may cause secondary VF which has a worse outcome than primary VF.

The activity of monoamine neurotransmitters was examined at dopamine D4 receptors. In competition binding with [3H]spiperone, noradrenaline and adrenaline exhibited a high affinity binding component (KH = 12.1 nM and 5.0 nM, respectively), similar to that of dopamine (KH = 2.6 nM), whereas serotonin (5-hydroxytryptamine, 5-HT) and histamine had low affinity (Ki>> 1000 nM). Noradrenaline and adrenaline acted as agonists at dopamine D4 receptors, stimulating receptor-mediated [35S]guanylyl-gamma-thiotriphosphate ([35S]GTP gamma S) binding (EC50 = 7.8 and 5.8 microM, respectively, versus 0.1 microM for dopamine). The dopamine D4 receptor-selective ligand, 3-(4-[4-chlorophenyl]piperazin-1-yl)methyl-1H-pyrrolo[2,3b]-pyridi ne (L 745,870) and the dopaminergic antagonists, spiperone, haloperidol and clozapine, inhibited noradrenaline-stimulated [35S]GTP gamma S binding whereas alpha 1-, alpha 2- and beta-adrenoceptor antagonists did not. These results indicate that dopamine D4 receptors are activated by noradrenaline and adrenaline, although at 50-100-fold higher concentrations than dopamine.

ECL cells are numerous in the acid-producing part of the rat stomach. They are rich in histamine and pancreastatin, a chromogranin A-derived peptide, and they secrete these products in response to gastrin. We have examined how isolated ECL cells respond to a variety of neuromessengers and peptide hormones. Highly purified (85%) ECL cells were collected from rat stomach using repeated counter-flow elutriation and cultured for 48 h before experiments were conducted. The ECL cells responded to gastrin, sulphated cholecystokinin-8 and to high K+ and Ca2+ with the parallel secretion of histamine and pancreastatin. Glycine-extended gastrin was without effect. Forskolin, an activator of adenylate cyclase, induced secretion, whereas isobutylmethylxanthine, a phosphodiesterase inhibitor, raised the basal release without enhancing the gastrin-evoked stimulation. Maximum stimulation with gastrin resulted in the release of 30% of the secretory products. Numerous neuromessengers and peptide hormones were screened for their ability to stimulate secretion and to inhibit gastrin-stimulated secretion. Pituitary adenylate cyclase activating peptide (PACAP)-27 and -38 stimulated secretion of both histamine and pancreastatin with a potency greater than that of gastrin and with the same efficacy. Related peptides, such as vasoactive intestinal peptide, helodermin and helospectin, stimulated secretion with lower potency. The combination of EC100 gastrin and EC50 PACAP produced a greater response than gastrin alone. None of the other neuropeptides or peptide hormones tested stimulated secretion. Serotonin, adrenaline, noradrenaline and isoprenaline induced moderate secretion at high concentrations. Muscarinic receptor agonists did not stimulate secretion, and histamine and selective histamine receptor agonists and antagonists were without effect. This was the case also with GABA, aspartate and glutamate. Somatostatin and galanin, but none of the other agents tested, inhibited gastrin-stimulated secretion. Our results reveal that not only gastrin but also PACAP is a powerful excitant of the ECL cells, that not only somatostatin, but also galanin can suppress secretion, that muscarinic receptor agonists fail to evoke secretion, and that histamine (and pancreastatin) does not evoke autofeedback inhibition.

Experiments were carried out on the isolated papillary muscle of the rabbit in order to further characterize the alpha-adrenoceptors mediating the positive inotropic effect. For this purpose dose-response relations of seven sympathomimetic amines were compared under the influence of alpha- and/or beta-adrenolytic drugs. Phentolamine (10(-6) M) shifted the lower part of the dose-response curves for norfenephrine, synephrine and epinine as for phenylephrine and adrenaline to the right, while prindolol (10(-8) M) affected only the upper part of the curves. In the presence of both alpha- and beta-adrenoceptor blocking agents the entire dose-response curves for sympathomimetic amines were shifted in a parallel manner. Noradrenaline affected preferentially beta-adrenoceptors, whereas its effect on alpha-adrenoceptors was so weak that it could be detected only when the neuronal and extraneuronal uptake mechanism of amines were blocked by cocaine (3 X 10(-5) M) and corticosterone (4 X 10(-5) M), respectively. The effect of dopamine was not affected either by phentolamine or by prindolol, but was antagonized by the simultaneous application of both alpha- and beta-adrenoceptor blocking agents. From the present results, it appears that the following relationships are present between the structure of amines and the alpha-adrenoceptor stimulating activity in the heart: (1) N-methylation increases the potency: (2) Absence of the hydroxyl group either in 3 or in 4 position decreases the intrinsic and beta-adrenoceptor stimulating activities, but increases the alpha-adrenoceptor stimulating activity.

