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Notes: Summary In the present study we set out to explain the complex atropine dose-response curves in man in relation to M-cholinoceptor subtype occupancy. In healthy volunteers the effects of atropine on heart rate and salivary flow were quantified. M-cholinoceptor subtype occupancy by antagonist present in plasma samples was detected in an in vitro radioreceptor assay. Atropine effects were studied without and after propranolol (240 mg oral dose) and without and after pirenzepine (1.1 mg i. v.) to differentiate β-adrenoceptor and M-cholinoceptor subtype mediated effects. 1. In receptor binding studies, M-cholinoceptors in bovine cerebral cortex membranes were labelled with 3H-pirenzepine (pK d = 8.05), M-cholinoceptors in rat salivary gland membranes with 3H-N-methylscopolamine (pK d = 9.02). Atropine competed for binding of these ligands with a small (2.1-fold) preferential selectivity via the cerebral in comparison to the glandular receptors (pK i = 9.18 versus 8.86). Pirenzepine showed a marked selectivity (40-fold) in this respect with pK i-values of 8.05 (M1: cerebral cortex) and 6.45 (M2: salivary glands). 2. At heart rate and at salivary flow, bivalent dose-response curves of atropine were observed with opposite effect vectors. The typical antagonist effects at M-cholinoceptors (i. e. an increase of heart rate and an inhibition of salivary flow) were observed at doses 〉 1 μg/kg, whereas “paradoxical” cholinomimetic effects of atropine became apparent at lower doses. From a superposition of two isotherms with opposite effect vectors ED50-values were calculated, which were in the range of half-maximal M-cholinoceptor occupancy in the in vitro radioreceptor assay of plasma samples. 3. The time-dependent decline of atropine effects after the highest dose (40 μg/kg) and the respective in vitro M-cholinoceptor occupancy were in good agreement with the dose-response data. 4. β-Adrenoceptor blockade did not influence the pattern of the atropine dose-response relation. After pirenzepine (∼ 70% of M1-cholinoceptor occupancy), the cholinomimetic effects of atropine were abolished and only monovalent atropine dose-response curves were observed. Maximal effects of atropine were not different in comparison to the respective controls without pirenzepine. 5. The standard deviation of the RR-intervals in the ECG as a measure of postsynaptic M-cholinoceptor stimulation was increased after pirenzepine by 58% and decreased after the maximum atropine dose by 85%. It is concluded, that the cholinomimetic effects observed after atropine result from its antagonism at peripheral M1-cholinoceptors. A negative feedback mechanism of acetylcholine release via M1-autoreceptors is discussed as a possible mechanism involved.

Notes: Summary The aim of the present study was to investigate the M-cholinoceptor subtype selectivity of pirenzepine in man. In parallel with effects on the heart rate and salivary flow, M-cholinoceptor subtype occupancy by antagonist present in plasma samples was detected in radioreceptor assays. Bovine cerebral cortex membranes labelled with 3H-pirenzepine (M1) and rat salivary gland membranes labelled with 3H-N-methylscopolamine (M2) were used in these in vitro assays. A half-maximal occupancy of M1-cholinoceptors in the in vitro assay of plasma samples was detected after 0.25 mg of pirenzepine i.v. The respective half-maximal M2-cholinoceptor occupancy was observed after 10 mg. Doses 〈 3 mg decreased the heart rate by maximally 10.7 beats/min with an ED50 of about 0.1 mg. An increase in heart rate (relative to control values) was observed at doses 〉 10 mg. This bivalent dose-response relationship was also observed after β-blockade. Salivary flow tended to increase at doses 〈 1 mg and was half-maximally inhibited after 10 mg. Combining the in vitro and in vivo results, the typical antimuscarinic effects (tachycardia and inhibition of salivary flow) can be attributed to the blockade of M2-cholinoceptors, whereas the reduction of heart rate coincides with the blockade of the M1-subtype. With respect to the typical antimuscarinic effects, pirenzepine was 70-fold less potent than atropine; in contrast, with respect to the reduction of heart rate, pirenzepine was equipotent with atropine. It is concluded that pirenzepine does not discriminate between cardiac and salivary gland M2-cholinoceptors but shows pronounced selectivity for the M1-cholinoceptors through which it mediates the decrease in heart rate. The latter effect may be explained by inhibitory M1-auto-receptors.

