First measurement of the velocity of slow antihydrogen atoms.

The speed of antihydrogen atoms is deduced from the fraction that passes through an oscillating electric field without ionizing. The weakly bound atoms used for this first demonstration travel about 20 times more rapidly than the average thermal speed of the antiprotons from which they form, if these are in thermal equilibrium with their 4.2 K container. The method should be applicable to much more deeply bound states, which may well be moving more slowly, and should aid the quest to lower the speed of the atoms as required if they are to be trapped for precise spectroscopy.

First laser-controlled antihydrogen production.

Lasers are used for the first time to control the production of antihydrogen (H ). Sequential, resonant charge exchange collisions are involved in a method that is very different than the only other method used so far-producing slow H during positron cooling of antiprotons in a nested Penning trap. Two attractive features are that the laser frequencies determine the H binding energy, and that the production of extremely cold H should be possible in principle-likely close to what is needed for confinement in a trap, as needed for precise laser spectroscopy.

Driven production of cold antihydrogen and the first measured distribution of antihydrogen states.

Cold antihydrogen is produced when antiprotons are repeatedly driven into collisions with cold positrons within a nested Penning trap. Efficient antihydrogen production takes place during many cycles of positron cooling of antiprotons. A first measurement of a distribution of antihydrogen states is made using a preionizing electric field between separated production and detection regions. Surviving antihydrogen is stripped in an ionization well that captures and stores the freed antiproton for background-free detection.

Background-free observation of cold antihydrogen with field-ionization analysis of its states.

A background-free observation of cold antihydrogen atoms is made using field ionization followed by antiproton storage, a detection method that provides the first experimental information about antihydrogen atomic states. More antihydrogen atoms can be field ionized in an hour than all the antimatter atoms that have been previously reported, and the production rate per incident high energy antiproton is higher than ever observed. The high rate and the high Rydberg states suggest that the antihydrogen is formed via three-body recombination.

Desensitization pattern of cardiac beta-adrenoceptor subtypes by prolonged in vivo infusion of pindolol and celiprolol in rats.

The regulatory effects of pindolol and celiprolol on cardiac beta-adrenoceptor density were studied in vivo in order to assess the subtype selectivity of their partial agonistic activity (PAA). The substances were continuously administered to rats for 1 week by means of implanted osmotic minipumps. The density of beta-adrenoceptor subtypes were estimated from ICYP saturation binding experiments performed on cardiac ventricular plasma membranes in the presence of a highly selective antagonist (CGP 20172 A or ICI 118,551). Both antagonists were employed at concentrations as high as to block one subtype only without affecting the complementary subtype. For control purposes, rats were also treated with isoprenaline (0.4 mg/kg/h) and propranolol (0.15 mg/kg/h), or vehicle. Pindolol (0.036 mg/kg/h) and celiprolol (0.36 mg/kg/h) reduced the density of ventricular beta 2-adrenoceptors by 46% and 23%, respectively, which--in the case of pindolol--was significant when compared to the non-treated controls. Both compounds, however, produced a small, but distinct increase in the number of beta 1-adrenoceptors by approximately 26%. This finding is in contrast to the propranolol--induced up-regulation of both beta 1- and beta 2-adrenoceptors by approximately 80%. Since supramaximal doses of each drug were administered, a significant smaller increase of beta 1-adrenoceptors by pindolol and celiprolol--as compared to the increase produced by propranolol--can be interpreted as evidence for a PAA of pindolol and celiprolol on beta 1-adrenoceptors as well. Isoprenaline as a full agonist caused a marked loss of of both beta-adrenoceptor subtypes.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for beta 2-adrenoceptor-mediated facilitation of 3H-noradrenaline release from isolated guinea pig papillary muscles.