1 In conscious unrestrained cats noradrenaline, alpha-methylnoradrenaline and clonidine, infused into the lateral cerebral ventricles (i.c.v.) caused dose-related falls in blood pressure and heart rate; both effects were abolished after i.c.v. phentolamine.2 In 12 out of 20 cats, i.c.v. isoprenaline and salbutamol when given caused dose-related pressor responses and tachycardias. These effects were abolished after i.c.v. beta-adrenoceptor blocking drugs but were unaffected by alpha-adrenoceptor blocking agents.3 In 5 out of 20 cats, i.c.v. isoprenaline regularly produced dose-related falls in blood pressure with associated tachycardias; both effects were abolished after i.c.v. beta-adrenoceptor blocking agents.4 Intracerebroventricular dopamine produced cardiovascular responses which were qualitatively similar to those produced by i.c.v. isoprenaline.5 Intracerebroventricular adrenaline produced complex responses in untreated animals but typical alpha-effects were obtained after prior i.c.v. treatment with a beta-adrenoceptor blocking agent and typical beta-effects after i.c.v. pretreatment with an alpha-adrenoceptor blocking agent.6 The cardiovascular changes produced by i.c.v. beta-adrenoceptor agonists were abolished after systemic administration of hexamethonium or bethanidine.7 The results are discussed in the light of the mode of action of beta-adrenoceptor stimulants and beta-adrenoceptor blocking agents in the treatment of hypertension.

Plasma testosterone, noradrenaline, and adrenaline concentrations during three bicycle ergometer tests of the same total work output (2160 J X kg-1) but different intensity and duration were measured in healthy male subjects. Tests A and B consisted of three consecutive exercise bouts, lasting 6 min each, of either increasing (1.5, 2.0, 2.5 W X kg-1) or constant (2.0, 2.0, 2.0 W X kg-1) work loads, respectively. In test C the subjects performed two exercise bouts each lasting 4.5 min, with work loads of 4.0 W X kg-1. All the exercise bouts were separated by 1-min periods of rest. Exercise B of constant low intensity resulted only in a small increase in plasma noradrenaline concentration. Exercise A of graded intensity caused an increase in both catecholamine levels, whereas, during the most intensive exercise C, significant elevations in plasma noradrenaline, adrenaline and testosterone concentrations occurred. A significant positive correlation was obtained between the mean value of plasma testosterone and that of adrenaline as well as noradrenaline during exercise. It is concluded that both plasma testosterone and catecholamine responses to physical effort depend more on work intensity than on work duration or total work output.

Neuropeptide Y-like immunoreactivity (NPY-LI) and catecholamine concentrations in plasma were analysed during and after 60 min of physical exercise at a work load corresponding to 70% of individual maximal oxygen uptake in nine healthy men of average physical fitness. Systemic plasma NPY-LI increased progressively from 18 +/- 3 to 81 +/- 19 pmol X 1(-1) in parallel with a 10-fold increase in noradrenaline (NA) concentration. The increase in plasma NPY-LI during exercise and the decrease after completion of exercise were much slower than the corresponding changes in NA concentration. This difference is probably related to a slower diffusion of NPY into systemic circulation after release, as well as to a longer half-life of NPY than of NA in plasma. Reversed phase HPLC and sephadex G-50 gel-filtration chromatography revealed that the main component of NPY-LI in plasma during exercise eluted in a similar position as synthetic human NPY. During exercise plasma NPY-LI correlated well with the plasma concentration of NA (r = 0.80), but not with that of adrenaline (ADR), suggesting a neuronal origin of NPY. The self-ratings of perceived exertion (RPE) were well correlated with the plasma concentrations of both NPY-LI and NA. No clear-cut veno-arterial concentration difference was observed for NPY-LI. Isometric handgrip and orthostatic test doubled plasma NA concentrations but did not cause any increase in plasma NPY-LI. No change in plasma tachykinin-like immunoreactivity was detected during exercise. The present data suggest that NPY is released together with NA during strong, but probably not during mild, sympathetic activation under physiological conditions in man.