Notes: Summary Bupranolol is a non-selective beta-adrenoceptor antagonist with a Ki-value of 6–15 nmol/l (equivalent to 1.5–4 ng/ml in plasma) at beta1- (rat salivary gland) and beta2-adrenoceptors (rat reticulocytes) in receptor binding studies with3H-CGP 12177 in the presence of human plasma. After oral administration of 200 mg bupranolol to healthy volunteers, the maximal plasma concentration was observed within 1.2 h but it only reached a level close to the Ki-value. Elimination from plasma was rapid (t1/2=2.0 h). Administration of 30 mg bupranolol in a transdermal delivery system (TTS) every 24 h to 6 healthy volunteers for 72 h yielded steady state plasma concentrations 4- to 5-times above the Ki-value as shown by in vitro inhibition of beta-adrenoceptor binding by plasma samples. The pharmacodynamic effect, measured as the reduction in exercise tachycardia, showed a stable inhibitory effect; antagonism of a bolus injection of isoprenaline indicated a 10- to 15-fold right shift of the dose-response curve during the observation period of 72 h. It is concluded that steady-state plasma concentrations and effect of the elsewise rapidly eliminated beta-blocker bupranolol can be achieved by a transdermal delivery system applied each day.

Notes: Summary In a double-blind, placebo-controlled study in 6 healthy volunteers, the correlation between beta-adrenoceptor binding, the time course of the effect and plasma concentration kinetics was investigated from 0 to 48 h after a single oral dose of propranolol 240 mg. First, the in vitro beta-adrenoceptor interaction of propranolol was investigated. Propranolol inhibited beta-adrenoceptor binding to rat parotid (beta1) and reticulocyte (beta2) membranes in the presence of pooled human plasma with a Ki of about 8 ng/ml plasma. After oral administration of 240 mg propranolol, concentration kinetics in plasma could be described by a Bateman function with a fictive concentration at time 0 of 275 ng/ml plasma, and a mean elimination half-life of 3.5 h. Using the concentration kinetics of propranolol in plasma together with its in vitro beta-adrenoceptor binding characteristics in the presence of placebo plasma from each individual, the time course of antagonism against beta-adrenoceptor mediated effects was predicted. The latter was in agreement with the time course of propranolol-induced inhibition of tachycardia due to orthostasis. After bicycle ergometry, however, the time course of inhibition of tachycardia was shorter than was predicted. Plasma sampled at various times after propranolol administration inhibited beta-adrenoceptor binding of the radioligand 3H-CGP 12177 to rat reticulocyte membranes in a fashion reflecting the time course of inhibition of exercise tachycardia observed in the volunteers. A direct, linear relation was shown between the in vitro inhibition of beta-adrenoceptor binding by the plasma samples withdrawn after propranolol administration and the inhibition of exercise tachycardia observed in parallel. The results show that the concentrations of antagonist present in plasma are representative of the concentrations in the effect compartment. Deep compartments of drug distribution appear irrelevant to the effects of the drugs. The relation between the plasma concentration of propranolol and the reduction in heart rate at various levels of physical effort shows no significant inhibition at rest and increasing IC50-values from orthostasis to 2 min and to 4 min of ergometry. IC50-values after orthostasis are in the range of the Ki-values from in vitro receptor binding studies, whereas the IC50-values after exercise are shifted 2-to 3-fold to the right relative to the Ki-values. This finding is in agreement with increased beta-adrenoceptor stimulation with increasing effort (release of endogenous noradrenaline), which shifts the antagonist concentration-effect curve to the right. Furthermore, the rightward shift can explain why with increasing effort the time course of the inhibitory effect of propranolol becomes shorter. Release of propranolol from presynaptic stores during exercise is irrelevant, since this would result in opposed effects on the concentration-effect relationship (leftward shift) and the time course of antagonism (longer effect) with increasing work load. It is concluded that the receptor interaction of propranolol together with its plasma concentration kinetics can fully explain the time course of effects after a single oral dose, and so receptor interaction will be the missing link in the correlation between concentration kinetics and effect kinetics of propranolol in man. In general, this mode of correlation should be expandable to any drug exerting its effects according to the law of mass action via receptors in the extracellular space. This approach provides a rational basis for the comparison of different drugs from one group irrespective of their receptor affinity and concentration kinetics.