The effects of beta-adrenoceptor agonists and antagonists on field-stimulated release of radioactivity from superfused guinea pig papillary muscles preincubated with 3H-noradrenaline were studied. Stimulation-evoked overflow of tritium was abolished in the absence of Ca2+ or the presence of tetrodotoxin. Isoprenaline (1 mumol/L) caused a slight facilitation of evoked overflow, whereas phentolamine (1 mumol/L) exerted a strong facilitatory action. However, when phentolamine (1 mumol/L) was present throughout superfusion, isoprenaline and the selective beta 2-adrenoceptor agonist, zinterol, caused concentration-dependent increases (half-maximal effects at 1 nmol/L). The effects of the agonists were inversely related to stimulation frequency. Furthermore, the concentration-response curve of isoprenaline was shifted to the right by the selective beta 2-adrenoceptor antagonist, ICI 118,551, but not by the selective beta 1-adrenoceptor antagonist, ICI 89,406. Schild-plot analysis revealed competitive antagonism and a pA2 value of 9.04 for ICI 118,551. Both ICI 118,551 and ICI 89,406, as well as beta-adrenoceptor antagonists with intrinsic sympathomimetic activity (pindolol and celiprolol; 1 mumol/L), had no effect on stimulation-evoked overflow of tritium (phentolamine present). It is concluded that guinea pig papillary muscles are endowed with prejunctional beta 2 adrenoceptors facilitating impulse-evoked noradrenaline release. The facilitation is markedly promoted by blockade of prejunctional alpha adrenoceptors.

The effects of midodrine and alpha-2,5-dimethoxyphenyl-beta-aminoethanol hydrochloride on the rat uterus in situ.

In urethane anaesthetized rats 1 mg/kg i.v. alpha-2,5-dimethoxyphenyl-beta-glycinamidoethanol hydrochloride (midodrine, Gutron) or 0.1 mg/kg of its main metabolite alpha-2,5-dimethoxyphenyl-beta-aminoethanol hydrochloride (ST 1059) do not increase the uterine motility while these doses elevate the arterial blood pressure, 5 mg/kg midodrine or 0.3 mg/kg ST 1059 increase the uterine motility with concomitant increases in blood pressure and decreases in heart rate. It is concluded that midodrine does not enhance the uterine activity in doses clinically used for the treatment of hypotensive circulatory disorders.

Does the beta 1-adrenoceptor blocking agent celiprolol have alpha 2-adrenoceptor blocking properties?

The beta 1-adrenoceptor blocking agent celiprolol was tested for alpha 2-adrenoceptor blocking properties in different pharmacological models. In radioligand binding studies celiprolol shows a tenfold higher affinity to alpha 2- in comparison to alpha 1-adrenoceptors; however, the affinity of celiprolol to alpha-adrenoceptors is at least 100 times lower than that to beta-adrenoceptors. Celiprolol enhances the inhibitory effect of the alpha 2-adrenoceptor agonist clonidine in the electrically stimulated rat vas deferens in vitro; this celiprolol effect is abolished, but not reversed by propranolol. In pithed rats celiprolol inhibits the tachycardia induced by spinal electrical stimulation; the inhibitory effect of clonidine on the same parameter is augmented by celiprolol, but reversed by rauwolscine. Also in pithed rats celiprolol does not affect the pressor effect of the alpha 2-adrenoceptor agonist B-HT 920. From these results it is concluded that celiprolol does not possess any relevant alpha 2-adrenoceptor blocking properties which could explain the broncho- and vasodilating actions of that substance.

[Beta blockade with celiprolol in tardive dyskinesia patients treated with neuroleptics]. / Betablockade mit Celiprolol bei neuroleptikabehandelten Patienten mit tardiver Dyskinesie.

The influence of celiprolol on the symptoms of tardive dyskinesia was compared with placebo in a randomized double blind study. 17 female patients were treated with a single daily dose of 200 mg celiprolol and 18 female patients received placebo for a period of 3 months. All patients got additional neuroleptic treatment. Celiprolol produced a small decrease in heart rate and systolic blood pressure, but had no influence on the diastolic blood pressure. The effects of celiprolol on the symptoms of tardive dyskinesia were similar to those of the placebo; in both groups improvements and deteriorations were observed. One patient of the celiprolol group became symptom free. Two cases of collapse occurred after 10 weeks of treatment with celiprolol. In one case collapse was associated with diarrhoea, in the other case the patient had preexisting hypotensive circulatory dysregulation. Sporadic reports about the effect of propranolol in patients with tardive dyskinesia might reflect the normal progress of the disease or the effect might depend on the different pharmacological profile of propranolol.

