Controlling fast-electron-beam divergence using two laser pulses.

This Letter describes the first experimental demonstration of the guiding of a relativistic electron beam in a solid target using two colinear, relativistically intense, picosecond laser pulses. The first pulse creates a magnetic field that guides the higher-current, fast-electron beam generated by the second pulse. The effects of intensity ratio, delay, total energy, and intrinsic prepulse are examined. Thermal and Kα imaging show reduced emission size, increased peak emission, and increased total emission at delays of 4-6 ps, an intensity ratio of 10∶1 (second:first) and a total energy of 186 J. In comparison to a single, high-contrast shot, the inferred fast-electron divergence is reduced by 2.7 times, while the fast-electron current density is increased by a factor of 1.8. The enhancements are reproduced with modeling and are shown to be due to the self-generation of magnetic fields. Such a scheme could be of considerable benefit to fast-ignition inertial fusion.

Development of a novel large bandwidth front-end system for high peak power OPCPA systems.

We present the development of a laser system capable of generating bandwidths sufficient to support a sub 30 fs pulse at 910 nm. These pulses have been amplified to 500 mJ of energy at 2 Hz in two stages. The contrast measurements show that the initial seed is clean and suggests that the close in contrast is limited by the evaluation stretcher and compressor. Such a system is suitable for seeding high energy high power OPCPA systems based on KD*P.

Time-resolved thermally induced aberrations in a flash-lamp pumped Nd:Glass disk amplifier using a 2 × 2 position sensitive detector array.

A novel technique of measuring the prompt, thermally induced wave-front aberrations in a large aperture flash-lamp pumped Nd3+ glass disk amplifier is presented. Implementing a 2 × 2 lens array and a 2 × 2 position sensitive detector array as a diagnostic system, the wave-front profile was successfully reconstructed for the first five Zernike terms for a temporal window of 8.5 ms.

Alzheimer disease: amyloidogenesis, the presenilins and animal models.

Alzheimer's disease is the most prevalent form of dementia. Neuropathogenesis is proposed to be a result of the accumulation of amyloid beta peptides in the brain together with oxidative stress mechanisms and neuroinflammation. The presenilin proteins are central to the gamma-secretase cleavage of the amyloid prescursor protein (APP), releasing the amyloid beta peptide. Point mutations in the presenilin genes lead to cases of familial Alzheimer's disease by increasing APP cleavage resulting in excess amyloid beta formation. This review discusses the molecular mechanism of Alzheimer's disease with a focus on the presenilin genes. Alternative splicing of transcripts from these genes and how these may function in several disease states is discussed. There is an emphasis on the importance of animal models in elucidating the molecular mechanisms behind the development of Alzheimer's disease and how the zebrafish, Danio rerio, can be used as a model organism for analysis of presenilin function and Alzheimer's disease pathogenesis.

Preparations of Rp-cyclic adenosine 3',5'-phosphorothioate (Rp-cAMPS) can contain biologically active amounts of adenosine.

Superoxide anion (O2-.) production from human neutrophils stimulated by N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP, 1 microM) was inhibited by preparations of the inhibitor of cAMP-dependent protein kinase, Rp-cyclic adenosine 3',5'-phosphorothioate (Rp-cAMPS, 100 microM). This effect of Rp-cAMPS was reversed by xanthine amine congener (0.1 microM), an adenosine receptor antagonist, and by low concentrations of adenosine desaminase (0.02 mg/ml). HPLC analysis shows that these preparations of Rp-cAMPS contained concentrations of adenosine which could produce significant inhibition of fMLP-induced O2-. production. These results suggest that Rp-cAMPS should be used with caution in cells or tissues containing adenosine receptors, and that preparations of Rp-cAMPS should be treated with adenosine desaminase before use to avoid activation of adenosine receptors.

Effect of phorbol ester and pertussis toxin on the enhancement of noradrenaline release by angiotensin II in mouse atria.

1. Mouse atria were incubated with [3H]-noradrenaline, and the outflow of radioactivity due to electrical field stimulation (5 Hz, 60 s) was used as an index of noradrenaline release. Angiotensin II (0.01 and 0.1 microM) significantly enhanced the stimulation-induced (S-I) outflow of radioactivity. 2. Phorbol 12-myristate 13-acetate (0.001, 0.03, 0.1 and 1.0 microM), a protein kinase C activating phorbol ester, significantly enhanced the S-I outflow of radioactivity. When angiotensin II (0.1 microM) was present with the concentration of phorbol 12-myristate 13-acetate that was maximally effective in increasing the S-I outflow (0.1 microM), the enhancement of S-I outflow produced by angiotensin II was maintained. 3. Polymyxin B (70 microM), an inhibitor of protein kinase C, significantly inhibited the S-I outflow. Polymyxin B also inhibited the enhancement of the S-I outflow produced by angiotensin II (0.1 microM). 4. In another series of experiments mice were injected with pertussis toxin (1.5 micrograms per mouse), 4 days before their atria were removed. The effectiveness of pertussis toxin pretreatment was determined indirectly using carbachol. Carbachol caused a concentration-dependent fall in both the rate and force of beating of isolated spontaneously beating atria from mice pretreated with vehicle. This effect of carbachol was not seen with atria from mice pretreated with pertussis toxin. 5. Pertussis toxin pretreatment did not alter the enhancement of the S-I outflow of radioactivity produced by angiotensin II (0.01 and 0.1 microM). 6. These results suggest that angiotensin II receptor modulation of noradrenaline release is not mediated through either a pertussis toxin sensitive guanine nucleotide-binding protein or activation of protein kinase C.

Harmane produces hypotension following microinjection into the RVLM: possible role of I(1)-imidazoline receptors.

The beta-carboline, harmane (0.1 - 1.0 nmol) produces dose dependent hypotension when microinjected unilaterally into the rostral ventrolateral medulla (RVLM) of the anaesthetized rat. The potency of harmane on blood pressure is similar to that of the imidazoline, clonidine. The hypotensive effects of both clonidine and harmane are reversed by microinjection of the relatively I(1)-receptor selective antagonist efaroxan (20 nmol). These results are consistent with harmane acting at an I(1)-receptor in the RVLM. This is the first report of an endogenous ligand for I(1)-receptors that has central effects on blood pressure.

Involvement of cyclic nucleotides in prejunctional modulation of noradrenaline release in mouse atria.

1 In mouse isolated atria previously incubated with [3H]-noradrenaline, 8-bromo-cyclic AMP (3-270 microM) produced a concentration-dependent increase in the fractional stimulation-induced outflow of radioactivity. 8-Bromo-cyclic GMP induced a lesser increase in the stimulation-induced outflow. 2 The phosphodiesterase inhibitors: M&B 22948 (90 microM); ICI 63197 (30 and 90 microM) and 3-isobutyl-1-methylxanthine (90 microM) increased the fractional stimulation-induced outflow. Together these results indicate that cyclic AMP may have a modulatory effect on noradrenaline release. 3 The inhibition of the stimulation-induced outflow produced by clonidine (0.03 microM) and its facilitation produced by phentolamine (1 microM) were unaltered in the presence of 8-bromo-cyclic AMP (90 microM). However, in the presence of 8-bromo-cyclic AMP (270 microM), the facilitatory effect of phentolamine was enhanced, but the inhibitory effect of clonidine (0.03 microM) was unaltered. In the presence of ICI 63197 (30 microM) the inhibitory effect of clonidine (0.03 microM) was unaltered, but the facilitatory effect of phentolamine (1 microM) was slightly enhanced. 4 Isoprenaline (0.003-0.1 microM) enhanced the fractional stimulation-induced outflow, an effect blocked by propranolol (0.1 microM). In the presence of 8-bromo-cyclic AMP (90 microM), the facilitatory effect of isoprenaline (0.01 microM) was blocked. In the presence of ICI 63197 (30 microM) the facilitatory effect of isoprenaline (0.003 microM) was potentiated. 5 These results suggest that whereas beta-adrenoceptor-mediated enhancement of noradrenaline release is linked to the stimulation of adenylate cyclase and enhanced formation of cyclic AMP, alpha-adrenoceptor-mediated inhibition of noradrenaline release is not linked to inhibition of adenylate cyclase activity.

Protein kinase C involvement in maintenance and modulation of noradrenaline release in the mouse brain cortex.

