Cardiovascular Drugs and Therapy 1993;7:547-554 © Kluwer Academic Publishers, Boston. Printed in U.S.A. Regulation of the Cardiac Delayed Rectifier K Current by Neurotransmitters and Magnesium H. Criss Hartzell I and Isabelle Duchatelle-Gourdon 2 ZHeartCell Laboratory, Department of Anatomy and Cell Biology, Emory University School of Medicine, Atlanta, GA and 2Laboratoire de Physiologie Animale et Bioinformatique, Universit~ de Caen, Caen, France Summary. The delayed rectifier K current plays an important role in cardiac electrophysiology: It is involved in the repolar- ization of the action potential and in frequency-dependent changes in action potential duration and waveform. The de- layed rectifier current I s is regulated by the autonomic ner- vous system: Beta-adrenergic agonists increase IK. This in- crease is due to an increase in the maximally activatable current as well as a shift of the activation curve to more negative potentials. Thus, in response to sympathetic nerve stimulation, the action potential would be expected to repo- larize more rapidly as a result of activation of more I K cur- rent and its activation at more negative potentials. Single- channel analysis suggests that the increase in I K is due to an increase in the availability of I K channels to respond to depolarization. IK is also regulated by internal free Mg 2+. When the internal solution contains high [Mg~+], I K de- creases, whereas low [Mg 2+ ] results in an increase in current. The effect of Mg 2+ is not detectably voltage dependent, sug- gesting that the mechanism of Mg 2+ action involves an allo- steric or enzymatic effect. Mg 2+ also affects the rate of wash- out of the response to beta-adrenergic agonists, suggesting that Mg~+ may be affecting the activity of a protein phospha- tase. Cardiovasc Drugs Ther 1993;7:547-554 Key Words. heart, delayed rectifier, K channels, beta- adrenergic agonists, patch clamp, calcium Beta-adrenergic agents have a variety of effects on cardiac contraction. The most notable effects are to increase the force and frequency of contraction and the rate of relaxation. These effects are mediated by the effects of these agents on many different effector systems. These effector systems include ion channels that are responsible for determining cardiac excitabil- ity and contractility (such as the voltage-gated Ca channel, delayed rectifier, If current, transient out- ward, chloride, and Na channels), phospholamban in the sacroplasmic reticulum, which regulates the activ- ity of the sarcoplasmic reticulum Ca pump, and sev- eral proteins in the contractile apparatus itself [1]. The increased rate of relaxation is due in part to an increase in the rate of repolarization of the cardiac action potential. One of the currents that is important in repolarization is the delayed rectifier current I K. For this reason, we have examined the effects of beta- adrenergic agonists on I K in isolated atrial myocytes from frog heart using the whole-cell and cell-attached single-channel configurations of the patch-clamp tech- nique. The data shown in this paper have previously been published [2-5]. Additional information can be obtained by consulting these references. A number of other laboratories [6-9] have made very important contributions to the understanding of the regulation of the delayed rectifier that is presented in this re- view. The delayed rectifier current is increased by beta- adrenergic stimulation (Fig. 1). In the upper panel of this figure are shown raw current traces in control and in the presence of isoproterenol. One can see that both Ica (the very rapid downward spike at the onset of the pulse on this time scale) and the outward I Kare increased by 0.3 ~M isoproterenol. The lower panel shows a diary of the time course of the effect of isopro- terenol on the amplitude of both IK and Ica. I Kis plot- ted in the upper part of the figure and Ic~ in the lower part. This figure shows two important points. First, IK and Ic~ are both increased by isoproterenol. Sec- ond, the two currents also can vary independently of one another. After patch break, I X runs down with time over the first 5 minutes, whereas Ic~ is stable. After exposure to isoproterenol, however, IK remains stably elevated while Ica runs down with time. It has been shown by Irisawa and colleagues [10] that I K in mammalian cardiac myocytes is also regu- lated by Ca-dependent processes. Thus, one might hy- pothesize that the increase in I Kis actually secondary to an increase in intracellular Ca due to the increase in Ica. However, the increase in I Kproduced by beta- Address for correspondence:H. Criss Hartzell, HeartCellLabora- tory, Departmentof Anatomy and CellBiology, EmoryUniversity Schoolof Medicine,Atlanta, GA30322. Received i August 1992, accepted in revisedform 5 March 1993. 547