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Background and Purpose: Pharmacological treatment of atrial fibrillation (AF) is limited by induction of malignant ventricular arrhythmias. Developing new drugs, a promising strategy is a more specific treatment of the atria. Muscarinic potassium current (IK[ACh]) is predominantly expressed in supraventricular tissue and mediates the induction of vagus-induced AF. The authors investigated the profile of representative class III drugs in respect to their effect on IK(ACh)., Methods: In rat atrial myocytes, IK(ACh) was activated by acetylcholine (ACh) measured with the whole-cell voltage clamp method. Drugs used: selective IKs blocker chromanole 293B (Cro); IKr blockers sotalol (Sot), dofetilide (Dof), ibutilide (Ibu), and terikalant (Ter). Data are expressed as mean values +/- standard deviation (SD)., Results: ACh-induced IK(ACh) density was 73 +/- 9 pA/pF (n= 9). IK(ACh) was almost completely desensitized in the presence of 50 micro M Ter, Ibu, or Dof. IC(50) of IK(ACh) inhibition by the three drugs was 0.9, 2.8, and 4.2 micro M (Dof, Ibu, and Ter, respectively). Receptor-independent GTP-gamma-S-induced IK(ACh) was sensitive to Ter, Ibu, and Dof as well. Sot is known to be a weak inhibitor of IKr. Inhibition of IK(ACh) by Sot was much less potent (IC(50) = 35.5 micro M) than inhibition by the high-affinity IKr blockers Ter, Ibu, and Dof. Superfusion of the cells with the IKs blocker Cro showed no desensitization of IK(ACh). Applied via the patch pipette (< 40 min) none of the class III drugs were effective., Conclusion: The results indicate inhibition of IK(ACh) and IKr but not IKs to be of similar mechanism (direct ion channel inhibition from the external side of the membrane). Potent desensitization of muscarinic potassium current could be of clinical relevance especially in patients with vagus-induced AF.

Puerperal uteri were stimulated by oxytocin, the uterine motility was recorded by transcervical catheter techniques, maternal pulse and blood-pressure were recorded continuously or intermittently. Oral tocolytics as Gynipral (Hexoprenaline), Partusisten (Fenoterol), Spiropent (Clenbuterol) and Prepar (Ritodrine) were administered orally in single or double dose. The inhibitory effect of these drugs were recorded, evaluated from the records and calculated statistically concerning their significant differences. It could be demonstrated that only Hexoprenaline in a three time higher dose than used usually and Partusisten in a dose of 10 and 20 mg were able to reduce uterine motility for more than 50%. All other substances definitely had an inhibitory effect on the puerperal uterus, but inhibition was not stronger than 30%. Cardiovascular side-effects were discussed. The question, if oral given betamimetics are effective in the treatment of threatening premature labour could not be answered definitively, but there are doubts according this study concerning the dose and the repetition of it for this purpose.

In 16 obese patients, the effect of beta-amino-isobutyl-benzol as polysterol-sulfonate on free fatty acids, triglycerides and i.v. GTT was compaired with that of a placebo. The question was to be answered if beta-amino-isobutyl-benzol worsens the GTT and if the lipolytic effect outranges lipolysis during fasting. No statistically significant change of the GTT, free fatty acids and triglycerides could be found between the beta-amino-isobutyl-benzol period and the placebo period.

In a single-blind random cross-over study the influence of a Norfenefrin infusion (2-4 mg/kg per minute) on circulation, carbohydrate and fat metabolism, catecholamines, growth hormone, cortisol, and insulin was investigated. The investigations were carried out on 12 healthy male physical education students at rest and during physical exercise. Under Norfenefrin, heart rate was reduced at rest (-30%) and under low and medium work load (150 watts: -9%); under maximal work load heart rate remained unchanged. Systolic blood pressure at rest increased by 29%; the results under physical exercise differ only slightly, and during increased work load they did not differ significantly. Diastolic blood pressure, in contrast, increased at rest (+23%) and under submaximal (150 watts: +12%) and maximal work load (+12.5%). The product of systolic blood pressure and heart rate was significantly decreased at rest under Norfenefrin, whereas it tended to decrease only slightly during work load. Adrenaline remained unchanged, while noradrenaline had a tendency to decrease only slightly during submaximal work load and was significantly lower during maximal work load. Glucose, lactate, glycerol, free fatty acids, and triglycerides, as well as growth hormone, cortisol, and insulin, remained unchanged. The physical working capacity remained unaffected. These observations confirm the predominant alpha-receptor-stimulating effect of Norfenefrin. The decrease in noradrenaline during exercise indicates the ability of Norfenefrin to interfere with the autoregulation of transmitter release and to replace endogenous noradrenaline.

