U. Borchard

Effects of the calcium entry blocker bepridil on repolarizing and pacemaker currents in sheep cardiac Purkinje fibres

Summary(1) Effects of bepridil (0.3–100 μmol/l) on transmembrane currents which are active during the repolarization of the cardiac action potential were studied in sheep cardiac Purkinje fibres with the two-microelectrode voltage-clamp technique. Transmembrane currents were activated at a frequency of 0.03 Hz. (2) The initial inwardly rectifying current (iK1) was reduced by 1.8 μmol/l bepridil to 70% of the reference iK1-current in the absence of the drug. (3) An initial outward current, which is activated at positive membrane potentials (iinst) was depressed to 70% of reference by 14 μmol/l bepridil. (4) The time-dependent outward current (iK) was decreased by 1.8 μmol/l bepridil to 70% of its amplitude in the absence of bepridil. The biexponential time course of iK-current activation changed to be monoexponential with 100 μmol/l bepridil. The effect of bepridil on iK-current resulted in a shift of the activation curve of iK-current to more positive membrane potentials (10 μmol/l bepridil) and an additional decrease of driving force and/or conductance of the iK-channels with higher bepridil concentrations (100 μmol/l). (5) The transient outward current (ito) was completely blocked by 30 μmol/l bepridil. Inhibition to 70% of reference occurred with 1 μmol/l bepridil. The voltage-dependent inactivation of ito-current was affected by bepridil: the amplitude of the steady-state inactivation curve was reduced and ito-current was inactivated faster after application of bepridil. Bepridil caused no pronounced shift of the steady-state inactivation curve along the voltage axis. (6) The pacemaker current (if) was slightly increased under the influence of low bepridil concentrations (0.3, 1 μmol/l) while it was reduced to 70% of reference by 100 μmol/l bepridil. (7) The blocking action of bepridil on outward currents in sheep cardiac Purkinje fibres will explain the action potential prolongation, which is observed in different mammalian cardiac tissues under the influence of bepridil.

Effects ofβ-adrenoceptor antagonist administration on β2-adrenoceptors density in human lymphocytes

SummaryAbrupt withdrawal of β-adrenoceptor antagonists may lead to “rebound-effects”. To study the mechanism underlying this phenomenon, the effects of the nonselective β-adrenoceptor antagonists propranolol [no intrinsic sympathomimetic activity (ISA)], alprenolol (weak ISA) and mepindolol (strong ISA) on lymphocyte β2-adrenoceptor density — assessed by (±)-[125I]-iodocyanopindolol (ICYP) binding — and plasma renin activity (PRA) were investigated in male healthy volunteers aged 23–35 years.1.Propranolol treatment (4×40 mg/day) increased the density of β2-adrenoceptors by 25% after 2 days; concomitantly PRA and heart rate were reduced. During treatment β2-adrenoceptor density remained elevated. After withdrawal of propranolol PRA reached pre-drug levels rapidly, while heart rate was significantly enhanced. β2-Adrenoceptor density, however, declined slowly being still significantly increased after 3 days, although propranolol was not detectable in plasma after 24 h. The affinity of ICYP to β2-adrenoceptors was not changed during or after treatment.2.Mepindolol treatment (2×5 mg/day) caused a 30% decrease of β2-adrenoceptor density and PRA after 2 days; both parameters remained reduced during treatment. After withdrawal, PRA reached rapidly pre-drug levels, whereas β2-adrenoceptor density was still after 4 days significantly diminished. TheKD-values for ICYP, however, were not changed. During and after treatment heart rate was not affected.3.Alprenolol treatment (4×100 mg/day) led to a rapid fall in PRA, but did not significantly affect β2-adrenoceptor density.4.It is concluded, that the ISA may play an important role in modulating β2-adrenoceptor density and hence tissue responsiveness to β-adrenoceptor stimulation. Propranolol (no ISA) caused increase in β2-adrenoceptor density still persisting after withdrawal, which might explain the “propranolol rebound-effect”. Since β-adrenoceptor antagonists with ISA did not increase, but rather decrease β2-adrenoceptor density, such “rebound-effects” may not occur after rapid cessation of drug treatment.

