Faculty Bibliography

INTRODUCTION: ATP-sensitive K+ channels (K(ATP)) are expressed abundantly in cardiovascular tissues. Blocking this channel in experimental models of ischemia can reduce arrhythmias. We investigated the acute effects of amiodarone on the activity of cardiac sarcolemmal K(ATP) channels and their sensitivity to ATP. METHODS AND RESULTS: Single K(ATP) channel activity was recorded using inside-out patches from rat ventricular myocytes (symmetric 140 mM K+ solutions and a pipette potential of +40 mV). Amiodarone inhibited K(ATP) channel activity in a concentration-dependent manner. After 60 seconds of exposure to amiodarone, the fraction of mean patch current relative to baseline current was 1.0 +/- 0.05 (n = 4), 0.8 +/- 0.07 (n = 4), 0.6 +/- 0.07 (n = 5), and 0.2 +/- 0.05 (n = 7) with 0, 0.1, 1.0, or 10 microM amiodarone, respectively (IC50 = 2.3 microM). ATP sensitivity was greater in the presence of amiodarone (EC50 = 13 +/- 0.2 microM in the presence of 10 microM amiodarone vs 43 +/- 0.1 microM in controls, n = 5; P < 0.05). Kinetic analysis showed that open and short closed intervals (bursting activity) were unchanged by 1 microM amiodarone, whereas interburst closed intervals were prolonged. Amiodarone also inhibited whole cell K(ATP) channel current (activated by 100 microM bimakalim). After a 10-minute application of amiodarone (10 microM), relative current was 0.71 +/- 0.03 vs 0.92 +/- 0.09 in control (P < 0.03). CONCLUSION: Amiodarone rapidly inhibited K(ATP) channel activity by both promoting channel closure and increasing ATP sensitivity. These actions may contribute to the antiarrhythmic properties of amiodarone

Clinical experience indicates that infants and young children respond to a variety of cardiovascular pharmacological and physiological interventions differently than adults. What is less clear, however, are the cellular and molecular mechanisms that contribute to these age-related differences. Based largely upon results from animal models, it is apparent that developmental changes occur in numerous pathways and proteins involved in the regulation of contractile function and in the determinants of inotropic responsiveness. The purposes of this review are to provide a brief overview of cardiac excitation-contraction and to illustrate some of the important age-related differences in the mechanisms involved in calcium regulation in the heart. This scientific foundation may help to explain certain clinical observations in the very young. Furthermore, it is hoped that a better understanding of the fundamental processes involved in controlling cardiac contractile function will stimulate additional research in the search for more specific, rational and age-appropriate cardiovascular therapeutics

The action of pharmacological openers of K(ATP) channels depends on the availability and levels of various intracellular nucleotides. Since these are subject to change during myocardial ischaemia, K(ATP) channel openers may affect ischaemic and non-ischaemic tissue differentially. Using a recently developed dual coronary perfusion method, we investigated the effects on arrhythmias of the prototypical K(ATP) channel opener levcromakalim when applied selectively to ischaemic and/or non-ischaemic tissue. A novel perfusion cannula was used to independently perfuse the left and right coronary beds of hearts isolated from rats. Selective infusion of levcromakalim (3, 10 or 30 muM) into the left coronary bed in the absence of ischaemia did not induce ventricular arrhythmias. Regional zero-flow ischaemia was induced by cessation of flow to the left coronary bed and hearts received levcromakalim selectively into either the left, right, or both coronary beds. When applied selectively to the ischaemic left coronary bed, levcromakalim (3, 10 or 30 muM; n=10/group) delayed the onset of ventricular tachycardia in a dose-dependent manner (by 21*, 43* and 112%* at 3, 10 and 30 muM; *P<0.05 vs. control). When applied only to the non-ischaemic right coronary bed, levcromakalim reduced the incidence of ventricular tachycardia during later phases of ischaemia (from 100% in controls to 30%*). When present in both coronary beds, levcromakalim had a striking anti-arrhythmic effect - the overall incidence of ventricular tachycardia being reduced from 100% in controls to 20%*. We conclude that levcromakalim may have an anti-arrhythmic effect when applied either to ischaemic or non-ischaemic tissue but that the mechanisms may differ depending on the metabolic state of the heart

Thyroid hormones play an important role in cardiac electrophysiology through both genomic and nongenomic mechanisms of action. The effects of triiodothyronine (T(3)) on the electrophysiological properties of ventricular myocytes isolated from euthyroid and hypothyroid rats were studied using whole cell patch clamp techniques. Hypothyroid ventricular myocytes showed significantly prolonged action potential duration (APD(90)) compared with euthyroid myocytes, APD(90) of 151 +/- 5 vs. 51 +/- 8 ms, respectively. Treatment of hypothyroid ventricular myocytes with T(3) (0.1 microM) for 5 min significantly shortened APD by 24% to 115 +/- 10 ms. T(3) similarly shortened APD in euthyroid ventricular myocytes, but only in the presence of 4-aminopyridine (4-AP), an inhibitor of the transient outward current (I(to)), which prolonged the APD by threefold. Transient outward current (I(to)) was not affected by the acute application of T(3) to either euthyroid or hypothyroid myocytes; however, I(to) density was significantly reduced in hypothyroid compared with euthyroid ventricular myocytes