The aim of this review is to provide basic information on the electrophysiological changes during acute ischemia and reperfusion from the level of ion channels up to the level of multicellular preparations. After an introduction, section II provides a general description of the ion channels and electrogenic transporters present in the heart, more specifically in the plasma membrane, in intracellular organelles of the sarcoplasmic reticulum and mitochondria, and in the gap junctions. The description is restricted to activation and permeation characterisitics, while modulation is incorporated in section III. This section (ischemic syndromes) describes the biochemical (lipids, radicals, hormones, neurotransmitters, metabolites) and ion concentration changes, the mechanisms involved, and the effect on channels and cells. Section IV (electrical changes and arrhythmias) is subdivided in two parts, with first a description of the electrical changes at the cellular and multicellular level, followed by an analysis of arrhythmias during ischemia and reperfusion. The last short section suggests possible developments in the study of ischemia-related phenomena.

Deletion of amino-acid residues 1505-1507 (KPQ) in the cardiac SCN5A Na(+) channel causes autosomal dominant prolongation of the electrocardiographic QT interval (long-QT syndrome type 3 or LQT3). Excessive prolongation of the action potential at low heart rates predisposes individuals with LQT3 to fatal arrhythmias, typically at rest or during sleep. Here we report that mice heterozygous for a knock-in KPQ-deletion (SCN5A(Delta/+)) show the essential LQT3 features and spontaneously develop life-threatening polymorphous ventricular arrhythmias. Unexpectedly, sudden accelerations in heart rate or premature beats caused lengthening of the action potential with early afterdepolarization and triggered arrhythmias in Scn5a(Delta/+) mice. Adrenergic agonists normalized the response to rate acceleration in vitro and suppressed arrhythmias upon premature stimulation in vivo. These results show the possible risk of sudden heart-rate accelerations. The Scn5a(Delta/+) mouse with its predisposition for pacing-induced arrhythmia might be useful for the development of new treatments for the LQT3 syndrome.

Background-Acquired QT prolongation enhances the susceptibility to torsades de pointes (TdP). Clinical and experimental studies indicate ventricular action potential prolongation, increased regional dispersion of repolarization, and early afterdepolarizations as underlying factors. We examined whether K ϩ -current alterations contribute to these proarrhythmic responses in an animal model of TdP: the dog with chronic complete atrioventricular block (AVB) and biventricular hypertrophy. Methods and Results-The whole-cell K ϩ currents I TO1 , I K1 , I Kr , and I Ks were recorded in left (LV) and right (RV) ventricular midmyocardial cells from dogs with 9Ϯ1 weeks of AVB and controls with sinus rhythm. I TO1 density and kinetics and I K1 outward current were not different between chronic AVB and control cells. I Kr had a similar voltage dependence of activation and time course of deactivation in chronic AVB and control. I Kr density was similar in LV myocytes but smaller in RV myocytes (Ϫ45%) of chronic AVB versus control. For I Ks , voltage-dependence of activation and time course of deactivation were similar in chronic AVB and control. However, I Ks densities of LV (Ϫ50%) and RV (Ϫ55%) cells were significantly lower in chronic AVB than control. Conclusions-Significant downregulation of delayed rectifier K ϩ current occurs in both ventricles of the dog with chronic AVB. Acquired TdP in this animal model with biventricular hypertrophy is thus related to intrinsic repolarization defects. (Circulation. 1999;100:2455-2461.)

Voltage clamp analysis of the transient outward (positive dynamic) current was performed in sheep Purkinje fibers at a pulse frequency of 1/min. 4-aminopyridine (4-AP, 1 mM) suppressed most of the transient outward current, thus revealing the slow inward current, isi, and an associated brief outward current ibo. The long lasting component of the current suppressed by 4-AP was labelled ilo. In the presence of 4-AP, ibo was suppressed either by caffeine 10 mM or when Sr was substituted for Ca, both conditions making isi clearly detectable. Mn ions suppressed both isi and ibo. Current decay was a monoexponential process for ibo (tau = 12 ms) and a two exponential process for ilo (tau 1 = 80-100 ms, tau 2 = 250-400 ms). The peak amplitude-Em relationships were different for the two currents. It was shown that the reversal potential of ilo was not measurable by the usual method probably because of the too fast activation-deactivation kinetics of the current. It is concluded that not one but two transient outward currents with different electrophysiological and pharmacological characteristics exist in the sheep Purkinje fiber. The reason of the caffeine-sensitivity of ibo is discussed.

According to the ionic theory of electrical activity the membrane potential depends on the unequal distribution of ions between the intraand extracellular phases, and on the relative permeability of the membrane towards them. For cardiac muscle the role played by sodium and potassium has been studied to some extent (see Hoffman & Cranefield, 1960) but that of chloride has received little attention. The present paper deals with the effects produced by the substitution for chloride ions of nitrate ions or large anions such as acetylglycinate and pyroglutamate. The results suggest that the contribution of chloride ions to the total membrane conductance is low in a resting fibre but increases when a fibre is depolarized. The findings and interpretations are in good agreement with those recently published by Hutter & Noble (1959). The main results of the present investigation have been reported in a preliminary communication (Carmeliet, 1959 inside, the other outside the fibre. The electrodes were filled with 3M-KCI and had a resistance between 10 and 20 MO. They were connected to the cathode-follower input of a differential amplifier by chlorided silver wires. In a series of experiments the relative membrane resistance was measured by passing current through a second micro-electrode within the same fibre. Square current pulses of about 100 msec duration were used which hyperpolarized the membrane, at a frequency of 4/sec. The distance separating the intracellular electrodes was small (50-100 ,) compared to the space constant of a Purkinje fibre (2 mm;Weidmann, 1952). The amplitude of the recorded potential changes could thus be squared to obtain relative values for the membrane resistance (Hodgkin & Huxley, 1947).In order to make measurements of membrane resistance at different membrane potentials the fibre was depolarized or hyperpolarized by means of a pair of external electrodes, as shown in Fig. 1. The bundle was pushed into a close-fitting hole in a Perspex block and solution was allowed to siphon along this part of the preparation. The two micro-electrodes were inserted at a distance of 1 mm from the hole. To insure that the recording micro-* Present address: