Adrenaline and insulin are two of the most important hormones regulating a number of physiological processes in skeletal muscle. Insulin's effects are generally requiring PKB and adrenaline effects cAMP and PKA. Recent evidence indicates cAMP can regulate PKB in some cell types via Epac (Exchange protein directly activated by cAMP). This suggests possible crossover between insulin and adrenaline signalling in muscle. Here we find that adrenaline alone did not influence PKB activation, but adrenaline dramatically potentiated insulin-stimulated phosphorylation of PKB (both Ser473 and Thr308) and of PKBalpha and PKBbeta enzyme activities. These effects were inhibited by wortmannin but adrenaline did not increase insulin-stimulated p85alpha PI 3-kinase activity. Adrenaline effects occurred via beta-adrenergic receptors and accumulation of cAMP. Interestingly, the Epac specific cAMP analogue 8-(4-chlorophenylthio)-2'-O-methyl-cAMP potentiated insulin-stimulated PKB phosphorylation in a similar manner as adrenaline did without activating glycogen phosphorylase. Inhibition of PKA by H89 decreased adrenaline-stimulated glycogen phosphorylase activation but increased PKB activation, which further supports that adrenaline increases insulin-stimulated PKB phosphorylation via Epac. Further, while adrenaline and the Epac activator alone did not promote p70(S6K) Thr389 phosphorylation, they potentiated insulin effects. In conclusion, adrenaline potentiates insulin-stimulated activation of PKB and p70(S6K) via cAMP and Epac in skeletal muscle. Furthermore, the fact that adrenaline alone did not activate PKB or p70(S6K) suggests that a hormone can be a potent regulator of signalling despite no effects being seen when co-activators are lacking.

Pituitary adenylate cyclase activating polypeptide (PACAP) provoked the rat chromaffin cells to secrete adrenaline. Within 20 min, the amount of adrenaline secreted by PACAP (10(-8) M) was as much as that caused by acetylcholine (10(-4) M). PACAP, but not acetylcholine, induced a long-term (over 120 min) increase in secretion of adrenaline. PACAP also activated adenylate cyclase and elevated cytosolic Ca2+ concentration. Furthermore, we found immunoreactive PACAP and PACAP binding sites in the rat adrenal medulla. These results suggest that PACAP has an important role in stimulating secretion of adrenaline in the adrenal medulla.

1. In a number of dogs the last two lumbar ganglia were removed unilaterally. At various dates up to the 56th day after operation the dogs were anaesthetized and the effect of oxytocin and adrenaline on hind-leg blood flow studied. Oxytocin alone reduced leg flow in all dogs after operation.2. Until approximately day 11 after operation oxytocin given during an infusion of adrenaline increased leg blood flow, as it does in normal dogs not given adrenaline infusion. After that date it reduced the flow even during adrenaline infusion. The timing of this change suggests that the normal response to adrenaline depends on the presence of undegenerated nerve fibres.3. In one animal the sympathetic nerves were crushed between the last two lumbar ganglia and beyond the last, and hind-leg blood flow frequently measured by means of venous occlusion plethysmography until day 204, when the animal was anaesthetized and acute observations made. Electrical stimulation of the sympathetic chain above the site of crushing caused a reduction in leg flow, indicating that at least some of the nerve supply had regenerated. However, oxytocin reduced leg flow when used alone and exerted no apparent effect in the presence of adrenaline.4. It is suggested that sympathetic nerves to vascular smooth muscle have a function or functions other than transmitter release and that when crushed nerves regenerate the functions do not recover at the same rate.

Stress-induced activation of haemostasis may be involved in the triggering of acute coronary syndromes. We compared the effects of mental stress, dynamic exercise and adrenaline infusion on platelet sensitivity to thrombin using flow-cytometric analysis of platelet fibrinogen binding in whole blood, and platelet aggregability using filtragometry ex vivo, in healthy volunteers. Furthermore, we assessed thrombin generation [prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin complexes in plasma] and thrombin activity (fibrinopeptide A in plasma). Exercise (bicycle ergometry) enhanced thrombin-induced platelet fibrinogen binding (P<0.05) and platelet aggregability (P<0.01), and elevated F1+2, thrombin-antithrombin complexes and fibrinopeptide A (P<0.05 for all three). Adrenaline infusion enhanced thrombin-induced platelet fibrinogen binding and platelet aggregability (P<0.05), and elevated thrombin-antithrombin complexes (P<0.05), whereas F1+2 and fibrinopeptide A levels were not significantly affected. Mental stress increased platelet sensitivity to high concentrations of thrombin only, and produced small increases in levels of thrombin-antithrombin complexes. Time control experiments showed no important changes with repeated measurements during rest. Platelet responses to exercise and adrenaline were reversible, with recovery 60 min later. Thus, heavy exercise and high levels of adrenaline reversibly increased platelet aggregability and platelet sensitivity to thrombin, and enhanced thrombin formation; the effects were most pronounced during exercise. Mental stress only weakly affected these parameters.

