KATP channel modulation in working rat hearts with coronary occlusion: effects of cromakalim, cicletanine, and glibenclamide

Abstract

(i) The anti-ischemic but not the anti-arrhythmic effect of cicletanine may involve opening of KATP. (ii) opening of KATP attenuates, inhibition of the channel exacerbates functional consequences of coronary occlusion, and (iii) KATP opening attenuates reperfusion-induced VF, but it triggers ischemia-induced VF. KATP blocking does not affect VF.

A KATP channel opener inhibited myocardial reperfusion action potential shortening and arrhythmias

“…The rat isolated perfused heart has been used extensively to study the pharmacological modulation of arrhythmias. With this model, Ferdinandy et al (1995) demonstrated that a relatively low concentration of the K ATP opener cromakalim, delivered prior to ischaemia, was anti-arrhythmic during reperfusion, despite the fact that higher concentrations caused marked pro-arrhythmia during ischaemia. These findings were consistent with earlier preliminary data that we presented (Workman et al, 1994) from a similar model, but using a different K ATP opener.…”

“…Reperfusion arrhythmias are also considered to be important clinically, as highlighted by reports of patients in 4 whom serious ventricular arrhythmias occurred shortly after spontaneous relief of episodes of coronary spasm-induced silent ischaemia (Tzivoni et al, 1983), or in whom persistent arrhythmias followed successful thrombolysis (Goldberg et al, 1983), or during reperfusion of the whole heart after a period of surgically-induced ischaemic arrest (Rubin et al, 1985). Despite the potential importance of post-ischaemic reperfusion arrhythmias, the effects of pharmacological K ATP activation on these arrhythmias have been reported infrequently, especially in the absence of arrhythmias during the preceding phase of ischaemia (Ferdinandy et al, 1995; Tosaki et al, 1993; Tanaka et al, 1996). The rat isolated perfused heart has been used extensively to study the pharmacological modulation of arrhythmias.…”

“…In each of these studies, reperfusion arrhythmias only occurred if (and often 5 immediately after) the action potentials had shortened. Moreover, when reperfusion arrhythmias were inhibited, either by shortening the ischaemic insult (Coronel et al, 1992;Culling et al, 1984) or by means of ischaemic preconditioning (Coronel et al, 1992;Perchenet and Kreher, 1995), or with pharmacological agents, eg: with sotalol (Culling et al, 1984), there was an accompanying inhibition of the reperfusion-induced acute action potential shortening.We therefore hypothesised that the anti-arrhythmic effect during reperfusion of K ATP openers delivered at low concentration prior to ischaemia, as seen in the rat (Ferdinandy et al, 1995;Workman et al, 1994) might involve some alteration to the time course of associated changes in action potential repolarisation. To our knowledge, the effect of K ATP modulators on the action potential duration during reperfusion has not been reported previously in intact hearts.…”

“…Whilst several studies have shown 14 that K ATP openers can prevent triggered activity induced by agents such as Cs + (D'Alonzo et al, 1993), there are few reports of any effect of K ATP openers on post-ischaemic reperfusion arrhythmias, particularly in the absence of any pro-arrhythmic effect demonstrable during the ischaemic episode. Nevertheless, the K ATP openers cromakalim, nicorandil and NIP-121 [((+)-7,8-dihydro-6,6-dimethyl-7-hyroxy-8-(2-oxo-1-piperidinyl)-6H-pyrano[2,3-f]benz-2,1,3-oxadiazole)] have each been reported to be anti-arrhythmic during reperfusion (Ferdinandy et al, 1995;Kempsford and Hawgood, 1989; Tanaka et al, 1996). Moreover, in close agreement with a previous report on rat hearts (Ferdinandy et al, 1995), the present data show that pharmacological K ATP activation may be both pro-arrhythmic during ischaemia and anti-arrhythmic during subsequent reperfusion, depending only upon the concentration of the K ATP opener used.…”

“…Nevertheless, the K ATP openers cromakalim, nicorandil and NIP-121 [((+)-7,8-dihydro-6,6-dimethyl-7-hyroxy-8-(2-oxo-1-piperidinyl)-6H-pyrano[2,3-f]benz-2,1,3-oxadiazole)] have each been reported to be anti-arrhythmic during reperfusion (Ferdinandy et al, 1995;Kempsford and Hawgood, 1989; Tanaka et al, 1996). Moreover, in close agreement with a previous report on rat hearts (Ferdinandy et al, 1995), the present data show that pharmacological K ATP activation may be both pro-arrhythmic during ischaemia and anti-arrhythmic during subsequent reperfusion, depending only upon the concentration of the K ATP opener used.Furthermore, the present data highlight that whilst a K ATP opener at low concentration could attenuate reperfusion arrhythmias without significant pro-arrhythmia during ischaemia, this should be interpreted cautiously due to the recognised significant risk of pro-arrhythmia with these drugs.In the absence of drugs, ventricular action potentials recorded from intact hearts in the present study underwent a rapid, marked and significant but transient period of shortening during postischaemic reperfusion. The question arises, however, of how faithfully do suction electroderecorded potentials reflect the time course of transmembrane action potentials recorded from the same region (Ino et al, 1988).…”