1. The role of protein kinase C in the modulation of noradrenaline release was investigated in mouse cortical slices which were pre-incubated with [3H]-noradrenaline. The aim was to investigate the hypothesis that protein kinase C is activated during high levels of transmitter release to maintain transmitter output. 2. The protein kinase C activators, phorbol myristate acetate (0.01-0.3 microM) and to a greater extent 4 beta-phorbol 12,13-dibutyrate (0.01-0.3 microM) significantly enhanced stimulation-induced noradrenaline release whereas 4 alpha-phorbol 12,13-dibutyrate (0.1 microM) which does not activate protein kinase C was without effect. The effect of the protein kinase C activator, phorbol myristate acetate, on noradrenaline release was attenuated by the protein kinase C inhibitor, polymyxin B (21 microM) which by itself inhibited stimulation-induced noradrenaline release. 3. Protein kinase C was down-regulated by 10 h exposure of the cortical slices to 4 beta-phorbol 12,13-dibutyrate (1 microM). In this case the facilitatory effect of 4 beta-phorbol 12,13-dibutyrate (0.1 microM) on noradrenaline release was abolished as was the inhibitory effect produced by polymyxin B. This indicates that polymyxin B was acting selectively at protein kinase C. 4. The inhibitory effect of polymyxin B on noradrenaline release, when expressed as a percentage of the appropriate frequency control, was constant at 1, 5 and 10 Hz. Furthermore, the ratio of release at 5 Hz to that at 10 Hz was not altered by protein kinase C down-regulation, indicating that there is no additional effect of protein kinase C at higher stimulation frequencies. 5. When transmitter release was elevated by blocking alpha 2-adrenoceptor auto-inhibition with idazoxan (0.1 microM) or K+ channels with tetraethylammonium (300 microM), the elevation in transmitter release was significantly attenuated by protein kinase C down-regulation, suggesting an involvement of protein kinase C. 6. We conclude that protein kinase C is involved in the modulation of noradrenaline release over a wide range of stimulation frequencies, in addition to a role when noradrenaline release is elevated by presynaptic mechanisms.

Alpha 2A-adrenoceptors mediate activation of non-selective cation channels via Gi-proteins in human erythroleukaemia (HEL) cells. No evidence for a functional role of imidazoline receptors in modulating calcium.

Human erythroleukaemia (HEL) cells were investigated to characterize their alpha 2-adrenoceptor and imidazoline receptor sites. Membranes from HEL cells bound [3H]2-(2-methoxy-1, 4-benzodioxan-2yl)-2-imidazoline ([3H]RX821002) in a saturable and specific manner with a KD of 0.64 +/- 0.07 nM and a Bmax of 126 +/- 4 fmol/mg protein. [3H]RX821002 was displaced from HEL membranes by adrenergic drugs with the order of potency being yohimbine approximately oxymetazoline >> prazosin = 2-[2-[4-(o-methoxyphenyl)piperazin-1-yl]ethyl]-4,4-dimethyl- 1,3(2H,4H)-isochinolindione HCl (ARC 239), consistent with this site being an alpha 2A-adrenoceptor. HEL membranes also bound [3H]idazoxan in the presence of adrenaline to block alpha 2-adrenoceptors. This binding was saturable and specific with a KD of 3.5 +/- 1.0 nM and a Bmax of 31 +/- 6 fmol/mg protein. Adrenergic drugs from both the phenylethylamine and imidazoline classes increased high-affinity GTPase activity, an index of activation of regulatory heterotrimeric guanine-nucleotide binding proteins (G-proteins), and produced increases in cytosolic free calcium concentration ([Ca2+]i). The effects of these agonists in both systems were abolished by pertussis toxin pretreatment, and oxymetazoline and clonidine were antagonists. The potency of adrenergic drugs to inhibit 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14304)-induced increases in [Ca2+]i was yohimbine approximately oxymetazoline >> ARC 239, consistent with the binding data and an action at alpha 2A-adrenoceptors. No evidence was found for a role of imidazoline receptors in stimulating G-proteins or modulating [Ca2+]i. The adrenergic agonist-induced increases in [Ca2+]i were due to both release of Ca2+ from intracellular stores and entry of extracellular Ca2+. Ca2+ entry was blocked by 1-(beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenylethyl)-1H- imidazole hydrochloride (SKF 96365), but not by nitrendipine. Adrenaline also stimulated Mn2+ entry in HEL cells. Taken together, these results suggest that HEL cells have alpha 2A-adrenoceptors that activate non-selective cation channels via pertussis toxin-sensitive G-proteins, i.e. Gi-proteins.

Human neutrophils and HL-60 cells do not possess alpha 2-adrenoceptors.