Notes: Zusammenfassung Ziel dieser kontrollierten, prospektiven, randomisierten Studie war die Untersuchung der Effektivität und der Sicherheit einer reduzierten Defibrillationsenergie mit biphasischer Schockform und einem endokardialem ICD-Sondensystem. 176 Patienten, die klinisch ein typisches ICD-Patientenkollektiv darstellten, wurden im Rahmen der Studie untersucht. Alle Patienten erhielten ein ICD-Aggregat mit der Möglichkeit der Episodenspeicherung (Ventak TM PRx II, PRx III) in Verbindung mit einem rein endokardialem Sondensystem (Endotak TM Serie 0070; 0090, CPI). Die intraoperative Defibrillationsschwelle (DFT) sollte ≤15 J betragen. Die DFT wurde in einem Protokoll mit absteigenden Energiemengen (15, 10, 8, 5 J) ermittelt. Die niedrigste effektive Energiemenge zur Terminierung von induziertem Kammerflimmern mußte einmal bestätigt werden und wurde als DFT+ definiert. Eine Überprüfung der Effektivität der DFT+ erfolgte im Rahmen der ICD-Implantation, vor der Krankenhausentlassung und nach einem Jahr. Die Randomisierung erfolgte in zwei Gruppen, wobei in der Studiengruppe der erste Schock auf einen Wert von 2× DFT+ und alle folgenden auf die maximale Energie (34 J) programmiert wurden. In der Kontrollgruppe wurden alle Schocks auf 34 J eingestellt. Verglichen wurden die Ergebnisse der reduzierten und maximalen Schockenergie bei induziertem Kammerflimmern sowie die Effektivität bei spontanen Arrhythmieepisoden im Langzeitverlauf. Eine DFT+ ≤15 J (im Mittel 9,6±3,2 J, Studiengruppe; 10,1±3,5 J, Kontrollgruppe) wurde bei 166/176 Patienten (94%) ermittelt. Die Reproduzierbarkeit der Defibrillationseffektivität mit der DFT+-Energie nach einem Jahr betrug 84%. Induziertes Kammerflimmern (VF) konnte in der Studiengruppe in 217/218 Fällen (99,5%) und in der Kontrollgruppe in 201/203 Fällen (99%) erfolgreich durch den ersten Schock terminiert werden. Im klinischen Verlauf wurden in der Studiengruppe 83/86 Episoden (96,5%) spontaner monomorpher Kammertachykardien (MVT) und 38/40 Episoden VF (95%) mit dem 2× DFT+-Schock beendet. In der Kontrollgruppe konnte eine erfolgreiche Konversion mit dem ersten Schock bei 151/156 spontaner MVT-Episoden (96,8%) und bei 30/33 VF-Episoden (91%) beobachtet werden. Die Effektivität des ersten Schocks in der Studiengruppe war unabhängig von der kardialen Grunderkrankung, der linksventrikulären Funktion, einer begleitenden Amiodarontherapie der Häufigkeit der spontanen Arrhythmieepisoden und von dem DFT+-Wert selbst. Die Inzidenz des plötzlichen Herztodes (2,4% Studien- vs. 3,8% Kontrollgruppe) unterschied sich nicht signifikant. Die Effektivität einer auf 2× DFT+-reduzierten Energiemenge des ersten Schocks unterscheidet sich nicht von der bei einer Einstellung auf 34 J, sowohl in bezug auf induziertes VF als auch bei spontanen Episoden von VT oder VF. Durch die Programmierung der 2× DFT+-Schockenergie wurde die Sicherheit der ICD-Therapie nicht beeinträchtigt.