12 compounds from the series of halogenated phenylethanolamines and phenoxypropanolamines were tested at the isolated rabbit jejunum, and the pD2-and pA2-values were determined. All the substances act beta-adrenolytically. Except for 3,4-dichloronoradrenaline, which stimulates the alpha-receptors, all the compounds still have pronounced beta-mimetic effects. The 2,5-dihalogenated phenylethanolamines and phenoxypropanolamines block the beta-receptors at lower concentrations than 2,4-dihalogen derivatives. The weakest beta-adrenolytic effects at the intestine were found with compounds halogenated at the 3,4-position.

N-Methylphenethylamine, a secondary amine present in vegetable foodstuffs, in concentrations up to 6.6 ppm, is an indirectly acting sympathomimetic amine; on i.v. injection the circulatory effects correspond to 1/80 to 1/100 of those of epinephrine. Following enternal application pressoric and positive chronotropic effects are observed during appr. 30 min; the no-effect level amounts to about 7 mg/kg.

A new, non-invasive method for measuring chemo-sensitivity of the respiratory center is described, one that may sensibly be applied in patients with airways obstruction. It is used for measurement of ventilation and gas-dynamic work of breathing in body plethysmography during a modified unsteady state of CO2 rebreathing technique. In 9 patients suffering from chronic obstructive bronchitis, a linear correlation between the end-expiratory CO2 partial pressure and the respiratory work rate vs. the airways resistance was established while between the end-expiratory PCO2 and the respiratory minute volume as well as the respiratory minute volume and the respiratory work rate vs. airways resistance, a non-linear correlation exists. In tests with 7-(3[2-(3 5-dihydroxyphenyl)-2-hydroxy-ethyl-amino]-propyl)-theophylline (reproterol, Bronchospasmin), a beta-phenylethyl-amino alkylxanthine, with known bronchodilating effects and a preparation for which pharmacological considerations of central-analeptic effects cannot definitely be excluded, this method revealed in patients with airways obstruction no breathing stimulation. In contrast, however, specific airways resistance in patients afflicted with bronchitis was statistically significantly reduced.

The pharmacological properties of fendiline N-(1-phenylethyl [1])-3,3 - diphenylpropylamine-hydrochloride; Sensit, were investigated in the isolated guinea pig heart and in isolated circular smooth muscle strips of bovine coronary arteries, pulmonary arteries and trachea. 1. Fendiline dose dependently increased coronary flow by up to 200% but, different from verapamil, did not inhibit contraction. 2. Fendiline dose dependently relaxed coronary strips and, more powerfully, tracheal and pulmonary arterial strips. 3. In cardiac muscle, fendiline was almost completely retained for a prolonged period of time. In the smooth muscle tissues under study, fendiline accumulated twenty-fold above the concentration present in the organ bath. 4. In paced hearts, fendiline non-competitively inhibited the positive inotropic effect of isoprenaline in doses that did not significantly depress the amplitude of isotonic contractions. 5. In the guinea pig heart, adenosine uptake becomes progressively inhibited when coronary flow increases. This "washout" effect was definitely counteracted by fendiline and by NaNO2, but was augmented by papaverine, hexobendine and dipyridamol. The counteraction of the "washout effect" by fendiline as well as by NaNO2 is most likely due to the opening of additional (previously closed) capillaries.

A report is given on the possible influence of hexoprenalinsulfate on the mucociliary wave frequency of the mucous membrane of the respiratory tract. The object of investigation was native human tracheaL mucosa obtained by tracheotomies. It was shown, that there was a significant decrease in frequency just on account of the usual gas fraction of the aerosol spray. If air was used instead of the gas, hexoprenaline did not influence the ciliary wave frequency.

1. 7-(3-[2-(3,5-Dihydroxyphenyl)-2-hydroxy-ethylamino]-propyl)-theophylline (reproterol, D 1959, Bronchospasmin) was developed as a bronchospasmolytic agent from the structure class of the phenylethyl-aminoalkyl-xanthines. 2. The pharmacological effects characterize reproterol as a bronchospasmolytic with preferential impact on the adrenergic beta2-receptors. 3. In the therapeutic dose range, reproterol stands out because of its nearly non-existent cardiovascular or central nervous side effects. Effects of over and above pharmacodynamically effective doses as well as toxic ones may be reversed with beta1-receptor blockers.

The 10 mm muscle-strips from the guinea pig terminal ileum digitalis glycosides (0.4 microgram/ml beta-acetyl-digoxin or 0.5 microgram/ml k-strophanthin) induce contractions which are dose-dependently and reversibly prevented by the calcium antagonist N-(2-benzyl-ethyl)-N-(1-phenyl-ethyl)-amine hydrochloride (fendiline, Sensit) (0.01--1 microgram/ml). Therapeutic use of calcium antagonists for manifest symptoms of digitalis intoxication (diarrhoea, intestinal infarctions) is discussed as these symptoms may be caused by digitalis-induced increase of intracellular calcium ions.

After long-therapy with 5 mg/kg body-weight of N-(2-benzhydryl-ethyl)-N-(1-phenyl-ethyl)amine hydrochloride (fendiline hydrochloride, Sensit) in dogs the development of functioning coronary collateral vessels can be proven by filling the vessel system with synthetic resin. From earlier studies, it is known that coronary collateral vessels can protect the heart from the consequences of stenoses and tissue damage due to hypoxia.