Human neutrophils have been reported to possess both alpha 2- and beta 2-adrenoceptors. While activation of beta 2-adrenoceptors is known to inhibit N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP)-induced superoxide anion (O2-) production, the functional role of alpha 2-adrenoceptors is not known. We studied the effects of a range of structurally unrelated alpha 2-adrenoceptor agonists on fMLP-induced O2- production and UTP-induced increases in cytosolic free calcium concentration ([Ca2+]i) in human neutrophils. No effect of alpha 2-adrenoceptor agonists was seen on either fMLP-induced O2- production or UTP-induced increases in [Ca2+]i. alpha 2-Adrenoceptor agonists by themselves had no effect on either O2- production or [Ca2+]i. We then studied a model for neutrophils, differentiated HL-60 cells and human erythroleukaemia (HEL) cells, a cell line known to possess alpha 2-adrenoceptors. While the alpha 2-adrenoceptor agonists 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14304) and 5-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]azepin- dihydrochloride increased the [Ca2+]i in HEL cells, they had no effect by themselves on either [Ca2+]i or UTP-induced increases in [Ca2+]i in differentiated HL-60 cells. Activation of high-affinity GTPase by UK 14304 was seen in membranes from HEL cells but not in membranes from differentiated HL-60 cells. Similarly, a selective alpha 2-adrenoceptor antagonist, [3H]2-(2-methoxy-1,4-benzodioxan-2yl)-2 imidazoline, bound specifically and saturably to membranes from HEL cells, but not to membranes from HL-60 promyelocytes or differentiated HL-60 cells. Taken together, these data suggest that neither HL-60 promyelocytes nor differentiated HL-60 cells possess alpha 2-adrenoceptors, and that the lack of functional responses to alpha 2-adrenoceptor agonists in human neutrophils is due to the absence of alpha 2-adrenoceptors.

Novel targets and techniques in imidazoline receptor research.

Imidazoline binding sites are now generally accepted as being receptors. Despite this acceptance, the molecular structure and signal transduction mechanisms of these receptors are still poorly understood. The I1-imidazoline binding site (I1-receptor) is localized to the plasma membrane, but it is not clear if this represents a conventional receptor. It is also not clear if there are multiple forms of the I1-receptor. The signal transduction mechanisms of I1-receptors are similarly unclear, but much progress has been made. Evidence clearly indicates that ligands with high affinity for I1-receptors stimulate a novel signal transduction pathway, phosphatidylcholine-selective phospholipase C, in the rat adrenal medullary tumor cell line PC-12. However, this may not be the case in all cell types as microphysiometry, a novel technique for determining cellular activation, could not detect receptor activation in cultured bovine adrenal medullary cells exposed to a number of imidazolines considered to be agonists at the I1-receptor. This suggests that there is no I1-receptor-mediated stimulation of phosphatidylcholine-specific phospholipase C in these cells. By contrast, nicotine-stimulated increases in ion entry were blocked by clonidine. Ion channels have been suggested as another possible I1-imidazoline "receptor" family and may represent the low affinity I1-receptor. I1-Receptor ligands can be shown to bind to, or block, the following members of the ligand-gated ion channel super family, the 5HT3, K+ATP, NMDA, and nicotinic acetylcholine receptors. The site of action appears to be the phencyclidine binding site in these channels, but other possibilities cannot be excluded. Molecular modeling suggests that I1-receptor-selective ligands share a common three-dimensional structure with phencyclidine, providing a basis for these actions. This suggests that a phencyclidine-binding site motif may represent a novel site of action for I1-receptor ligands and that searches for receptors based on this motif may reveal novel imidazoline "receptors."

Assembly of PRR-containing receptors on scaffolds: a model for imidazoline I(1)-receptor action.

IRAS, a putative clone of the I(1)-imidazoline receptor, possesses a proline-rich region (PRR) motif, which might interact with SH3 regions on tyrosine kinases, and an integrin-binding motif. Receptors with a PRR motif can generally assemble onto multi-element signaling complexes (eg., the beta(3)-receptor on the EGF receptor) and thereby modulate signal transduction. Integrins serve as scaffolds for multi-element signaling complexes, similar to that assembled with the EGF receptor. It is therefore possible that IRAS signals through a complex with other receptors.

Clonidine and cirazoline inhibit activation of nicotinic channels in PC-12 cells.

