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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 334 (1986), S. 294-302 
    ISSN: 1432-1912
    Keywords: H-receptor agonists ; Antihistamines ; Mammalian heart ; Action potentials ; Voltage clamp
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Histamine-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 $$\dot V_{\max } $$ , 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 $$\dot V_{\max } $$ and resting potential. These effects are completely reversed by the H1-antagonist dimetindene but not by cimetidine. IBMX decreases APD90 and does not potentiate the action of histamine. 3. $$\dot V_{\max } $$ of slow responses is increased in left atria by stimulation of H1-receptors and in papillary muscles by stimulation of H2-receptors. The results suggest that stimulation of atrial H1-receptors directly causes an increase in Ca-channel conductance. 4. Differentiation of the positive inotropic actions in left atria by means of TTX, diltiazem and vanadate suggests that histamine increases Ca-conductance but does not affect Na-dependent window current. 5. Histamine reduces AH-interval, increases $$\dot V_{\max } $$ of NH-cells and induces AV-arrhythmias at concentrations ≥ 1 μmol/l. The results indicate that these effects are due to stimulation of H2-receptors.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1420-908X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract H1-receptor reserves in guinea-pig left atria, trachea and pig coronary arteries were calculated by the use of phenoxybenzamine (Pba), a β-haloalkylamine that irreversibly blocks the H1-receptor response to histamine or 2-(2-pyridyl)-ethylamine (PEA). Equieffective concentrations of the H1-agonist in the absence (A) and presence (A′) of Pba were evaluated from concentration-response curves. By plotting the reciprocal values 1/A versus 1/A′ the amount of H1-receptors not occupied by the agonist was calculated. The size of the H1-receptor reserve could be estimated by comparison of the receptor occupation with the corresponding effect. Furthermore, the dissociation constants for histamine, PEA, Pba and the pD′2-values for Pba were determined for the different tissues. 5% and 6% H1-receptor occupation is necessary to achieve a half maximal contraction of the trachea with the agonists histamine and PEA, respectively. Only 0.5% H1-receptor occupation is needed for the half maximal positiv inotropic effect of histamine in left atria, while 5.5% of the H1-receptors have to be accupied using PEA as an agonist in this tissue. In the coronary artery of the pig 50% of the maximal contraction can be achieved by stimulation of 15.1% of the H1-receptors with histamine.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Inflammation research 18 (1986), S. 186-190 
    ISSN: 1420-908X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Electrophysiological investigations of histamine in different cardiac tissues have led to the following results: 1) Histamine and the H2-agonists dimaprit and impromidine show similar actions on electrophysiological parameters of ventricular myocardium (especially a decrease in action potential duration), which are completely blocked by cimetidine and enhanced by the phosphodiesterase inhibitor 1-methyl,3-isobutylxanthine (IBMX). These effects may be explained by an increase in cellular cAMP leading to an increase in slow inward current and outward currents as shown by voltage clamp experiments. 2) Histamine in contrast to IBMX increases action potential duration at 90% repolarization (APD90) in atria. Histamine effects in atrial myocardium are completely reversed by the H1-antagonist dimetindene. Stimulation of atrial H1-receptors is suggested to directly cause an increase in Ca-channel conductance independent of intracellular cAMP content. 3) Histamine reduces AH-interval, increases $$\dot V_{max} $$ of NH — cells and may induce AV — node arrhythmias (at concentrations ≥ 3 μmol/l). These effects remain unchanged by dimetindene, but are reversed by cimetidine. The results indicate that histamine increases AV — nodal conduction via H2-receptors. 4) Unspecific membrane actions of cimetidine are not observed up to 100 μmol/l. Dimetindene increases action potential duration (APD) in left atria and decreases $$\dot V_{max} $$ at concentrations ≥ 10 μmol/l. However, H1-antagonistic actions of dimetindene are already observed at concentrations 1,000 to 10,000 times lower (pA2—values 8.39–9.12) so that unspecific membrane actions are suggested not to occur on a therapeutic dose level.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 340 (1989), S. 696-704 
    ISSN: 1432-1912
    Keywords: Sheep Purkinje fibre ; Outward currents ; Pacemaker current ; (+)-Sotalol ; (±)-Sotalol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary This 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.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 339 (1989), S. 638-646 
    ISSN: 1432-1912
    Keywords: Sheep Purkinje fibre ; Voltage clamp ; Ionic outward currents ; Calcium entry blocker ; Bepridil
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: 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 (i K1) was reduced by 1.8 μmol/l bepridil to 70% of the reference i K1-current in the absence of the drug. (3) An initial outward current, which is activated at positive membrane potentials (i inst) was depressed to 70% of reference by 14 μmol/l bepridil. (4) The time-dependent outward current (i K) was decreased by 1.8 μmol/l bepridil to 70% of its amplitude in the absence of bepridil. The biexponential time course of i K-current activation changed to be monoexponential with 100 μmol/l bepridil. The effect of bepridil on i K-current resulted in a shift of the activation curve of i K-current to more positive membrane potentials (10 μmol/l bepridil) and an additional decrease of driving force and/or conductance of the i K-channels with higher bepridil concentrations (100 μmol/l). (5) The transient outward current (i to) was completely blocked by 30 μmol/l bepridil. Inhibition to 70% of reference occurred with 1 μmol/l bepridil. The voltage-dependent inactivation of i to-current was affected by bepridil: the amplitude of the steady-state inactivation curve was reduced and i to-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 (i f) 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.
    Type of Medium: Electronic Resource
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