Both beta 2-adrenoreceptor stimulants (such as adrenaline and salbutamol) and insulin can increase active Na+-K+ transport and hyperpolarise skeletal cells. Thus, adrenaline and insulin, which are otherwise antagonistic regulators of several metabolic processes, have one action in common, namely, stimulation of active ion translocation. This is especially interesting as cyclic AMP stimulates Na+-K+ transport, whereas a lowering of the cytoplasmic concentration of cyclic AMP has been proposed as an early signal in the action of insulin. Here we report the results of experiments in which the active Na+-K+ transport and membrane potential (EM) of rat soleus muscles were studied during the action of supramaximal doses of insulin and beta 2-adrenoreceptor stimulants, alone and in combination. We conclude that the stimulant action of insulin on active electrogenic Na+-K+ transport is unlikely to be evoked by a lowering of the intracellular concentration of cyclic AMP.

1. Variations in the output of glucocorticoids and catecholamines from the right adrenal gland, in response to insulin hypoglycaemia, have been investigated in calves 2-5 weeks after birth. These have been correlated with changes in the concentration of glucocorticoids and glucagon in arterial plasma. 2. Moderate hypoglycaemia for a limited period (0-1 u. insulin/kg), elicited a prompt increase in steroid output from the adrenal gland followed by a significant rise in plasma glucagon concentration. By comparison, changes in both catecholamine output and peripheral plasma glucocorticoid concentrations were found to be trivial in this group of animals. 3. Administration of a larger dose of insulin (0-5 u./kg) produced a more substantial fall in plasma glucose concentration followed by spontaneous recovery within 2-3 hr. This stimulus elicited the release of greater amounts of both cortisol and corticosterone, followed by a significant increase both in the output of adrenaline and in plasma glucagon concentration. Increase in steroid output was accompanied by an increase in adrenal blood flow and was associated with elevated concentrations of both steroids in arterial plasma. 4. The adrenal cortical response and associated changes in plasma steroid concentration were found to be transient even in response to persistent and intense hypoglycaemia (4 u. insulin/kg). The increase in plasma glucagon concentration in this group of animals was not significantly greater than that produced by smaller doses of insulin. However, substantial amounts of adrenaline (78 plus or minus 14 ng. kg-minus 1 min-minus 1; maximum; n equals 9) together with a little noradrenaline (10 plus or minus 3 ng.kg-minus 1 min-minus 1; maximum; n equals 9) were released from the right adrenal gland under these conditions. 5. Changes in adrenal blood flow could be related to adrenal glucocorticoid output in calves given 0-1 or 0-5 u. insulin/kg. In animals given the largest dose of insulin adrenal blood flow was found to increase coincidentally with rising steroid output but this hyperaemia then persisted after steroid output had subsided to values within the normal range. 6. Calves given the largest dose of insulin (4-0 u./kg) invariably collapsed and convulsed after 2-3 hr, but these symptoms could not be related to any particular endocrine response. No clinical signs of hypoglycaemia were observed in the other animals. 7. The results are discussed in relation to previous studies of adrenal function in this and other species.

BACKGROUND

The purpose of this pilot clinical study was to determine if a novel chest compression device would improve hemodynamics when compared to manual chest compression during cardiopulmonary resuscitation (CPR) in humans. The device is an automated self-adjusting electromechanical chest compressor based on AutoPulse technology (Revivant Corporation) that uses a load distributing compression band (A-CPR) to compress the anterior chest.