Clonidine and cirazoline bind with high affinity to a nonadrenergic site in the brain stem, the so-called imidazoline I1 receptor. Our aim was to determine the mechanism by which these receptors act and their possible linkage to signal-transducing heterotrimeric G-proteins. We examined the effects of clonidine and cirazoline on PC-12 cells, a neuronal cell line that is reported to possess the I1 site and have no alpha 2-adrenoceptors. In undifferentiated PC-12 cells loaded with the Ca2+ indicator dye fura-2, clonidine and cirazoline (10-100 microM) inhibited the increase in [Ca2+]i produced by nicotine (10 microM). This inhibition was not reversed by yohimbine (100 microM), and adrenaline and BHT 920 were ineffective at 100 microM. This effect was not inhibited by pretreatment with pertussis toxin (24 hours, 100 ng/ml) and not modulated by pretreatment with IBMX (100 microM). The nicotine-induced increase in [Ca2+]i is apparently due to Ca2+ entering via the intrinsic ion channel of the nicotinic acetylcholine receptor. Clonidine and cirazoline inhibited the inward current produced by nicotine (10 microM) as measured by the whole cell patch-clamp technique in differentiated PC-12 cells, recorded at a holding potential of -60 mV. In agreement with the results found with fura-2, inhibition of inward current was concentration dependent and not blocked by yohimbine (100 microM) or mimicked by adrenaline (100 microM). Pretreatment of PC-12 cells with pertussis toxin or infusion of GDP-beta-S (2 mM) via the patch pipette did not alter the inhibition of the nicotine-induced inward current by clonidine or cirazoline. Clonidine and cirazoline, but not adrenaline, displayed [3H]phencyclidine from Torpedo electroplaque membranes enriched in nicotinic acetylcholine receptors in a concentration-dependent manner (10-100 microM). Taken together, these results suggest that clonidine and cirazoline inhibit Na+ and Ca2+ entry through the nicotinic acetylcholine receptor via a nonadrenergic mechanism that is independent of G-proteins and cyclic nucleotides, presumably by direct blockade of the intrinsic ion channel of the nicotinic acetylcholine receptor.

A comparison of cardiovascular and catecholamine responses to three stimuli in mild hypertension.

In five males with mild essential hypertension, simultaneous hemodynamic and arterial and venous plasma catecholamine responses to three stimulation tests (mental arithmetic, isometric handgrip exercise, and cold) were studied. Plasma norepinephrine (NE), epinephrine (EPI), and dopamine (DA) were measured radioenzymatically. Isometric exercise was the best stimulus for systolic and diastolic blood pressure and NE. Mental arithmetic produced the highest levels of plasma EPI, but there was great intersubject variability. Dopamine levels did not increase with any of these stimuli. Consistent arterio-venous differences across the forearm were seen for EPI but not NE, consistent with local production of NE. Isometric exercise produced the closest correlations between peripheral plasma catecholamine levels, blood pressure, and heart rate. Good correlations were seen with mental arithmetic, but with the stimulus of cold correlation was poor.

Inhibition of noradrenaline release by neuropeptide Y does not involve protein kinase C in mouse atria.

In this study, we investigated the possible involvement of protein kinase C in the inhibitory effect of neuropeptide Y (NPY) on the electrical stimulation-induced release of radioactivity from mouse atria incubated with [3H]-noradrenaline. The protein kinase C activators, phorbol dibutyrate (PDB, 0.001-1 mumol/l) and phorbol myristate acetate (PMA, 0.001-1 mumol/l), increased the release of noradrenaline in a concentration-dependent manner. Interestingly, the maximum effect on noradrenaline release was significantly greater for phorbol dibutyrate compared to phorbol myristate acetate. The enhancement produced by both phorbol esters was significantly reduced by the protein kinase C inhibitor, K-252a (1 mumol/l). In the presence of the concentration of either phorbol ester (PMA, 0.1 mumol/l, PDB 1 mumol/l), that was supramaximal for increasing the release of noradrenaline, NPY (0.3 mumol/l) significantly inhibited the release of noradrenaline. Moreover, in the presence of the protein kinase C inhibitors, K-252a (1 mumol/l) or polymyxin B (70 mumol/l), NPY (0.3 mumol/l) also significantly inhibited the release of noradrenaline. Therefore, it is concluded that protein kinase C is not involved in the prejunctional inhibitory effect of NPY on noradrenaline release in the mouse atria. Furthermore, since K-252a also inhibits cyclic AMP-dependent protein kinase, cyclic GMP-dependent protein kinase and myosin light chain kinase, it is likely that these kinases are also not involved in the inhibitory mechanism of NPY.

Pertussis toxin does not attenuate alpha 2-adrenoceptor mediated inhibition of noradrenaline release in mouse atria.

