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During heart failure (HF), cardiac metabolic substrate preference changes from fatty acid (FA) toward glucose oxidation. This change may cause progression toward heart failure. We hypothesize that a diet rich in FAs may prevent this process, and that dietary 3-FAs have an added antiarrhythmic effect based on action potential (AP) shortening in animals with HF.

Cardioprotection by KATPchannel openers during ischemia is well documented although ill understood. Proarrhythmic effects may be an important drawback. KATPchannel modulation influences neurotransmitter release during ischemia in brain synaptosomes. Therefore, we studied the effects of KATPchannel modulation on myocardial noradrenaline release and arrhythmias in ischemic rabbit hearts. Isolated rabbit hearts were perfused according to Langendorff and stimulated. Local electrograms were recorded and Kselective electrodes were inserted in the left ventricular free wall. Cromakalim 3 Mor glibenclamide 3 Mwas added 20 min prior to induction of global ischemia. After 15, 20, or 30 min of ischemia, hearts were reperfused and noradrenaline content of the first 100 ml of reperfusate was measured. Cromakalim n 16 prevented the second rise of extracellular K in accordance with its cardioprotective effect. Cromakalim significantly reduced noradrenaline release after 15 min mean, 169 ± SEM 97 pmolgr dry weight vs. control 941 ± 278 p < 0.05 and 20 min of ischemia 230 ± 125 pmolgr dry wt vs. control 1,460 ± 433 p < 0.05, but after 30 min of ischemia, the difference in noradrenaline release was no longer significant cromakalim 2,703 ± 1,195 pmolgr dry wt vs. control 5,413 ± 1,310 p 0.08. Ventricular fibrillation or ventricular tachycardia occurred in 10 of 13 control hearts 77 n19, in six of 10 glibenclamidetreated hearts 60 n 15, and in six of 14 cromakalimtreated hearts 43 p NS. Cromakalim significantly accelerated onset of ventricular tachycardia or fibrillation mean ± SEM onset after 12.5 ± 1.6 min ischemia vs. control 16.2 ± 0.7 min p < 0.05. Noradrenaline release occurred only in cromakalimtreated hearts with earlyonset arrhythmias whereas no noradrenaline release was observed in cromakalimtreated hearts without ventricular tachycardia or fibrillation. Our results show that activation of the KATPchannel by cromakalim during ischemia reduces myocardial noradrenaline release and postpones the onset of irreversible damage, contributing to the cardioprotective potential of KATPopeners during myocardial ischemia.

Adrenoceptor stimulation enhances repolarising and depolarising membrane currents to different extents in cardiac myocytes. We investigated the opposing effects of the repolarising Ca2+-activated Cl- current (ICl(Ca)) and depolarising L-type Ca2+ current (ICa,L) on the action potential configuration of sheep ventricular myocytes stimulated with noradrenaline. Whole-cell current-clamp recordings revealed that noradrenaline accelerated and prolonged phase-1 repolarisation. We define the minimal potential at the end of phase-1 repolarisation as 'notch level'. Noradrenaline (1 µM) caused the notch level to fall from 14 ± 2.6 to 7.8 ± 2.8 mV (n = 24), but left action potential duration, resting membrane potential or action potential amplitude unaffected. Whole-cell voltage-clamp recordings showed that 1 µM noradrenaline increased both ICa,L and ICl(Ca), but it had no significant effect on the principal K+ currents. Blockage of ICl(Ca) by 0.5 mM 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS) in both the absence and the presence of noradrenaline abolished phase-1 repolarisation. In the presence of noradrenaline, DIDS caused elevation of the plateau phase amplitude and an increase in the action potential duration. In conclusion, elevation of the plateau phase amplitude and action potential prolongation associated with an increased ICa,L upon adrenoceptor stimulation is prevented by an increased ICl(Ca) in sheep ventricular myocytes. Experimental Physiology (2001) 86.2, 151-159.

Adrenoceptor stimulation enhances repolarising and depolarising membrane currents to different extents in cardiac myocytes. We investigated the opposing effects of the repolarising Ca2+‐activated Cl−current (ICl(Ca)) and depolarising L‐type Ca2+current (ICa,L) on the action potential configuration of sheep ventricular myocytes stimulated with noradrenaline. Whole‐cell current‐clamp recordings revealed that noradrenaline accelerated and prolonged phase‐1 repolarisation. We define the minimal potential at the end of phase‐1 repolarisation as ‘notch level’. Noradrenaline (1 μM) caused the notch level to fall from 14 ± 2.6 to 7.8 ± 2.8 mV (n= 24), but left action potential duration, resting membrane potential or action potential amplitude unaffected. Whole‐cell voltage‐clamp recordings showed that 1 μM noradrenaline increased both ICa,Land ICl(Ca), but it had no significant effect on the principal K+currents. Blockage of ICl(Ca)by 0.5 mM 4,4′‐diisothiocyanatostilbene‐2,2′‐disulphonic acid (DIDS) in both the absence and the presence of noradrenaline abolished phase‐1 repolarisation. In the presence of noradrenaline, DIDS caused elevation of the plateau phase amplitude and an increase in the action potential duration. In conclusion, elevation of the plateau phase amplitude and action potential prolongation associated with an increased ICa,Lupon adrenoceptor stimulation is prevented by an increased ICl(Ca)in sheep ventricular myocytes.

The incidence of ventricular arrhythmias is higher in failing hearts than in control hearts, especially during acute ischemia. Electrophysiological and extracellular ionic changes during acute ischemia in normal and failing rabbit myocardium were assessed. Heart failure was induced in rabbits by combined volume and pressure overload. In perfused papillary muscles, the onset of electrical uncoupling and changes in action potential duration and conduction velocity during acute ischemia were determined. In Langendorff-perfused rabbit hearts the changes in extracellular potassium concentration ( [K+]0) and pH during acute global ischemia were studied. In perfused papillary muscles, during the first 10 min of ischemia, action potential duration at 80 % of repolarization decreased more in preparations from failing than from control hearts (from 174 to 104 ms and from 156 to 119 ms respectively (P<0.001)). Conduction velocity was significantly lower in failing hearts during ischemia (P<0.005). The onset of electrical uncoupling was similar in failing and control hearts (mean ±s.e.m., 17 ±1 and 15 ±1 min respectively, n.s.). Langendorff-perfused hearts [K+]0, after 10 min of ischemia, was 11.0 ±0.4 mmin failing and 9.5 ±0.3 mmin control hearts (P<0.01), while the change in pH was the same. After pretreatment with glibenclamide, an ATP sensitive K+channel blocker, [K+]0reached lower values after 10 min of ischemia in both failing (8.8 ±0.5 mm) and control hearts (7.2 ±0.4 mm). During ischemia, action potential duration shortening is more pronounced and conduction velocity is lower in failing myocardium than in control myocardium. [K+]0reaches higher values during acute ischemia in failing compared with normal myocardium. These changes are not caused by an earlier activation of IK,ATP. Increased spatial dispersion in electrophysiological parameters and [K+]0over the ischemic border in failing hearts may explain the higher propensity for reentrant arrhythmias during acute regional ischemia in failing hearts.