[Comparative pharmacokinetics of the beta-1 receptor blookader celiprolol after a single oral administration in subjects with health kidneys and in patients with impaired renal function]. / Vergleichende Pharmakokinetik des Beta 1-Rezeptoren-Blockers Celiprolol nach oraler Einzelgabe an Nierengesunde und an Patienten mit eingeschränkter Nierenfunktion.

Pharmacokinetic parameters were determined after the oral administration of a single tablet containing 200 mg celiprolol HCl to 8 healthy volunteers with normal kidney function and 6 patients with stable impaired renal function of different degrees of severity. The plasma levels and the urinary excretion of celiprolol were followed up for 48 hours after administration with the help of specific chemo-analytical methods. The substance was equally well absorbed both by healthy volunteers and patients with renal disease. While the cumulative renal excretion (0 to 48 hours after administration) was reduced from 18.2% in healthy volunteers to 2.3% of the applied dose in kidney patients, the global elimination constant k fell from 0.104 h-1 in healthy volunteers to 0.072 h-1 in the patients with renal disease. It can be assumed that in patients with impaired renal function at least a part of the lacking renal elimination of celiprolol can be taken over by "extrarenal elimination". According to the method of Dettli a reduction in dosage of the beta 1-blocker, celiprolol is not necessary in patients with more or less impaired kidney function.

[Intrinsic sympathomimetic action and its special features as demonstrated by the beta-1-receptor blocker celiprolol]. / Die sympathomimetische Eigenwirkung und ihre Besonderheiten am Beispiel des Beta-1-Rezeptoren-Blockers Celiprolol.

The Intrinsic Sympathetic Activity (ISA) of the beta-1-adrenoceptor blocker celiprolol was tested in a series of pharmacological and clinical investigations. Celiprolol shows much more pronounced positive chronotropic effects in spontaneously beating atria of cats than in those of guinea-pigs and rats. Positive inotropic effects of celiprolol are much pronounced in the left kitten atrium, but scarcely demonstrable in the kitten papillary muscle. Celiprolol has no influence on the adenylyl cyclase activity of the dog heart. In reserpinized rats and reserpinized, adrenalectomized, vagotomized cats celiprolol increases the heart rate to the same extent as the beta-blocker pindolol. In ganglion-blocked dogs celiprolol distinctly increases heart rate and left ventricular contraction force. Celiprolol relaxes isolated human arterial and venous strips and induces a transient increase of the femoral arterial blood flow in anaesthetized dogs. Celiprolol relaxes isolated bovine tracheal muscle preparations and reduces the airway resistance in anaesthetized cats infused with serotonin. The intrinsic chronotropic effects of celiprolol in cat atria in vitro and in reserpinized rats in vivo and the relaxing effects of celiprolol in isolated bovine tracheal muscles are antagonized by propranolol, and therefore these actions may be explained by the ISA of celiprolol. However the vascular relaxing effects of celiprolol in vitro and in vivo and the bronchodilating effects in the serotonin-infused cat are not blocked by propranolol. In order to obtain a more precise characterization of these surprising effects, further pharmacological investigations were done. In the isolated femoral artery of the dog the concentration-response curve of calcium chloride is not influenced by celiprolol while it is antagonized by verapamil. A serotonin antagonistic effect cannot be demonstrated for celiprolol either in receptor binding studies or on the blood pressure of anaesthetized dogs. Celiprolol inhibits the methacholine bronchospasm in rats and the prostaglandin F2 alpha-induced bronchoconstriction in cats. The histamine-induced bronchoconstriction in dogs is scarcely affected by celiprolol while it is enhanced by propranolol. In radioligand studies celiprolol shows a tenfold higher affinity for alpha-2 in comparison to alpha-1 receptors. Celiprolol enhances the inhibitory effect of clonidine in the electrically stimulated vas deferens of the rat in vitro.(ABSTRACT TRUNCATED AT 400 WORDS)

[Diagnosis and therapy of hypotensive circulatory disorders in general practice. Experiences with Gutron using the Thulesius-diagram for diagnosis and supervision of therapy]. / Zur Diagnostik und Therapie hypotoner Kreislauf-Regulationsstörungen in der Allgemeinpraxis. Erfahrungen mit Gutron unter Anwendung des Thulesius-Diagramms für Diagnostik und Therapiekontrolle.