A new method for the separation from plasma and washing of human platelets is described. The use of prostacyclin (PGI2) throughout the procedure prevents the activation of platelets. The method allows a 60-70% yield of platelets from PRP. The platelet sensitivity to ADP, collagen, adrenaline, arachidonic acid and thrombin is the same as in PRP. The platelet suspension is stable for long periods and the reactivity to aggregating agents remains unchanged for periods greater than 48 h when platelets are stored at 4 degrees C.

1. The effect of ambient temperature on the properties of adrenoceptors mediating inotropic responses was assessed in isolated frog hearts on the basis of the effects and tissue uptake of alpha- and beta-adrenoceptor antagonists. 2. At temperatures of 23degree C and above inotropic responses to adrenaline were antagonized by propranolol (0-4-4-0muM), but were unaffected by phentolamine (26-5muM) and were potentiated by phenoxybenzamine (POB) (0-7-29-5muM). Below 17degree C the activity of propranolol was reduced at least tenfold, and the alpha-adrenoceptor antagonists inhibited responses to both adrenaline and isoprenaline, but not those to CaCL2. 3. The responses of hearts exposed to POB at 14degree C and then tested, after thorough washing, at both 14 and 24degree C were similarly inhibited at both temperatures, i.e. the usual beta-adrenoceptor response did not appear at the higher temperature. Conversely, exposure to POB at 24degree C produced only potentiation at both test temperatures. 4. Parallel to the reciprocal changes in their blocking actions, significantly more (14C)propranolol was retained by hearts exposed at high temperatures and significantly more (3H)POB was bound to the myocardium at low temperatures. Changes in binding and in the pharmaco logical effects of both blocking agents occurred entirely within a relatively narrow temperature range (17-22degree C) Parallel to the change from alpha- to beta-adrenoceptor characteristics with increasing temperature, the sensitivity of the hearts to adrenaline increased about tenfold. 5. Phentolamine (26-5muM) effectively protected hearts from block by (3H)POB at 14degree C, unmasked a potentiation of responses to adrenaline equivalent to that produced by POB at 24degree C, and reduced binding of the label to approximately the level found in unprotected hearts exposed at the higher temperature. At 24degree C, phentolamine did not alter the potentiation produced by (3H)POB, and reduced binding only slightly. There was no significant temperature differential in the amount of (3H)POB bound in the presence of phentolamine. 6. The results presented indicate a close functional and, probably, morphological association of alpha- and beta-adrenoceptors in the frog heart. It is suggested that the two classes of adrenoceptors may represent allosterie conformations of the same structure.

Plasma catecholamines are routinely measured using high-performance liquid chromatography (HPLC) with electrochemical detection. Most of the present assays require sample volumes of at least 500 microL and are complex and labour-intensive procedures, or require large capital investment to reduce the sample size. This paper describes a liquid/liquid plasma catecholamine extraction procedure, HPLC separation and electrochemical detection method which is simple, sensitive and reproducible. The resting catecholamine concentration of 50 microL adult human plasma can be assayed using standard electrochemical detection. The limits of detection were 0.1 fmol injected onto the column for each catecholamine. This method allows the routine assay of plasma catecholamine concentrations within the normal adult ranges in both 500 and 50 microL samples. The within assay coefficient of variation (CV) for noradrenaline (NA) was 1.2% in 500 microL plasma and 1.9% for 50 microL plasma, corresponding values for adrenaline (A) were 8.5 and 6.6%. The between assay CVs were 3.9 and 7.8% for NA, and 9.9 and 5.7% for A.