METHODS

A total of 31 sequential subjects with in-hospital sudden cardiac arrest were screened with institutional review board approval. All subjects had received prior treatment for cardiac disease and most had co-morbidities. Subjects were included following 10 min of failed standard advanced life support (ALS) protocol. Fluid-filled catheters were advanced into the thoracic aorta and the right atrium and placement was confirmed by pressure waveforms and chest radiograph. The coronary perfusion pressure (CPP) was measured as the difference between the aortic and right atrial pressure during the chest compression's decompressed state. Following 10 min of failed ALS and catheter placement, subjects received alternating manual and A-CPR chest compressions for 90 s each. Chest compressions were administered without ventilation pauses at 100 compressions/min for manual CPR and 60 compressions/min for A-CPR. All subjects were intubated and ventilated by bag-valve at 12 breaths/min between compressions. Epinephrine (adrenaline) (1mg i.v. bolus) was given at the request of the attending physician at 3-5 min intervals. Usable pressure signals were present in 16 patients (68 +/- 6 years, 5 female), and data are reported from those patients only. A-CPR chest compressions increased peak aortic pressure when compared to manual chest compression (153 +/- 28 mmHg versus 115 +/- 42 mmHg, P < 0.0001, mean +/- S.D.). Similarly, A-CPR increased peak right atrial pressure when compared to manual chest compression (129 +/- 32 mmHg versus 83 +/- 40 mmHg, P < 0.0001). Furthermore, A-CPR increased CPP over manual chest compression (20 +/- 12 mmHg versus 15 +/- 11 mmHg, P < 0.015). Manual chest compressions were of consistent high quality (51 +/- 20 kg) and in all cases met or exceeded American Heart Association guidelines for depth of compression.

CONCLUSIONS

Previous research has shown that increased CPP is correlated to increased coronary blood flow and increased rates of restored native circulation from sudden cardiac arrest. The A-CPR system using AutoPulse technology demonstrated increased coronary perfusion pressure over manual chest compression during CPR in this terminally ill patient population.

The possibility that Ca2+ ions are involved in the control of the increased phosphatidylinositol turnover which is provoked by alpha-adrenergic or muscarinic cholinergic stimulation of rat parotid-gland fragments has been investigated. Both types of stimulation provoked phosphatidylinositol breakdown, which was detected either chemically or radiochemically, and provoked a compensatory synthesis of the lipid, detected as an increased rate of incorporation of 32Pi into phosphatidylinositol. Acetylcholine had little effect on the incorporation of labelled glycerol, whereas adrenaline stimulated it significantly, but to a much lower extent than 32P incorporation: this suggests that the response to acetylcholine was entirely accounted for by renewal of the phosphorylinositol head-group of the lipid, but that some synthesis de novo was involved in the response to adrenaline. The responses to both types of stimulation, whether measured as phosphatidylinositol breakdown or as phosphatidylinositol labelling, occurred equally well in incubation media containing 2.5 mm-Ca2+ or 0.2 mm-EGTA [ethanedioxybis(ethylamine)-tetra-acetic acid]. Incubation with a bivalent cation ionophore (A23187) led to a small and more variable increase in phosphatidylinositol labelling with 32Pi, which occurred whether or not Ca2+ was available in the extracellular medium: this was not accompanied by significant phosphatidylinositol breakdown. Cinchocaine, a local anaesthetic, produced parallel increases in the incorporation of Pi and glycerol into phosphatidylinositol. This is compatible with its known ability to inhibit phosphatidate phosphohydrolase (EC 3.1.3.4) and increase phosphatidylinositol synthesis de novo in other cells. These results indicate that the phosphatidylinositol turnover evoked by alpha-adrenergic or muscarinic cholinergic stimuli in rat parotid gland probably does not depend on an influx of Ca2+ into the cells in response to stimulation. This is in marked contrast with the K+ efflux from this tissue, which is controlled by the same receptors, but is strictly dependent on the presence of extracellular Ca2+. The Ca2+-independence of stimulated phosphatidylinositol metabolism may mean that it is controlled through a mode of receptor function different from that which controls other cell responses. Alternatively, it can be interpreted as indicating that stimulated phosphatidylinositol breakdown is intimately involved in the mechanisms of action of alpha-adrenergic and muscarinic cholinergic receptor systems.