Notes: Zusammenfassung Ziel vorliegender Untersuchung war es, die Reproduzierbarkeit der Effektivität der nach einem modifizierten Protokoll intraoperativ bestimmten Defibrillationsschwellenenergie im Langzeitverlauf zu überprüfen. Hierzu wurden im Rahmen einer Substudie einer prospektiven, randomisierten Multizenterstudie (“Low Energy Endotak Trial” LEET)) zwischen Dezember 1993 und Januar 1996 83 Patienten, die im Rahmen einer Erstversorgung mit einem implantierbaren Kardioverter-Defibrillator (ICD) in Kombination mit einem transvenösen Einzelelektrodensystem eine intraoperativ bestimmte Defibrillationsschwelle (DFT) ≤15 J aufwiesen, eingeschlossen. Zur Bestimmung der DFT wurde ein Protokoll mit absteigenden Energiemengen (15, 10, 8, 5 J) eingesetzt. Die Defibrillationseffektivität der DFT wurde intraoperativ unter Verwendung der gleichen Energiemenge bestätigt (DFT+). Nach Implantation des ICD, vor Krankenhausentlassung und ein Jahr nach ICD-Implantation erfolgte eine erneute Überprüfung der Defibrillationseffektivität der DFT+ (erster Schock: DFT+, zweiter Schock; 2×DFT+). Die intraoperativ bestimmte DFT+ lag bei 9,6+3,3 J. Unmittelbar nach ICD-Implantation war eine Konversion von induziertem Kammerflimmern bei 70/79 (89%) der Patienten unter Verwendung der DFT+ möglich. Bei 7/8 (89%) Patienten gelang eine Konversion in Sinusrhythmus nach Abgabe eines Schocks, der auf 2×DFT+ programmiert war, und bei einem Patienten war erst eine dritte Entladung mit maximaler Energie (34 J) erfolgreich. Die DFT+ war vor Krankenhausentlassung bei 61/77 (79%) Patienten reproduzierbar effektiv, die verbliebenen 16 Patienten konnten erfolgreich mit 2×DFT+ defibrilliert werden. Bei 52/62 (84%) Patienten ließ sich ein Jahr nach ICD-Implantation induziertes Kammerflimmern mit der intraoperativ bestimmten DFT+ und bei den übrigen 10 Patientem mit 2×DFT+ terminieren. Insgesamt konnten 183/218 (84%) Episoden von induziertem Kammerflimmern erfolgreich unter Verwendung der Energiemenge an der DFT+ terminiert werden. Ein Zusammenhang zwischen der intraoperativ bestimmten DFT+ oder der kardialen Grunderkrankung und der Reproduzierbarkeit der Defibrillationseffektivität bestand nicht. In vorliegender Untersuchung konnte unmittelbar nach ICD-Implantation, bei Krankenhausentlassung und ein Jahr nach Implantation eine vergleichbare Defibrillationseffektivität der intraoperativ bestimmten DFT+ gezeigt werden. Eine auf das Doppelte der DFT+ programmierte Energie scheint eine äußerst zuverlässige Defibrillation im ersten Jahr nach ICD-Implantation zu ermöglichen.

Notes: Summary In chronic heart failure cardiac β-adrenoceptors are decreased. In this study we investigated whether a) in severely failing human ventricles β-adrenoceptors are uniformly decreased or regional variations exist, and b) the β-adrenoceptor decrease is caused by increased internalization or is a real loss in β-adrenoceptors. For this purpose we assessed β-adrenoceptor number and subtype distribution in a particulate fraction (mainly sarcolemmal plasma membranes) and a light vesicle fraction of right and left ventricular segments (obtained by cutting transversal, rings of 2 cm from the midventricular regions) of explanted hearts from 2 patients with end-stage congestive dilated cardiomyopathy (DCM) and one patient with end-stage ischemic cardiomyopathy (ICM). In all three hearts ventricular β-adrenoceptor number was very low (7.5–10 and 21–26 fmol/mg protein in DCM, 15–22 fmol/mg protein in ICM compared to 68–74 fmol/mg protein in non-failing ventricles). β-Adrenoceptors were uniformly decreased over the whole ventricular region and no considerable regional variations existed. The same held true for β1- and β2-adrenoceptors. In ICM decrease in β-adrenoceptors was due to a concomitant reduction in β1- and β2-adrenoceptors, in DCM it was mainly caused by β1-adrenoceptor down-regulation. In all ventricular segments investigated light vesicle β-adrenoceptors amounted to about 5–7% of total ventricular β-adrenoceptors and this was not significantly different from non-failing left ventricles. We conclude that a) in severely failing human ventricles β-adrenoceptors are evenly down-regulated and no regional variations exist and b) the decrease in β-adrenoceptors is not due to enhanced internalization but is a real loss of β-adrenoceptors.

