A Voltage Clamp Study of the Effects of AR-L 115 BS on the Pacemaker Current of Cardiac Purkinje Fibres

Overview

Journal Basic Res Cardiol

Specialty Cardiology & Vascular Diseases

Date 1982 Sep 1

PMID 7181833

Authors

R Ziskoven

C Achenbach

J Wiemer

O HAUSWIRTH

Affiliations

Soon will be listed here.

Abstract

The new cardiotonic agent AR-L 115 BS was investigated by means of the double-micro-electrode voltage clamp technique on sheep cardiac Purkinje fibres. Clinical and pharmacological studies show that AR-L 115 BS increases heart rate as a side effect at medium to high therapeutic doses. The classical analysis of the pacemaker current was therefore performed to study the possible mechanism of this effect at a cellular level. The kinetic parameter s infinity and the reversal potential of the pacemaker current were shifted in the depolarizing direction after exposure to AR-L 115 BS. Peak values of the fully activated pacemaker current were either increased or diminished, while potassium leakage was slightly increased. These results are not related to the action of AR-L 115 BS on beta-adrenergic receptors but possibly due to enhanced intracellular calcium (see third paper in this series). Despite its tendency to increase heart rate, high concentrations of AR-L 115 BS should not be expected to promote arrhythmias in the Purkinje system since the electrophysiological effects tend to counteract each other.

References

Hashimoto K, HAUSWIRTH O, Wehner H, Ziskoven R . The relation between the current underlying pacemaker activity and beta-adrenoceptors in cardiac Purkinje fibres: a study using adrenaline, procaine, atenolol and penbutolol. Naunyn Schmiedebergs Arch Pharmacol. 1979; 307(1):9-19. DOI: 10.1007/BF00506546. View

Trube G, TRAUTWEIN W . Experiments with AR-L 115 BS on skinned cardiac fibers. Arzneimittelforschung. 1981; 31(1a):185-8. View

Ferrier G, MOE G . Effect of calcium on acetylstrophanthidin-induced transient depolarizations in canine Purkinje tissue. Circ Res. 1973; 33(5):508-15. DOI: 10.1161/01.res.33.5.508. View

DiFrancesco D, Ohba M, Ojeda C . Measurement and significance of the reversal potential for the pace-maker current (iK2) in sheep Purkinje fibres. J Physiol. 1979; 297(0):135-62. PMC: 1458712. DOI: 10.1113/jphysiol.1979.sp013032. View

Chapman J, Kootsey J, Johnson E . A kinetic model for determining the consequences of electrogenic active transport in cardiac muscle. J Theor Biol. 1979; 80(3):405-24. DOI: 10.1016/0022-5193(79)90101-2. View

Isenberg G . Cardiac Purkinje fibres: the slow inward current component under the influence of modified [Ca2+]i. Pflugers Arch. 1977; 371(1-2):61-9. DOI: 10.1007/BF00580773. View

DIEDEREN W, KADATZ R . Effects of AR-L 115 BS, a new cardiotonic compound, on cardiac contractility, heart rate and blood pressure in anaesthetized and conscious animals. Arzneimittelforschung. 1981; 31(1a):146-50. View

Kass R, Tsien R . Control of action potential duration by calcium ions in cardiac Purkinje fibers. J Gen Physiol. 1976; 67(5):599-617. PMC: 2214953. DOI: 10.1085/jgp.67.5.599. View

Siegelbaum S, Tsien R . Calcium-activated transient outward current in calf cardiac Purkinje fibres. J Physiol. 1980; 299:485-506. PMC: 1279238. DOI: 10.1113/jphysiol.1980.sp013138. View

10.

Isnberg G . Is potassium conductance of cardiac Purkinje fibres controlled by (Ca2+)?. Nature. 1975; 253(5489):273-4. DOI: 10.1038/253273a0. View

11.

McAllister R, Noble D, Tsien R . Reconstruction of the electrical activity of cardiac Purkinje fibres. J Physiol. 1975; 251(1):1-59. PMC: 1348375. DOI: 10.1113/jphysiol.1975.sp011080. View

12.

HAUSWIRTH O, Noble D, Tsien R . Adrenaline: mechanism of action on the pacemaker potential in cardiac Purkinje fibers. Science. 1968; 162(3856):916-7. DOI: 10.1126/science.162.3856.916. View

13.

HAUSWIRTH O, Singh B . Ionic mechanisms in heart muscle in relation to the genesis and the pharmacological control of cardiac arrhythmias. Pharmacol Rev. 1978; 30(1):5-63. View

14.

Herzig J, Feile K, Ruegg J . Activating effects of AR-L 115 BS on the Ca2+ sensitive force, stiffness and unloaded shortening velocity (Vmax) in isolated contractile structures from mammalian heart muscle. Arzneimittelforschung. 1981; 31(1a):188-91. View

15.

Kutter E, Austel V . Application of the theory of sets to drug design. Development of a new cardiotonic drug AR-L 115 BS. Arzneimittelforschung. 1981; 31(1a):135-41. View

16.

Attwell D, Eisner D, Cohen I . Voltage clamp and tracer flux data: effects of a restricted extra-cellular space. Q Rev Biophys. 1979; 12(3):213-61. DOI: 10.1017/s0033583500005448. View

17.

Isenberg G . Cardiac Purkinje fibres: resting, action, and pacemaker potential under the influence of [Ca2+]i as modified by intracellular injection techniques. Pflugers Arch. 1977; 371(1-2):51-9. DOI: 10.1007/BF00580772. View

18.

Isenberg G . Cardiac Purkinje fibres: [Ca2+]i controls steady state potassium conductance. Pflugers Arch. 1977; 371(1-2):71-6. DOI: 10.1007/BF00580774. View

19.

HODGKIN A, HUXLEY A . A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol. 1952; 117(4):500-44. PMC: 1392413. DOI: 10.1113/jphysiol.1952.sp004764. View

20.

Brown Jr R, Noble D . Displacement of activator thresholds in cardiac muscle by protons and calcium ions. J Physiol. 1978; 282:333-43. PMC: 1282742. DOI: 10.1113/jphysiol.1978.sp012466. View