Adrenal medullary arteries have been followed from their origins in the capsular or subcapsular plexus to the medullary plexus in the mouse, rat, hamster, cat, guinea-pig, rabbit and bovine. Adrenal medullary arteries have a zonal distribution to the medullary capillary plexus and the number of arteries present in species variable and proportional to the size of the medulla. Cortical veins drain through distinct venous channels between groups of chromaffin cells, and may run adjacent to either adrenaline-storing (A) or noradrenaline-storing (NA) cells. In the normal unstimulated gland both A and NA cells lie adjacent to capillaries of the medullary plexus which derive their blood supply from adrenal medullary arteries. In the normal unstimulated gland no evidence of selective supply of arterial or venous blood to either A or NA cells has been obtained.

1. In postganglionic sympathetic neurones and adrenal chromaffin cells, catecholamines are co-stored in vesicles with soluble peptides, including chromogranin A (CgA) and neuropeptide Y (NPY), which are subject to exocytotic co-release with catecholamines. 2. Plasma catecholamine, CgA and NPY responses to stimulators and inhibitors of sympatho-adrenal catecholamine storage and release were measured in humans. Short-term, high-intensity dynamic exercise, prolonged low-intensity dynamic exercise, and assumption of the upright posture, in decreasing order of potency, predominantly stimulated noradrenaline (NA) release from sympathetic nerve endings. Only high-intensity exercise elevated CgA and NPY, which did not peak until 2 min after exercise cessation. Stimulated NA correlated with plasma CgA 2 min after exercise, and with NPY 5 min after exercise. 3. Insulin-evoked hypoglycaemia and caffeine ingestion, in decreasing order of potency, predominantly stimulated adrenaline (AD) release from the adrenal medulla. During insulin hypoglycaemia AD and CgA rose, but NPY was unchanged. Neither NPY nor CgA were altered by caffeine. The rise in CgA after intense adrenal medullary stimulation was greater than its rise after intense sympathetic neuronal stimulation (1.4-versus 1.2-fold, respectively). 4. Infusion of tyramine, which disrupts sympathetic neuronal vesicular NA storage, elevated systolic blood pressure and NA, while NPY and CgA were unchanged. After reserpine, another disruptor of neuronal NA storage, NA transiently rose and then fell; NPY and CgA were unaltered. After the non-exocytotic adrenal medullary secretory stimulus glucagon. AD rose while NA, CgA and NPY did not change. After amantadine, an inhibitor of protein endocytosis, both CgA and fibrinogen rose, while NA and NPY remained unaltered. Neither CgA, NPY, nor catecholamines were altered by the catecholamine uptake and catabolism inhibitors desipramine, cortisol, and pargyline. 5. Human sympathetic nerve contained a far higher ratio of NPY to catecholamines than human adrenal medulla, while adrenal medulla contained far more CgA than sympathetic nerve. 6. It is concluded that peptides are differentially co-stored with catecholamines, with greater abundance of CgA in the adrenal medulla and NPY in sympathetic nerve. Activation of catecholamine release from either the adrenal medulla or sympathetic nerves, therefore, results in quite different changes in plasma concentrations of the catecholamine storage vesicle peptides CgA and NPY. Only profound, intense stimulation of chromaffin cells or sympathetic axons measurably perturbs plasma CgA or NPY concentration; lesser degrees of stimulation perturb plasma catecholamines only. Neither CgA nor NPY are released during non-exocytotic catecholamine secretion.

The development of thrombosis involves 4 main factors: the vessel wall, the formed elements of the blood, blood coagulation, and blood flow. In venous thrombosis, however, the major part in both the initiation and growth of thrombi is played by the platelets. In selecting drugs which inhibit platelet function it is helful to know which of the platelet reactions that contribute to thrombus formation can be inhibited by various agents. Platelets adhere to the damaged vessel wall, collagen being probably the most important constituent involved. They are then stimulated to release the contents of their storage granules. Release-inducing agents promote the discharge of adenosine diphosphate (ADP) which causes platelets in the vicinity to swell to a more spherical shape, extend pseudopods and adhere to each other. Platelet aggregation is reversible, and a number of drugs have been shown to be capable of inhibiting platelet function at various stages, both in vitro and in vivo. Adrenaline, noradrenaline, oestrogens and nicotine enhance aggregation. Drugs which inhibit platelet function include the non-steroidal anti-inflammatory drugs, the pyrimido-pyrimidines (e.g. dipyridamole), hydroxychloroquine, clofibrate, and dextran. In this review the effects of drugs which inhibit platelet function are outlined and the extent to which they can be used to influence the course of thromboembolic disease in man is discussed. It is suggested that combination of anti-platelet drugs with anticoagulants could prove clinically useful.