1. The alpha 2-adrenoceptor agonist clonidine (0.03 and 0.1 mumol/l) significantly inhibited stimulation-induced overflow of radioactivity from mouse isolated atria preincubated with [3H]-noradrenaline. This effect of clonidine was blocked by idazoxan (0.3 mumol/l) but not prazosin (0.3 mumol/l), indicating that an alpha 2-adrenoceptor was involved. 2. In some experiments mice were injected with pertussis toxin (1.5 micrograms/mouse) 4 days before their atria were removed and subsequently incubated with [3H]-noradrenaline. Alternatively, isolated atria from untreated mice were suspended in Krebs-Henseleit solution, incubated for 16 h with pertussis toxin (1.0 and 4.0 micrograms/ml) or vehicle and subsequently incubated with [3H]-noradrenaline. The effectiveness of pertussis toxin pretreatment was assessed indirectly using carbachol. Carbachol caused a dose dependent fall in both the rate and force of contraction of isolated, spontaneously beating atria from mice pretreated with vehicle in vivo or in vitro. This effect of carbachol was not seen in atria from mice pretreated with pertussis toxin in vivo or in vitro, suggesting that active toxin penetrated the myocardium. 3. Pertussis toxin pretreatment, either in vivo or in vitro did not alter the inhibitory effect of clonidine (0.03 and 0.1 mumol/l), or the facilitatory effect of the alpha-adrenoceptor antagonist phentolamine (1.0 mumol/l), on the stimulation-induced overflow of radioactivity. These results suggest that alpha 2-adrenoceptor modulation of noradrenaline release from sympathetic nerve terminals is not dependent on an inhibitory guanine-nucleotide-binding protein.

Effect of phorbol esters and polymyxin B on modulation of noradrenaline release in mouse atria.

Phorbol 12-myristate 13-acetate (PMA; 0.03, 0.1 and 1.0 mumol/l), a protein kinase C activating phorbol ester, significantly enhanced the stimulation-induced (S-I) outflow of radioactivity at 5 Hz stimulation in mouse atria preincubated with [3H]-noradrenaline, whereas a phorbol ester which does not activate protein kinase C, phorbol 13-acetate (0.1 mumol/l), had no effect. This suggests that protein kinase C may have a role in modulating sympathetic neurotransmission. Polymyxin B (7 and 21 mumol/l), an inhibitor of protein kinase C, had no effect on the S-I outflow of radioactivity. However, it had a significant inhibitory effect in a concentration of 70 mumol/l. Polymyxin B (21 mumol/l) reduced the facilitation of the S-I outflow of radioactivity produced by PMA (0.03 mumol/l), 8-bromo-cyclic AMP (90 mumol/l), tetraethylammonium chloride (300 mumol/l), and idazoxan (0.1 mumol/l). Furthermore, when a higher frequency of stimulation was applied (10 Hz rather than 5 Hz), polymyxin B (21 mumol/l) by itself inhibited the S-I outflow of radioactivity. In the presence of a concentration of PMA (0.1 mumol/l) that was maximally effective in enhancing the S-I outflow of radioactivity, both idazoxan (0.1 mumol/l) and 8-bromo-cyclic AMP (90 mumol/l) still enhanced the S-I outflow. This suggests that these agents are not operating through protein kinase C and further suggests that the inhibitory effect of polymyxin B on these agents cannot be due to inhibition of protein kinase C. The effects of clonidine on the S-I outflow were not affected by a maximally effective concentration of PMA (0.1 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Structure and function of protein kinases and protein phosphatases.

The International Union of Pharmacologists comes together every four years to discuss the latest research in pharmacology. The theme of this congress was "From molecular to integrative pharmacology". Among the highlights of this congress was the symposium on protein kinases and protein phosphatases. Protein serine-thronine kinases, such as protein kinase A (PKA) and protein kinase C (PKC), and the tyrosine kinases, such as the growth factor receptors, with their respective phosphatases, are key regulators of cellular homeostasis and gene transcription. Since the 1994 meeting in Montreal, considerable progress has been made in understanding the structure and function of these enzymes. The structures of several key enzymes have been fully or partially resolved and important structures in the binding and catalytic domains elucidated. This area is of particular interest for rational drug design. Furthermore, some key pathways that had previously been poorly understood have now been largely described.

Increased plasma noradrenaline during adrenaline infusion in man.

Arterial and venous plasma noradrenaline in recumbent mild hypertensives, and in normotensives with one adrenal gland, increased significantly during infusion of adrenaline to achieve levels similar to those seen during mental arithmetic stress. Although decreased noradrenaline clearance has not been excluded as an explanation of increased plasma levels, these results are consistent with the hypothesis that physiological concentrations of adrenaline are capable of facilitating noradrenaline release in man.