Effects of (+)- and (±)-sotalol on repolarizing outward currents and pacemaker current in sheep cardiac Purkinje fibres

SummaryThis study was aimed to differentiate the action of (+)- and (±)-sotalol (10–1000 μmol/l) on membrane currents which are active during the repolarization of cardiac action potentials Effects where studied in shortened sheep cardiac Purkinje fibres with the two-microelectrode voltage-clamp technique Action potentials were activated at a frequency of 0.25 Hz and membrane currents at 0.03 Hz or 0.05 Hz in most experiments.Out of the currents investigated the transient outward current (ito) reacted most sensitively to (+)- and (±)-sotalol. Ito-amplitude was decreased on the average to 77% of reference at 10 μmol/l and to 53% at 1000 μmol/l (+)- or (±)-sotalol. The maximally available ito-current was decreased but the voltage-dependent control of inactivation was left nearly unchanged. The initial inwardly rectifying current (iKi), which propels the last repolarization phase of the action potential and controls resting potential to a large extent was reduced on the average to 93% of reference at 10 μmol/l and to 62% at 1000 μmol/l (+)- or (±)-sotalol. Time-dependent (delayed) outward current (iK) was on the average not affected by (+)- or (±)-sotalol up to 100 μmol/l and was decreased to 84% of reference current under the influence of 1000 μmol/l. An initial outward current, which is activated at positive membrane potentials (iinst) was not clearly affected by (+)- or (±)-sotalol at concentrations up to 1000 μmol/l Pacemaker current (if) was not influenced by the drugs up to 100 μmol/l. Only at 1000 μmol/l was the amount of available if-current decreased to 79% of reference. (The potential-dependent control of activation was not affected) Time constants of time-dependent currents ito, iK and if did not change in concentrations up to 1000 μmol/l of the drug.Action potential duration increased at (+)- or (±)-sotalol concentrations ≥ 10 μmol/l and maximal prolongation was achieved at concentrations of 100–300 μmol/l Resting potential remained nearly unchanged at these concentrations, but the membranes depolarized at 1000 μmol/l. According to our data action potential prolongation in sheep Purkinje fibres under the influence of (+)- and (±)-sotalol correlates to the drug-induced block to ito-current and inwardly rectifying iK1-current.

β-Adrenoceptor antagonists (non-selective as well as β1-selectiveβ2-adrenoceptor density in human lymphocytes

SummaryIn the present study the effects of pindolol [nonselective β-adrenoceptor antagonist with strong partial agonistic activity (PAA)] on β2-adrenoceptor density in lymphocytes (assessed by (-)-[125I]iodocyanopindolol (ICYP) binding) were compared with those of the β1-selective antagonists celiprolol (with PAA) and bisoprolol (no PAA) in normotensive young volunteers to get further insights into the nature of PAA.1)Administration of pindolol (2×5 mg/day) caused an about 25% decrease in lymphocyte β2-adrenoceptor density after 2 days; during treatment β2-adrenoceptor density declined further (maximum decrease after 7 days: 50%). After withdrawal of pindolol lymphocyte β2-adrenoceptor density recovered very slowly being still after 4 days significantly reduced, although no pindolol was detectable in plasma after 36 h. The KD-values for ICYP, however, did not change during or after pindolol treatment. The decrease in lymphocyte β2-adrenoceptor density induced by pindolol could be completely prevented by simultaneous administration of propranolol (3×40 mg/day) indicating that the PAA of pindolol is the cause of its β-adrenoceptor decreasing effect.2)Administration of the non-selective β-adrenoceptor antagonist bopindolol (1×2 mg/day) with PAA caused decreases in lymphocyte β2-adrenoceptor density (maximum decrease after 7 days: 40%); concomitantly the 10 μmol/l (-)-isoprenaline evoked increases in the intracellular level of lymphocyte cyclic AMP were attenuated to a similar extent indicating that the β-adrenoceptor antagonist-induced decrease in β-adrenoceptor density is accompanied by a loss in β-adrenoceptor function.3)Administration of the β1-selective antagonist celiprolol (1×200 mg/day) with PAA produced effects comparable to those of pindolol and bopindolol: during celiprolol treatment lymphocyte β2-adrenoceptor density and 10 μmol/l (-)-isoprenaline evoked cyclic AMP increases decreased significantly (maximum effect after 7 days: 35%). On the other hand, the β1-selective antagonist bisoprolol (1×10 mg/day) without PAA did not affect lymphocyte β2-adrenoceptor density which strongly supports the view that drug-induced changes in lymphocyte β-adrenoceptors are subtype-selective changes in β2-adrenoceptors.4)The celiprolol evoked reduction in lymphocyte β2-adrenoceptor density and 10 μmol/l (-)-isoprenaline evoked cyclic AMP increases were abolished by simultaneous administration of propranolol (3×40 mg/day), but not by concomitant application of the β1-adrenoceptor antagonist bisoprolol (1×10 mg/day).5)It is concluded that the PAA of β-adrenoceptor antagonists possesses a β2-agonistic component since all β-adrenoceptor antagonists with relatively strong PAA-irrespective of to whether they are non-selective (pindolol, bopindolol) or β1-selective (celiprolol)-decrease lymphocyte β2-adrenoceptor density. Whether the PAA of β-adrenoceptor antagonists is solely a β2-effect or tissuedependently a β1- or β2-effect, remains to be elucidatedIn the present study the effects of pindolol [non-selective beta-adrenoceptor antagonist with strong partial agonistic activity (PAA)] on beta 2-adrenoceptor density in lymphocytes (assessed by (-)-[125I]iodocyanopindolol (ICYP) binding) were compared with those of the beta 1-selective antagonists celiprolol (with PAA) and bisoprolol (no PAA) in normotensive young volunteers to get further insights into the nature of PAA. Administration of pindolol (2 X 5 mg/day) caused an about 25% decrease in lymphocyte beta 2-adrenoceptor density after 2 days; during treatment beta 2-adrenoceptor density declined further (maximum decrease after 7 days: 50%). After withdrawal of pindolol lymphocyte beta 2-adrenoceptor density recovered very slowly being still after 4 days significantly reduced, although no pindolol was detectable in plasma after 36 h. The KD-values for ICYP, however, did not change during or after pindolol treatment. The decrease in lymphocyte beta 2-adrenoceptor density induced by pindolol could be completely prevented by simultaneous administration of propranolol (3 X 40 mg/day) indicating that the PAA of pindolol is the cause of its beta-adrenoceptor decreasing effect. Administration of the non-selective beta-adrenoceptor antagonist bopindolol (1 X 2 mg/day) with PAA caused decreases in lymphocyte beta 2-adrenoceptor density (maximum decrease after 7 days: 40%); concomitantly the 10 mumol/l (-)-isoprenaline evoked increases in the intracellular level of lymphocyte cyclic AMP were attenuated to a similar extent indicating that the beta-adrenoceptor antagonist-induced decrease in beta-adrenoceptor density is accompanied by a loss in beta-adrenoceptor function.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential changes in lymphocyte beta 2-adrenoceptor density by beta-blocker administration: role of intrinsic sympathomimetic activity.

