Electrophysiological effects or procainamide in acute and healed experimental ischemic injury of cat myocardium.

Abstract

SUMMARY. We studied the effects of a membrane-active antiarrhythmic agent, procainamide (PA), on cellular electrophysiological consequences of ischemic injury to cat ventricular muscle. The left ventricles of 90-to 120-minute acute myocardial infarctions (AMI) (n = 14), and 2-to 4-month healed myocardial infarctions (HMI) (n = 17), were studied by microelectrode techniques in isolated tissue bath. Control action potential duration at 90% repolarization (APD90) recorded from ventricular muscle cells in AMI areas were short (114 ± 4 msec) compared to recordings from cells in normal areas (136 ± 6 msec) (P < 0.001). In contrast, APD90 of cells surviving ischemia in HMI preparations were longer than normals (159 ± 5 vs. 140 ± 5 msec, P < 0.001). After 60 minutes of exposure to PA, the APD90 of all cells was prolonged, but the absolute and relative magnitudes of prolongation were greater in AMI cells (mean = +40 msec, +35%), than in HMI cells (mean = +19 msec, +13%), P < 0.001. The prolongation of APD90 of normal cells was intermediate. Local refractory period changes paralleled APD90 changes. In seven additional HMI preparations, sustained ventricular activity was induced by premature stimulation. APD90 of HMI cells prolonged less than APD90 of normal cells during exposure to PA in these preparations, and decreased differences of APD90 between normal and HMI cells was associated with loss of inducibility of sustained ventricular activity. The effect of tetrodotoxin (TTX) was compared to the effect of PA in four HMI preparations to determine whether impaired delivery of test substances caused only an apparent decreased responsiveness to PA in HMI zones. TTX caused nearly identical prolongations of conduction times in HMI zones and normal zones, whereas PA caused different effects on APD90 in the two zones. In conclusion, PA alters the time course of repolarization of AMI cells more than that of HMI cells, decreasing the dispersion of repolarization in a given AMI or HMI preparation. The decreased dispersion correlated with loss of ability to induce sustained ventricular activity. Finally, the decreased responsiveness of HMI cells to PA does not appear to be due to impaired delivery to cell membranes, but, rather, appears to be a membrane difference persisting in cells which have survived ischemic injury. (Circ Res 50: 386-393, 1982) IN STUDIES of experimental myocardial infarction in cats, we have observed that the cellular electrophysiological abnormalities resulting from acute ischemic injury (90-120 minutes) differ from those which persist long-term (2-4 months) after healing from acute injury (Myerburg et al., 1978; Myerburg et al., in press). Transmembrane action potentials recorded from endocardial cells overlying acute myocardial infarction areas had variable decreases in resting membrane potential, upstroke amplitude, and dV/dt m ax, and shortened action potential durations. In contrast, the majority of surviving endocardial ventricular muscle cells overlying healed myocardial infarction scars were charac...

Role of abnormal repolarization in the mechanism of cardiac arrhythmia

“…Finally, procainamide may promote arrhythmia by inducing multiple repolarization abnormalities. Procainamide has been shown to inhibit I Kr in rabbit ventricular myocytes and human embryonic kidney cells expressing the HERG channel, an effect translating to the dose‐dependent prolongation of ventricular APD in human patients and various animal models . This change can also contribute to excessive QT lengthening and increased torsadogenic risks during procainamide treatment, as mentioned above.…”

“…These changes are likely to account, at least in part, for the interindividual variability of cardiac responses (antiarrhythmic, proarrhythmic, or neutral) to procainamide seen in a clinical setting. In this context, careful consideration should be given to physiological factors that critically determine the amount of procainamide‐induced conduction slowing, such as myocardial ischaemia, fast heart rates, high extracellular K + levels, and the concomitant administration of other antiarrhythmic drugs …”

Dissimilarities in the electrophysiological abnormalities of lateral border and central infarct zone cells after healing of myocardial infarction in cats.

“…Grids (6-12 mm 2 ) were constructed to provide a consistent sampling technique to sample cells from normal, border, and central infarct myocardial tissues. This sampling technique was reported in detail elsewhere (Myerburg et al, 1977(Myerburg et al, , 1982a(Myerburg et al, , 1982b. Depending on the interelectrode distance (0.5-1.0 mm), 12-30 cells distributed evenly among the three zones were sampled within each recording grid.…”

“…Fishbein et al (1980), using histochemical techniques, demonstrated that the border and central infarct zones continuously change in size and character up to 72 hours after acute coronary occlusion in the rat. We have developed an experimental myocardial infarction model in the cat which maintains electrophysiological abnormalities after complete healing of infarction (Myerburg et al, 1977;Myerburg et al, 1982aMyerburg et al, , 1982b. The present study was designed to determine whether an electrophysiological endocardial border zone persists 2 months or longer after acute myocardial infarction in the cat.…”

Characteristics of IK and its Response to Quinidine in Experimental Healed Myocardial Infarction

“…In a report from this laboratory a number of years ago, we speculated that a potential mechanism of antiarrhythmic drug effect involves its reduction of heterogeneity by an effect on normal tissue with a limited effect on abnormal tissues. 22 Voltage clamp studies in multicellular and single cell cardiac preparations reveal that quinidine inhibits a number of ionic currents including-^N;r V' ^Ca' ^^ window current, pacemaker current (I,), and I,^,. (Reduction of plateau voltage in normal cells by quinidine in the present study may reflect its actions on one or more such currents.)…”