A combination of tests consisting of a compensation task with differential value indication, a tachystoscopic arrangement with verbal identification of characteristic features and an arrangement for a visually induced motor reaction was carried out on 12 healthy volunteers aged from 20-30 to determine psychomotor efficiency under the influence of the new antiparkinson drug selegiline (Eldepryl). The results were compared with the effects of the psychostimulant fenetylline and the depressant-antihistamine chlorphenoxamine, and with a placebo. While fenetylline and chlorphenoxamine produced the anticipated effects with regard to an improvement or deterioration in performance in all parameters, selegiline resulted in a slightly longer motor reaction time and an increase in control errors, and in a significantly longer mental processing time. In comparison with the placebo, selegiline increased the motor reaction time by 0.8 +/- 1.95% and mental processing time by 4.1 +/- 1.7%. This depressant effect of selegiline, however, only attained 1/8 and 2/3, resp., of the sedative effect of the normal dose of the antihistamine chlorophenoxamine. Under the influence of chlorphenoxamine, performance becomes less regular and under fenetylline more regular. Selegiline does not differ significantly from the placebo. In spite of selegiline metabolites 1-metamphetamine and 1-amphetamine, which act as mild stimulants, the slightly depressant effect of selegiline detected can be explained by the increased effect of dopamine inhibitory neurons, particularly in the inhibitory system of the formatio reticularis and the cortex frontalis as a result of a concentration of dopamine.

Structure-activity relationships of 90 bronchospasmolytic compenylethyl-aminoalkyl-xanthines are reported. Particularly the influence of substituents in the phenyl moiety as well as of the carbon bridge between the xanthine residue and the beta-phenylethylamine moiety is described. 2. A method is shown for the selection of one optimally bronchospasmolytic substance from many potential compounds synthetised via multiple screening steps to profound biological studies.

The alpha-adrenolytic activity of BE 2254 was investigated in in vitro as well as in vivo assays. On the isolated rat anococcygeus muscle, 2-[beta-(4-hydroxyphenyl)-ethyl-amino-methyl]tetralone(1) (BE 2254) shows a high affinity for postsynaptic alpha-adrenoceptors (pA2 = 8.9), in contrast to its much weaker potency (pA2 = 6.7) in inhibiting clonidine on the electrically driven rat vas deferens, thus suggesting a relative preference for postsynaptic alpha-adrenoceptors. BE 2254 effects on other catecholamine receptors are either negligible or not detectable. The hypotensive action of BE 2254 is shown to be solely due to alpha-blockade. All alpha-adrenolytic actions studied were of competitive nature.

The circulatory effects of Akrinor were investigated in anaesthetized patients during extracorporeal circulation and following open heart surgery. Arterial pressure, cardiac index and the maximal rate of rise of left ventricular pressure increased, whereas the resistance to flow in both circuits and the cardiac filling pressures remained unchanged. The compliance of the extrathoracic capacitance vessels during extracorporeal circulation was unaltered compared with the control group, but the volume content was less after Akrinor (200 ml). If this volume is shifted to the intrathoracic compartment in the intact circulation, the amounts seems too small to explain the increase in cardiac index. This increase and the subsequent rise of the arterial pressure seemed to be due to increased myocardial contractility.

The influence of rather low doses of reserpine (0.125--2.0 mg/kg) on the pressor effect of noradrenaline (NA) was studied in pithed rats. In addition it was investigated whether the blocking activity of alpha-sympathicolytic agents is influenced by pretreatment with reserpine. 24 h after injection of these doses of reserpine this drug only increased the pressor effect of lower doses of NA without shifting the dose-response curve to the left. As a rule in rats pretreated with reserpine the affinity of alpha-blocking agents (derivatives of phenylethylamine and phenoxyethylamine) to alpha-adrenoceptors is not considerably altered. Only two phenylethylamine derivates substituted with a p-hydroxy group possessed considerably higher blocking activity in reserpine pretreated animals than in rats not pretreated. The increase in sensitivity of blood vessels against low doses of NA (250 pg and 1 ng) observed in rats pretreated with reserpine is abolished even by alpha-blocking substances with low affinity to alpha-adrenoceptors.

In a double blind trial NAD 365 (3 X 10 and 20 mug), Salbutamol (3 X 2,0 mg), and Terbutalin (3 X 2,5 mg) were compared for 14 days. In a total of 96 patients five parameters concerning function were tested-p02, pC02, airway resistance (Rt), intrathoracic gas volume (IGV), and forced expiratory flow. Although the doses for NAB 365 were considerably lower than those of the comparative substances, the degree of efficacy for NAB 365, Salbutamol and Terbutalin was the same. Adverse reactions of all three substances under consideration were negligible. The higher dose of NAB 365 showed the least favoralbe result in this respect.