Mechanisms of action of beta-adrenergic agents on the arrhythmogenic transient inward current in rabbit Purkinje fibers.
Catecholamines increase the amplitudes of oscillatory afterpotentials (OAP) and peak magnitude of the transient inward current (Iti) responsible for OAP. The objectives of this study were to determine whether beta-adrenoceptor stimulation can induce Iti, and to determine the mechanism by which beta-adrenoceptor stimulation increases the magnitude of Iti. Experiments were performed using standard two electrode voltage--clamp techniques in isolated rabbit Purkinje fibers. Holding potential was either -50 or -80 mV. The Iti was elicited by repolarizing steps, following 1.5 or 3 s activating steps to potentials near 0 mV. Isoproterenol (ISO) failed to induce the Iti at concentrations from 10(-8) to 10(-6)M. However ISO (10(-7)M) significantly increased peak magnitude of spontaneously occurring Iti (P less than 0.05), or Iti induced by acetylstrophanthidin (AS) (P less than 0.05). ISO also shifted the minimum activation voltage 10 mV more negative (P less than 0.05). The current-voltage relationship demonstrated that ISO significantly increased the range of potentials over which Iti greater than or equal to 5 nA occurred, but did not significantly shift the voltage at which maximum peak current was observed. Effects of ISO on Iti were blocked by 10(-7)M propranolol or atenolol. Mn2+ (2 mM) or verapamil (2 microM) blocked the slow inward current (Isi) more than 80% before substantially decreasing peak Iti. Either agent blocked stimulation of Isi but not Iti by ISO at 10(-7)M. In contrast, quinacrine (20 microM), an inhibitor of Na(+)-Ca2+ exchange, abolished stimulation of Iti by ISO while having no significant effect on Isi. Our results indicate that beta-adrenoceptor stimulation cannot induce Iti in rabbit Purkinje fibers, but can enhance the Iti induced by other means, by stimulating Na(+)-Ca2+ exchange.
Han
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Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
Ferrier
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D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D066298:In Vitro Techniques; D007474:Ion Exchange; D007545:Isoproterenol / Q000494:pharmacology*; D007700:Kinetics; D008345:Manganese / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D011690:Purkinje Fibers / Q000187:drug effects / Q000378:metabolism*; D011796:Quinacrine / Q000494:pharmacology; D011817:Rabbits; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism
D011943:Receptors, Adrenergic, beta; D008345:Manganese; D012964:Sodium; D011796:Quinacrine; D007545:Isoproterenol; D002118:Calcium