COMBINED ADMINISTRATION OF AN I(K)(ATP) ACTIVATOR AND I(TO) BLOCKER INCREASES CORONARY FLOW INDEPENDENTLY OF EFFECTS ON HEART-RATE, QT INTERVAL, AND ISCHEMIA-INDUCED VENTRICULAR-FIBRILLATION IN RATS

The effects of combined administration of the ATP-dependent K+ channel opener cromakalim and the transient outward K+ current (I(to)) blocker tedisamil on ventricular tachyarrhythmias, QT interval, and coronary flow were investigated in isolated rat heart (n = 12/group) subjected to 30-min regional ischaemia. When administered alone, beginning 5 min before onset of ischaemia and continuously thereafter, neither cromakalim (10 muM nor tedisamil (3 muM had any significant influence on the incidence of VF, although tedisamil abolished sustained VF (SVF, defined as VF lasting >2 min). Cromakalim did not affect tedisamil's ability to abolish SVF when administered concurrently with tedisamil and had no effect on SVF when administered alone; incidences of SVF were 64, 0 (p < 0.05), 66, and 0% (p < 0.05) in control, tedisamil, cromakalim, and combined treatment groups, respectively. Occurrence of SVF was related to the width of the ventricular complex at 50% of repolarisation (QT50). Pretreatment with tedisamil widened QT50 (p < 0.05), and this effect was not attenuated by combined treatment with cromakalim. Cromakalim increased coronary flow (14 +/- 0.4 in controls versus 21 +/- 0.6 ml/min/g in cromakalim-treated hearts, p < 0.05). This effect was not reduced by coadministration of tedisamil (20 +/- 0.9 ml/min/g in hearts cotreated with both drugs). Tedisamil alone had no significant effect on coronary flow. In further studies (n = 60 hearts), tedisamil (3 muM administered 10 s after onset of VF was ineffective in terminating the arrhythmia; the incidence of ischaemia-induced SVF was 71% as compared with 80% in controls. Findings were similar for reperfusion-induced SVF. In 7 other hearts (not subjected to ischaemia), tedisamil significantly widened QT interval less-than-or-equal-to 1 min of its administration, but its effects had not reached a maximum 9 min later. This QT widening was diminished slightly when extracellular K+ concentration was increased from 3 to 8 mM so that it mimicked K+ levels reached during acute ischaemia. The combination of tedisamil and cromakalim appears to be of greater potential value in acute ischaemia than either drug alone since beneficial effects on VF (dependent on QT widening and presumably mediated by I(to) blockade) and a potentially beneficial increase in coronary flow (presumably mediated by opening of I(K(ATP)) channels) appear to occur independently of one another.