1. Studies on the urine outflow, blood ADH concentration and electrolyte excretion were carried out in alpha-chloralose anaesthetized hydrated dogs; the agonists and antagonists of specific cholinoceptors and adrenoceptors were injected by the intracerebroventricular technique, to delineate the role of the C.N.S. receptors in the control of ADH secretion.2. Central injection of acetylcholine elicited a dose-dependent antidiuretic response which was associated with an increase in the blood ADH titre. Central atropinization partially blocked the antidiuretic response. The remaining antidiuretic response was reversed to a diuretic one by further pretreatment with phenoxybenzamine. The diuretic response thus obtained could be blocked by propranolol.3. The alpha-adrenoceptor agonists, phenylephrine and noradrenaline, induced dose-dependent antidiuretic responses with a concomitant rise in blood ADH concentration. Their effect could be blocked by pretreatment centrally with phenoxybenzamine. Low doses of adrenaline induced a diuretic response and a decrease in blood ADH concentration, higher doses elicited a dose-dependent antidiuretic response and increase in the titre of ADH in blood. Central phenoxybenzamine pretreatment reversed the antidiuretic effect of high doses of adrenaline to a diuretic effect which could be blocked by propranolol.4. Isoprenaline elicited a dose-dependent diuretic response and a decrease in blood ADH titre and propranolol competitively blocked the effect of isoprenaline.5. It is concluded that central muscarinic cholinoceptors and the alpha-adrenoceptors are concerned in the release of ADH, whereas the beta-adrenoceptors are concerned with inhibition of ADH release.

Catecholamine neurotransmitters--dopamine, noradrenaline (norepinephrine), adrenaline (epinephrine)--are synthesized in catecholaminergic neurons from tyrosine, via dopa, dopamine and noradrenaline, to adrenaline. Four enzymes are involved in the biosynthesis of adrenaline: (1) tyrosine 3-mono-oxygenase (tyrosine hydroxylase, TH); (2) aromatic L-amino acid decarboxylase (AADC, or DOPA decarboxylase, DDC); (3) dopamine beta-mono-oxygenase (dopamine beta-hydroxylase, DBH); and (4) noradrenaline N-methyltransferase (phenylethanolamine N-methyltransferase, PNMT). We cloned full-length complementary DNAs (cDNAs) and genomic DNAs of human catecholamine-synthesizing enzymes (TH, AADC, DBH, PNMT) and determined the nucleotide sequences and the deduced amino acid sequences. We discovered multiple messenger RNAs (mRNAs) of human TH, human DBH, and human PNMT. Four types (types 1, 2, 3, and 4) of human TH mRNAs are produced by alternative mRNA splicing mechanism from a single gene. We found the multiple forms of TH in two species of monkeys, but only a single mRNA corresponding to human TH type 1 in Sunkus murinus and rat, suggesting that the multiplicity of TH mRNA is primate-specific. Total TH mRNA, especially the most abundant type 2 and type 1 mRNAs in the human brain, were found to be reduced during the process of aging. The multiple forms of human TH may give additional regulation to the human enzyme, probably through altered phosphorylation and activation. We have succeeded in producing transgenic mice carrying multiple copies of the human TH gene in brain and adrenal medulla. The level of human TH mRNA in brain was about 50-fold higher than that of endogenous mouse TH mRNA. In situ hybridization demonstrated an enormous region-specific expression of the transgene in substantia nigra and ventral tegmental area. TH immunoreactivity in these regions, Western blot analysis, and TH activity measurements proved definitely increased TH in transgenic mice, though not comparable to the increment of the mRNA. However, catecholamine levels in transgenics were not significantly different from those in non-transgenics. The results suggest complex regulatory mechanisms for human TH gene expression and for the catecholamine levels in transgenic mice. Kohsaka and Uchida in collaboration with us applied genetically engineered (human TH cDNA-transfected) non-neuronal cells to brain tissue transplantation in parkinsonian rat models. We isolated and sequenced a full-length cDNA encoding human AADC.(ABSTRACT TRUNCATED AT 400 WORDS)