The alpha-adrenergic stimulating agent Gutron, given orally for 10 days, induced a subjective and objective improvement of orthostatic disorders in a total of 114 hypotensive patients in 7 general practices. The use of the Thulesius diagram in diagnosing orthostatic disorders further improved the rate of success and diminished the frequency of side effects distinctly. Gutron is indicated in all patients with a systolic blood pressure fall of at least 10 mmHg and a concomitant rise in heart rate when changing from lying to standing position (asympathicotonic and sympathicotonic hypotension).

Relaxation of coronary artery strips by adenosine and acidosis.

Cumulative dose-response curves of Ca2+-induced tension increments were studied in K+-depolarized helical strips of dog coronary arteries. Adenosine 10(-4) M reduced the Ca2+ sensitivity of the strips without altering the maximal tension with full Ca2+ activation. In contrast, acidosis of pH 7.05 significantly diminished the maximal tension with full Ca2+ activation. The relaxing effect of acidosis was almost completely abolished by 10(-4) M adenosine. It is concluded that adenosine inhibits Ca2+ influx, whereas acidosis depresses the contractile process of vascular smooth muscle directly.

Effects of midodrine, ST 1059, methoxamine and glycine on spontaneously beating guinea-pig atria.

The chronotropic effects of midodrine, glycine (10(-8) to 3.10(-3) M), ST1059 and methoxamine (10(-8) to 10(-3) M) were investigated in the spontaneously beating guinea-pig right atrial preparation. Midodrine and glycine produced a slight, but significant rise in atrial rate over a wide concentration range. The midodrine-induced rise in atrial rate was not influenced by the beta-adrenergic receptor blocking drug propranolol (10(-6) M). The histamine (H2)-receptor blocking drug metiamide (3.10(-5) M) abolished the positive chronotropic actions of both midodrine and glycine. No positive chronotropic effect was seen after the administration of ST 1059 or methoxamine. A decrease in atrial rate was elicited by high concentrations (above 10(-4) to 10(-3) M) of the sympathomimetic agents midodrine, ST 1059, and methoxamine, but not by the amino acid glycine.

Pharmacodynamic actions of midodrine, a new alpha-adrenergic stimulating agent, and its main metabolite, ST 1059.

Pharmacodynamic actions of alpha-(2,5-dimethoxyphenyl)-beta-glycinamido-ethanol-hydrochloride (midodrine, Gutron) and alpha-(2,5-dimethoxy-phenyl)-beta-aminoethanol (ST 1059), the main metabolite of midodrine, were investigated in various experimental procedures. Midodrine raises arterial blood pressure both after parenteral and enteral administration in animal experiments. Midodrine increases peripheral vascular tone when given in doses still ineffective in raising blood pressure. The d(+)-isomer of midodrine is by far less effective than the racemic mixture. Pretreatment with atropine, reserpine, guanethidine or hexamethonium has no influence on midodrine activity. Midodrine effects are greatly reduced by phentolamine but rather enhanced by propranolol pretreatment. Midodrine raises blood pressure in pithed rats, too; in the experiments performed the drug is devoid of central effects even when high doses are given. Chronic pretreatment with midodrine over a longer period reduces the effect of a subsequent single injection of this substance. Because of the results cited above midodrine may be classified as a direct peripheral alpha-adrenergic stimulating agent. alpha-Adrenergic receptor stimulation induced by midodrine can be demonstrated in various smooth muscle organs (blood vessels, nictitating membrane, intestine, pupil, urinary bladder, bronchi). In contrast to other pressor sympathomimetic agents, midodrine is of long duration of action and good efficacy after enteral administration. ST 1059, the main metabolite of midodrine, is an active alpha-adrenergic stimulating agent with a shorter duration of action than midodrine. It is suggested that midodrine is the well-absorbed "transport form", from which ST 1059, the actural pressor agent, is formed enzymatically in organism.