Dispersion of repolarization following double and triple programmed stimulation. A clinical study using the monophasic action potential recording technique

To study the dispersion of ventricular repolarization following double and triple programmed stimulation and its correlation with the inducibility of ventricular arrhythmias, monophasic action potentials were simultaneously recorded from the right ventricular apex and outflow tract during programmed stimulation in 12 patients with ventricular arrhythmias and a normal QT interval. The time difference between the ends of the two monophasic action potentials were used as a measure of the dispersion of ventricular repolarization, which consists of the activation time difference and the monophasic action potential duration difference. During double and triple programmed stimulation, the dispersion of ventricular repolarization increased significantly with the shortening of the coupling interval but decreased slightly with the shortening of the preceding interval. The induction of the ventricular arrhythmias in these patients was invariably associated with a marked increase in the dispersion of ventricular repolarization. The maximal dispersion of ventricular repolarization was significantly larger in the seven patients with polymorphic ventricular tachycardia and/or ventricular flutter/fibrillation induced than in the four patients with monomorphic ventricular tachycardia induced. Analysis of the two components of the dispersion of ventricular repolarization revealed that the increased dispersion of ventricular repolarization was mainly caused by an increase in the activation time difference in the monomorphic ventricular tachycardia subgroup, and by increases in both the activation time difference and monophasic action potential duration difference in the polymorphic ventricular tachycardia/fibrillation subgroup. These findings suggest that increased dispersion of ventricular repolarization is one of the underlying mechanisms accounting for the myocardial vulnerability to ventricular arrhythmias and that repolarization disturbance is important for the genesis of polymorphic ventricular tachycardia/fibrillation.     

alpha 1-Adrenoceptor stimulation partially inhibits ATP-sensitive K+ current in guinea pig ventricular cells: attenuation of the action potential shortening induced by hypoxia and K+ channel openers

Effects of alpha 1-adrenoceptor stimulation on the action potential shortening produced by K+ channel openers (KCOs) or hypoxia and on the ATP-sensitive K+ current (IK.ATP) activated by KCOs were examined in guinea-pig ventricular cells by using conventional microelectrode and patch-clamp techniques. In papillary muscles, nicorandil (1 mM) or cromakalim (30 microM) markedly shortened the action potential duration (APD) (to 51 +/- 2% and 40 +/- 5% of each control value). Addition of 100 microM methoxamine, an alpha 1-adrenoceptor agonist, partially but significantly reversed the KCOs-induced APD shortening (to 69 +/- 3% and 50 +/- 4% of each control value). The APD-prolonging effect of methoxamine was antagonized by 1 microM prazosin (alpha 1-antagonist) and 100 nM WB4101 (alpha 1A-antagonist) but not by 10 microM chloroethylclonidine (alpha 1B-antagonist). In papillary muscles exposed to a hypoxic, glucose-free solution, APD declined gradually. In the presence of 100 microM methoxamine or 10 microM glibenclamide, the hypoxia-induced action potential shortening was significantly inhibited. In single ventricular myocytes, the KCOs increased a steady-state outward current that was abolished by glibenclamide (1 microM), thereby suggesting that these KCOs activate IK.ATP. Methoxamine (100 microM) significantly inhibited the nicorandil-induced IK.ATP by 18 +/- 5% and the cromakalim-induced IK.ATP by 16 +/- 2%. 4 beta-Phorbol 12-myristate 13-acetate (100 nM), a protein kinase C activator, failed to mimic the alpha 1-adrenoceptor-mediated inhibition of the nicorandil-induced outward current. Staurosporine (30 nM), a protein kinase C inhibitor, also failed to affect the partial inhibition of IK.ATP by methoxamine. Neither intracellular loading of heparin (100 micrograms/ml), an inositol 1,4,5-trisphosphate (IP3)-dependent Ca2+ release inhibitor, nor IP3 (20 microM) plus inositol 1,3,4,5-tetrakisphosphate (IP4 5 microM) could affect the inhibitory action of methoxamine. In conclusion, alpha 1A-adrenergic stimulation partially inhibits IK.ATP in cardiac cells. Neither protein kinase C activation nor IP3 formation appears to be involved in the partial inhibition of IK.ATP. The alpha 1A-adrenoceptor-mediated inhibition of IK.ATP may be deleterious for ischemic myocardium and partly offset the cardioprotective effect of KCOs because attenuation of action potential shortening may potentially increase Ca2+ influx in ischemic cells.