To determine whether an autonomic nervous system imbalance might underlie the nocturnal dyspnoea in patients with chronic airflow obstruction (CAO), we determined FEV1, sinus arrhythmia gap (SA gap), heart rate and urinary adrenaline and noradrenaline excretion every 4 h over 24 h. Measurements were performed in eight non-allergic patients with CAO and eight age- and sex-matched normal controls. The amplitude of the circadian changes in FEV1 in patients and controls was 27 +/- 2% and 7 +/- 1% respectively (P less than 0.001). Both an increased SA gap and a decreased heart rate are features of increased vagal activity. This vagal activity was significantly increased in patients, compared with normal controls (difference P less than 0.01), the difference being maximal at night. This increased activity might contribute to a bronchial obstruction in these patients. Urinary adrenaline excretion was significantly higher by day than by night in both patients and normal controls (P less than 0.01). The urinary levels of adrenaline in the patients were significantly decreased at all hours of observation as compared with levels in normal controls (P less than 0.05). Urinary noradrenaline levels were significantly lower in patients as compared with normal subjects (P less than 0.01), and lower by night than by day. Urinary histamine and Nt-methylhistamine excretion were in the normal range in each individual. Urinary levels, however, were significantly higher in patients at all hours of observation (P less than 0.05). No circadian rhythm was shown. Plasma cortisol levels showed a normal circadian variation, similar in patients and normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrocardiographic abnormalities, cardiac injury, and autonomic nervous function were investigated in patients with acute-phase subarachnoid hemorrhage (SAH) (42 patients with SAH related to ruptured aneurysm and 42 control subjects). Electrocardiogram and Holter electrocardiogram for spectral analysis of heart rate variability (HRV) were recorded. Concentrations of cardiogenic enzymes (ie, creatine kinase-myocardial fraction [CK-MB], myosin light chain I, and troponin T), plasma concentrations of catecholamine (ie, noradrenaline, adrenaline, 3-methoxy-4-hydroxy-phenylethylene glycol [MHPG]) and HRV were compared in the acute and chronic phase of SAH, and with the values in the controls subjects. As previously reported, patients with acute SAH exhibited electrocardiographic (ECG) abnormalities and increased concentrations of both cardiogenic enzymes and plasma catecholamines, suggesting that acceleration of sympathetic activity is involved. However, HRV analysis showed enhanced parasympathetic activity, probably associated with increased intracranial pressure after the onset of SAH, which may be explained by accentuated antagonism, negative feedback of noradrenaline to the center, and reduction of sympathetic activity after reaching a peak level. The results suggest that not only sympathetic activity but also vagal activity is enhanced during the acute phase of SAH, thus contributing to the ECG abnormalities and the onset of cardiac injury.

In anaesthetized cats the effect on antidromically identified single sympathetic preganglionic neurones (SPN) in the third thoracic segment of microelectrophoretically applied monoamines, amino acids and acetyl choline was examined. 5-Hydroxytryptamine (5-HT) creatinine sulphate and bimaleate excited a majority of SPN. A few cells were inhibited by 5-HT creatinine sulphate. These effects were observed on spontaneously active SPN (cardiac and non-cardiac type) and on silent SPN. Noradrenaline, adrenaline and dopamine inhibited all 'types' of SPN, including spontaneously active neurons, silent neurones activated by glutamate or DL-homocysteic acid and neurones synaptically activated by electrically stimulating a brain stem excitatory region. Acetyl choline had no effect on different types of SPN.

1. Blood platelets containing different amounts of 5-hydroxytryptamine (5-HT) were produced in vivo by the injection of 5-hydroxytryptamine or of reserpine into normal rabbits and of 5-hydroxytryptamine into reserpinized rabbits. Before and after these injections the aggregation of platelets was measured in vitro.2. Platelets of untreated rabbits were aggregated by adenosine diphosphate (ADP) and by 5-hydroxytryptamine; (-)-adrenaline alone did not produce aggregation but markedly increased aggregation by 5-hydroxytryptamine.3. Platelets saturated with 5-hydroxytryptamine in vivo were no longer aggregated in vitro by 5-hydroxytryptamine or by 5-hydroxytryptamine plus adrenaline, but their aggregation by ADP was unchanged.4. Platelets from reserpinized rabbits lost about 99% of their 5-hydroxytryptamine; the aggregation of these platelets did not differ significantly from that of platelets from control rabbits.5. Platelets from reserpinized rabbits injected with 5-hydroxytryptamine were aggregated neither by the amine alone nor by 5-hydroxytryptamine plus adrenaline, although these platelets contained much less 5-hydroxytryptamine than saturated platelets and only about one tenth as much as platelets from untreated rabbits.6. The findings support the hypothesis that the inhibitory effect of 5-hydroxytryptamine administered in vivo on platelet aggregation in vitro is due to the association of the amine with the platelet membrane.

