KATP channels and 'border zone' arrhythmias: role of the repolarization dispersion between normal and ischaemic ventricular regions

Abstract

1. In order to investigate the role of KATP channel activation and repolarization dispersion on the 'border zone' arrhythmias induced by ischaemia-reperfusion, the effects of glibenclamide and bimakalim, agents modifying action potential (AP) duration, were studied in an in vitro model of myocardial 'border zone'. 2. The electrophysiological effects of 10 microM glibenclamide and 1 microM bimakalim (n=8 each), respectively KATP channel blocker and activator, were investigated on guinea-pig ventricular strips submitted partly to normal conditions (normal zone, NZ) and partly to simulated ischaemic then reperfused conditions (altered zone, AZ). 3. By preventing the ischaemia-induced AP shortening (P<0.0001), glibenclamide reduced the dispersion of AP duration 90% (APD90) between NZ and AZ (P<0.0001), and concomitantly inhibited the 'border zone' arrhythmias induced by an extrastimulus (ES), their absence being significantly related to the lessened APD90 dispersion (chi2=8.28, P<0.01). 4. Bimakalim, which also reduced the APD90 dispersion (P<0.005) due to differential AP shortening in normal and ischaemic tissues, decreased the incidence of myocardial conduction blocks (25% of preparations versus 83% in control, n=12, P<0.05) and favoured 'border zone' spontaneous arrhythmias (75% of preparations versus 25% in control, P<0.05). 5. During reperfusion, unlike bimakalim, glibenclamide inhibited the ES-induced arrhythmias and reduced the incidence of the spontaneous ones (12% of preparations versus 92% in control, P<0.05), this latter effect being significantly related (chi2=6.13, P<0.02) to the lessened ischaemia-induced AP shortening in the presence of glibenclamide (P<0.0001). 6. These results suggest that KATP blockade may protect the ischaemic-reperfused myocardium from 'border zone' arrhythmias concomitantly with a reduction of APD90 dispersion between normal and ischaemic regions. Conversely, KATP channel activation may modify the incidence of conduction blocks and exacerbate the ischaemia-induced 'border zone' arrhythmias.

Figure 1

Effects of glibenclamide and bimakalim on action potential duration 90% (APD₉₀) in normal and ischaemic conditions. Data are expressed as mean±s.e.mean. APD₉₀ values were measured simultaneously on both normal zone (A) and altered zone (B) during 30 min of the ischaemic phase. Results of ANOVA (for repeated measures) are given for both treated groups: Glibenclamide 10 μM (n=8) and Bimakalim 1 μM (n=7), versus control (n=8). Note that glibenclamide lessened the ischaemic-induced action potential (AP) shortening (B) whereas bimakalim reduced APD₉₀ in normoxia (A) and worsened the AP shortening induced by ischaemia (B).

Figure 2

Effects of glibenclamide and bimakalim on the dispersion of action potential duration 90% (APD₉₀) between normal and ischaemic myocardial zones (A) and on the incidence of electrical disturbances during simulated ischaemia (B). In (A) data are expressed as mean±s.e.mean and the dispersion of APD₉₀ is represented by ratio APD₉₀ normal zone/APD₉₀ altered zone. Results of ANOVA (for repeated measures) are given for group and time factors. In (B), for each time interval (2 min) of the ischaemic period (30 min), values are expressed as a percentage of preparations presenting (i) conduction block between the two myocardial regions, (ii) Extrastimulus-induced repetitive responses and (iii) spontaneous arrhythmias. Patterns are shown in absence of drug (control) and in presence of 10 μM glibenclamide or 1 μM bimakalim. Note that the APD₉₀ dispersion between AZ and NZ was effectively lessened by glibenclamide, concomitantly with a reduced occurrence of arrhythmias. Note also that the APD₉₀ dispersion was slightly reduced in presence of 1 μM bimakalim and, concomitantly with a decreased incidence of conduction blocks, the occurrence of arrhythmias was not prevented.

Figure 3

Representative action potentials (APs) recordings illustrating the arrhythmia severity progressively worsened by 1 μM bimakalim during simulated ischaemia. APs were recorded simultaneously in normal zone (NZ) and altered zone (AZ). During the early phase of ischaemia (A, at 6 min), the Extrastimulus (ES) induced a unique repetitive response, namely an extrasystole following the ES-induced AP. As the simulated ischaemia prolonged (B, at 17 min), the ES-induced repetitive response became a salvos of four extrasystoles. Finally, during the late ischaemic period (C, at 28 min), the arrhythmia was a sustained spontaneous activity (frequency ≈10 Hz) which persisted in absence of stimulation.

Figure 4

Effects of glibenclamide and bimakalim on the incidence of conduction disturbances and arrhythmias during simulated reperfusion. For each time interval (2 min) of the reperfusion period (30 min), values are expressed as a percentage of preparations presenting (i) conduction blocks between the two myocardial regions, (ii) Extrastimulus (ES)-induced repetitive responses and (iii) spontaneous arrhythmias. Patterns are shown in absence of drug (A, control) and in presence of 10 μM glibenclamide (B) or 1 μM bimakalim (C). Note that, unlike bimakalim, glibenclamide prevented the occurrence of both spontaneous and ES-induced arrhythmic events.