To study the role of intrinsic sympathomimetic activity (ISA) in beta-blocker-induced changes of beta-adrenoceptors, the effects of administration of several beta-blockers for 9 days on lymphocyte beta 2-adrenoceptor density--assessed by 125iodocyanopindolol binding--were investigated in 47 normotensive volunteers. Propranolol (unselective; no ISA; 4 X 40 mg/day) increased beta 2-adrenoceptor density by 25-40%; after withdrawal beta 2-adrenoceptor density declined slowly, being still elevated for 3 days. In contrast, the unselective beta-blockers pindolol (ISA (isoprenaline = 1.0) = 0.39; 2 X 5 mg/day) and mepindolol (ISA = 0.27; 2 X 5 mg/day) decreased beta 2-adrenoceptor density by 50% and 35%, respectively, while alprenolol with weak ISA (=0.066; 4 X 100 mg/day) had no effect. Among the beta 1-selective blockers studied, celiprolol with ISA (=0.32; 1 X 200 mg/day) decreased beta 2-adrenoceptor density by 30% whereas bisoprolol without ISA (1 X 10 mg/day) had no effect. It is concluded that the ISA determines the direction and amount of beta-adrenoceptor alterations induced by beta-blockers. Furthermore, changes in human lymphocyte beta-adrenoceptors reflect subtype-selective changes in beta 2-adrenoceptors, since the beta 1-selective blocker bisoprolol without ISA--in contrast to propranolol--did not affect lymphocyte beta 2-adrenoceptors. Accordingly, the fact that the beta 1-selective blocker celiprolol with ISA decreased lymphocyte beta 2-adrenoceptors, is consistent with the hypothesis that celiprolol possesses in addition to its beta 1-antagonistic activity a beta 2-agonistic activity.

Electrophysiological characterization of histamine receptor subtypes in mammalian heart preparations

SummaryHistamine-induced electrophysiological effects have been investigated in guinea-pig left atria, papillary muscles and rabbit AV-nodal preparations by means of intracellular recording of action potentials, slow responses in the presence of 27 mmol/l (K+)o and voltage clamp experiments. Differentiation of the H-receptor subtypes was performed by the use of the H2-selective agonists dimaprit and impromidine and the H1- and H2-selective antagonists dimetindene and cimetidine, respectively. The following results were obtained:1.Histamine and the H2-agonists dimaprit and impromidine show similar actions on electrophysiological parameters of ventricular myocardium. Histamine at concentrations <1 μmol/l leads to a small increase in APD30 and APD90, but to a marked decrease at concentrations ≥ 1 μmol/l, whereas

Effects of vanadate on isolated vascular tissue: biochemical and functional investigations.

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Effects of the bradycardic agent ZD 7288 on membrane voltage and pacemaker current in sheep cardiac Purkinje fibres

, resting potential and amplitude remain nearly unchanged. The effects on APD are completely blocked by cimetidine and not changed by dimetindene. Changes in action potential may be explained by an increase in slow inward current and outward currents as shown by voltage clamp experiments.2.In left atria histamine increases APD30 and APD90, whereas there is only a minor increase in amplitude with no changes in