Ceruloplasmin is a blue copper protein found in the alpha 2-globulin fraction of vertebrate plasma. It is a single-chain glycoprotein of molecular weight 132 000. It contains six copper atoms per molecule, comprising three or possibly four different types of copper. Its many functions may be related to the heterogeneous nature of these six copper atoms and to the various catalytic activities which they provide. Caeruloplasmin resembles albumin and transferrin in that all three serum proteins are regarded primarily as transport proteins. However, each has numerous other action as important as this transport function. Caeruloplasmin directly mobilizes iron into the serum and provides the major molecular link between copper and iron metabolism; it is the most prominent serum antioxidant, preventing deleterious oxidation of polyenoic acids and other substrates; it scavenges superoxide radicals; it serves as an acute-phase reactant (an endogenous modulator) of the inflammatory response; finally, caeruloplasmin may regulate the serum concentration of the biogenic amines, adrenaline (epinephrine) and serotonin (5-HT).

Adipocytes from hypothyroid rats do not respond to adrenaline with increased glycerol release. Adenosine deaminase largely restores lipolytic sensitivity. This effect is reversed by 2-deoxycoformycin, an inhibitor of the enzyme, and by N6-(phenylisopropyl)adenosine, which is not deaminated. Lipolytic response of normal cells to adrenaline is only 50% inhibited by phenylisopropyladenosine, whereas in cells from hypothyroid rats blockage is total. Inhibition of 50% was seen at 100 and 1 nM concentrations respectively. Insensitivity to adrenaline of hypothyroid-rat adipocytes can, at least partly, be explained by increased sensitivity to adenosine.

Platelet aggregation is mediated via binding of fibrinogen to sites on the membrane glycoprotein IIB-IIIA complex which become exposed when the cells are stimulated. We report here evidence of a dynamic and reversible exposure of binding sites for fibrinogen. In the absence of fibrinogen, exposed sites (B*) gradually lose their capacity to bind fibrinogen and close (Bo). On stimulation with platelet-activating factor (PAF, 500 nM) at 22 degrees C, closing of B* is enhanced by agents that raise cyclic AMP levels (10 ng of prostaglandin I2/ml; 5 mM-theophylline), inhibit protein kinase C (PKC; 25 microM-sphingosine; 1 microM-staurosporine), or disrupt the energy supply (30 mM-2-deoxy-D-glucose + 1 mM-CN-), or by raising the temperature to 37 degrees C. Conversely, activation of PKC 1 microM-1,2-dioctanoyl-sn-glycerol; 55 nM-phorbol 12-myristate 13-acetate) and an increase in intracellular [Ca2+] (100 nM-ionomycin + extracellular Ca2+) oppose the disappearance of B*. Phosphorylation of the 47 kDa protein illustrates the tight coupling between PKC and B* under all conditions tested, except when the cyclic AMP level is raised, and B* is converted to Bo without affecting PKC activity. Although the increase in PKC activity is much smaller with ADP or even absent upon stimulation with adrenaline, the control of B* is equally sensitive to modulation of cyclic AMP and PKC activity. We conclude that PAF, ADP and adrenaline regulate exposure of fibrinogen binding sites through a common mechanism consisting of two independent pathways, one dominated by PKC and the other by an as yet unidentified cyclic AMP-sensitive step.