The ability of an antagonist to bind to a receptor is an innate property of that ligand-receptor chemical interaction. Provided no change in the antagonist or receptor chemical nature occurs, this affinity should remain constant for a given antagonist-receptor interaction, regardless of the agonists used. This fundamental assumption underpins the classification of receptors. Here, measurements of beta2-adrenoceptor-mediated cAMP accumulation and cAMP response-element (CRE)-mediated reporter-gene transcription revealed differences in antagonist affinity that depended upon agonist incubation time and the efficacy of the competing agonist. In cAMP accumulation studies (10-min agonist incubation), antagonist affinities were the same regardless of the agonist used. The CRE-reporter gene assay (5 h of incubation) antagonist affinities were 10-fold lower in the presence of isoprenaline and adrenaline than when salbutamol or terbutaline were present (e.g., log KD propranolol -8.65 +/- 0.08, n = 22, and -9.68 +/- 0.07, n = 17, for isoprenaline and salbutamol-induced responses, respectively). Isoprenaline and adrenaline were more efficacious in functional studies, and their ability to internalize GFP-tagged human beta2-adrenoceptors. Longer-term cAMP studies also showed significant differences in KD values moving toward that seen with gene transcription. Agonist-dependent differences in antagonist affinity were reduced for reporter-gene responses when a phosphorylation-deficient mutant of the beta2-adrenoceptor was used. This study suggests that high-efficacy agonists induce a chemical modification in beta2-adrenoceptors (via phosphorylation) that reduces antagonist affinities. Because reporter-gene assays are used for high-throughput screening in drug discovery, less efficacious or partial agonists may be more reliable than highly efficacious agonists when reporter-gene techniques are used to estimate antagonist affinity.

1. In rat whole brain homogenates, saturation analysis revealed that both [3H]-idazoxan and [3H]-RX821002, a selective alpha 2-adrenoceptor ligand, bound with high affinity to an apparent single population of sites. However, the Bmax for [3H]-idazoxan was significantly (P less than 0.01) greater than that for [3H]-RX821002. 2. In competition studies, (-)-adrenaline displaced 3 nM [3H]-idazoxan binding with an affinity consistent with [3H]-idazoxan labelling alpha 2-adrenoceptors. However, this displacement was incomplete since 23.68 +/- 1.11% of specific [3H]-idazoxan binding remained in the presence of an excess concentration (100 microM) of (-)-adrenaline. In contrast, unlabelled idazoxan promoted a complete displacement of [3H]-idazoxan binding with a Hill slope close to unity and an affinity comparable with its KD determined in saturation studies. 3. Displacement of [3H]-idazoxan binding by the alpha 2-adrenoceptor antagonists yohimbine, RX821002 (2-(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline) and RX811059 (2-(2-ethoxy-1,4-benzodioxan-2-yl)-2-imidazoline) was more complex, with Hill slopes considerably less than unity, and best described by a two-site model of interaction comprising a high and low affinity component. The proportion of sites with high affinity for each antagonist was similar (60-80%). 4. The rank order of antagonist potency for the high affinity component in each displacement curve (RX821002 greater than RX811059 greater than yohimbine) is similar to that determined against the binding of [3H]-RX821002 to rat brain, suggesting that these components reflect the inhibition of [3H]-idazoxan binding to alpha 2-adrenoceptors.The remaining component in each displacement curve exhibiting low affinity towards these antagonists is attributable to the displacement of [3H]-idazoxin from a non-adrenoceptor idazoxan binding site (NAIBS) since a comparable amount of [3H]-idazoxan binding was not displaced by an excess concentration of (-)-adrenaline.5. The displacement of [3H]-idazoxan binding by RX801023 (6-fluoro-(2-(1,4-benzodioxan-2-yl)-2-imidazoline) was also best described by a model assuming a two site interaction with 20.07 +/- 3.11% of the sites labelled displaying high affinity for RX801023. The Ki of RX801023 for the remainder of the sites labelled was similar to its Ki versus [3H]-RX821002, indicating that this drug displays improved affinity and NAIBS/z2-adrenoceptor selectivity compared with idazoxan.6. In autoradiographical studies, the distribution of 5 nM [3H]-idazoxan binding to sections of rat whole brain was consistent with that reported from previous studies and resembled the distribution ofM2-adrenoceptors. However, when sections of brain were coincubated with concentrations of alpha2-adrenoceptor agonists or antagonists predicted to saturate alpha2-adrenoceptors, there remained distinct areas of binding corresponding to discrete brain nuclei. This remaining binding was however displaced by unlabelled idazoxan (3 microM) or RX801023 (3 microM) indicative of the labelling of NAIBS.7. Quantitative autoradiography of NAIBS revealed several brain nuclei which contained higher densities of these sites than alpha2-adrenoceptors, notably the area postrema, interpeduncular nucleus,arcuate nucleus, ependyma and pineal gland.