Notes: Summary A variety of electrocardiographic manifestations of dual AV nodal physiology have been reported. The specific subtype dual ventricular response is considered as a very rare phenomenon. We present the case of a 53 year old lady who suffered from paroxysmal regular tachycardias for more than seven years. In the last 6 months the symptomatology of the cardiac arrhythmia changed to more persistent und irregular rhythm disturbances. Treatment with class Ia antiarrhythmic drugs and beta-blocking agents failed. The latter even seemed to worsen her very disturbing palpitations. After examination of the ECG recordings, the diagnosis of dual AV nodal physiology with double ventricular response was made – the lady was referred to our institution for electrophysiological testing and radiofrequency catheter ablation of the slow pathway. An invasive electrophysiological study reconfirmed the diagnosis of a dual AV nodal conduction pattern with irregular double ventricular response. The radiofrequency catheter ablation of the the slow pathway achieved a complete cessation of the double ventricular response. This satisfactory outcome was confirmed by analysis of a postinterventional 24hour holter recording and an exercise stress test. During a follow-up period of three months, the patient remained free of symptoms and there was no recurrence of dual AV nodal conduction physiology in the surface ECG.

Notes: Summary Background: Clinical drawbacks of beta-blocker treatment in stable angina have motivated researchers to provide alternative heart rat lowering agents, such as tedisamil which additionally exerts antiischemic and antiarrhythmic effects by blockade of cellular repolarizing K+ currents. Methods and Results: 48 patients with stable angina pectoris were investigated (double-blind, randomized, parallel grouped) comparing the hemodynamic, antiischemic, metabolic and neurohumoral effects of tedisamil 100 mg b.i.d and atenolol 50 mg b.i.d. after a single dose and over 6 days of treatment. Tedisamil and atenolol produced a decrease in heart rate both at rest (day 1: –13.6 vs –15.4 bpm; p 〉 0.05; day 6: –14.8 vs –22.2 bpm; resp.; p 〉 0.05) and exercise (day 1: –9.1 vs –18.3 bpm; p = 0.001; day 6: –12.0 vs –24.8 bpm, resp.; p = 0.001), while anginal threshold increased. Cardiac output decreased with tedisamil and atenolol at rest (day 1: –1.01 vs –1.19 l/min; p 〉 0.05; day 6: –0.86 vs –1.10 l/min, resp.; p 〉 0.05) and exercise (day 1: –0.82 vs –1.28 l/min; p 〉 0.05; day 6: –0.65 vs –2.68 l/min, resp.; p = 0.03), while stroke volume remained unchanged. Right atrial pressure changed during exercise only: It decreased with tedisamil (–1.7 mm Hg) and increased with atenolol (+3.7 mm Hg). Mean pulmonary capillary wedge pressures decreased at rest (–0.5 mm Hg) and exercise (–6.9 mm Hg) in the tedisamil group, but tended to increase with atenolol on day 6 (rest: +1.7; exercise: +3.7 mm Hg) (p = 0.03). Arterial pressure decreased under atenolol treatment only. Exercise-induced plasma norepinephrine levels were reduced by tedisamil (–93 pg/ml) but elavated by atenolol (+172 pg/ml) (p = 0.001). As compared to atenolol, tedisamil produced a significant prolongation of QT c interval (+31 vs –8 ms) (p = 0.002) at initial values of 0.408 ± 0.018 s with PQ and QRS remaining unaltered. Conclusions: In the present study, tedisamil (100 mg b.i.d.) generated favorable hemodynamic, neurohumoral and antiischemic effects in patients with stable angina pectoris. The antiischemic efficacy of tedisamil, as measured by ST segment depression and angina threshold, is comparable to that of atenolol (50 mg b.i.d.).