Neuraxial drug administration describes techniques that deliver drugs in close proximity to the spinal cord, i.e. intrathecally into the CSF or epidurally into the fatty tissues surrounding the dura, by injection or infusion. This approach was initially developed in the form of spinal anaesthesia over 100 years ago. Since then, neuraxial drug administration has evolved and now includes a wide range of techniques to administer a large number of different drugs to provide anaesthesia, but also analgesia and treatment of spasticity in a variety of acute and chronic settings. This review concentrates on the pharmacological agents used and the clinical basis behind currently utilised approaches to neuraxial drug administration. With regard to local anaesthetics, the main focus is on the development of the enantiomer-specific compounds ropivacaine and levobupivacaine, which provide similar efficacy to bupivacaine with a reduced risk of severe cardiotoxicity. Opioids are the other group of drugs widely used neuraxially, in particular to provide analgesia alone or more commonly in combination with other agents. The physicochemical properties of the various opioids explain the main differences in efficacy and safety between these drugs when used intrathecally, of which morphine, fentanyl and sufentanil are most commonly used. Another group of drugs including clonidine, dexmedetomidine and epinephrine (adrenaline) provide neuraxial analgesia via alpha-adrenergic receptors and are used mainly as adjuvants to local anaesthetics and opioids. Furthermore, intrathecal baclofen is in routine clinical use to treat spasticity in a number of neurological conditions. Beside these established approaches, a wide range of other drugs have been assessed for neuraxial administration to provide analgesia; however, most are in various early stages of investigation and are not used routinely. These drugs include neostigmine, ketamine, midazolam and adenosine, and the conotoxin ziconotide. The latter is possibly the most unusual compound here; it has recently gained registration for intrathecal use in specific chronic pain conditions.

Acute hypoxia increases heart rate (HR) and cardiac output (Qt) at a given oxygen consumption (VO2) during submaximal exercise. It is widely believed that the underlying mechanism involves increased sympathetic activation and circulating catecholamines acting on cardiac beta receptors. Recent evidence indicating a continued role for parasympathetic modulation of HR during moderate exercise suggests that increased parasympathetic withdrawal plays a part in the increase in HR and Qt during hypoxic exercise. To test this, we separately blocked the beta-sympathetic and parasympathetic arms of the autonomic nervous system (ANS) in six healthy subjects (five male, one female; mean +/- S.E.M. age = 31.7+/-1.6 years, normoxic maximal VO2 (VO2,max)=3.1+/-0.3 l min(-1)) during exercise in conditions of normoxia and acute hypoxia (inspired oxygen fraction=0.125) to VO2,max. Data were collected on different days under the following conditions: (1)control, (2) after 8.0 mg propranolol i.v. and (3) after 0.8 mg glycopyrrolate i.v. Qt was measured using open-circuit acetylene uptake. Hypoxia increased venous [adrenaline] and [noradrenaline] but not [dopamine] at a given VO2 (P<0.05, P<0.01 and P=0.2, respectively). HR/VO2 and Qt/VO2 increased during hypoxia in all three conditions (P<0.05). Unexpectedly, the effects of hypoxia on HR and Qt were not significantly different from control with either beta-sympathetic or parasympathetic inhibition. These data suggest that although acute exposure to hypoxia increases circulating [catecholamines], the effects of hypoxia on HR and Qt do not necessarily require intact cardiac muscarinic and beta receptors. It may be that cardiac alpha receptors play a primary role in elevating HR and Qt during hypoxic exercise, or perhaps offer an alternative mechanism when other ANS pathways are blocked.

1. Cholinomimetic and adrenomimetic substances were tested on the chemosensitive zones of the ventral surface of the medulla oblongata using a plexiglas ring method. Tidal volume and respiratory frequency, arterial pressure and heart frequency were observed. 2. The increase of ventilation and the depression of arterial blood pressure by locally applied acetylcholine could be blocked by previous local application of atropine. It is therefore assumed that the acetylcholine receptors have muscarinic properties. 3. Nicotine in a small dose raises arterial pressure and with higher doses a drop is observed. The responses of respiration and of arterial pressure to nicotine were blocked by previous intravenous administration of hexamethonium. 4. Local application of atropine in the caudal (L) and rostral (M) chemosensitive zones reduced resting ventilation and the slope of the ventilatory response to CO2-inhalation. Physostigmine in these areas enhanced resting ventilation leaving unchanged the slope of the ventilatory response to CO2-inhalation. 5. With high concentrations of (L)-noradrenaline and (L)-adrenaline a slight increase of arterial pressure was seen while serotonin caused a drop. 6. These results together with those of Fukuda and Loeschcke (1978) suggest that a cholinergic transmission in the surface layer of the ventral medulla is a component in the respiratory and circulatory control systems.