Assessment of local atrial repolarization in a porcine acetylcholine model of atrial flutter and fibrillation

Objectives: Progressive electrical alternans followed by conduction block and fibrillatory conduction have been suggested to precede disorganization of atrial flutter (Afl) to atrial fibrillation (AF). The purpose of the present study was to investigate patterns of local repolarization in the high and low right atrium to determine the site with pronounced propensity to action potential disorganization during Afl and AF. Methods: Combination pacing/recording contact monophasic action potential (MAP) catheters were utilized to evaluate repolarization from the upper and low atrial endocardium in 16 pigs.To induce sustained atrial flutter (Afl) or fibrillation (AF), programmed atrial stimulation was carried out prior to and during intravenous acetylcholine (ACh) infusion at a dosage rate of 2.7 mg/min.Atrial repolarization was measured at 30, 50, and 90% of total MAP duration. Results: Two main types of atrial MAPs were distinguished: MAPs originated from high atrial regions showing a prominent notch and longer duration and MAPs recorded from the lower atrium displaying a much slower slope of phase I repolarization and shorter duration. Control stimulation did not elicit any significant atrial tachyarrhythmias. After ACh all animals developed reproducibly induced sustained and non-sustained whole Afl or AF during programmed stimulation. A total of 40 sustained arrhythmia episodes were selected for evaluation: fourteen episodes of primary AF and 26 episodes of Afl.Whole Afl and AF in all animals were associated with MAPs of almost regular morphology in lower parts of atrium and disorganized activation in higher atrial regions. ACh significantly reduced (P<0.001) both high and low atrial effective refractory periods as well as MAP duration determined at 30, 50, and 90% repolarization. Conclusions: ACh facilitated the induction of Afl more than AF in this experimental model. MAPs recorded from high atrial regions revealed discordant repolarization during Afl or AF, whereas low atrial MAPs maintained their baseline regular morphology.These findings may help expand knowledge about mechanisms underlying instability and perpetuation of these arrhythmias

Assessment of local atrial repolarization in a porcine acetylcholine model of atrial flutter and fibrillation

Objectives - Progressive electrical alternans followed by conduction block and fibrillatory conduction have been suggested to precede disorganization of atrial flutter (Afl) to atrial fibrillation (AF). The purpose of the present study was to investigate patterns of local repolarization in the high and low right atrium to determine the site with pronounced propensity to action potential disorganization during Afl and AF. Methods - Combination pacing/recording contact monophasic action potential (MAP) catheters were utilized to evaluate repolarization from the upper and low atrial endocardium in 16 pigs. To induce sustained atrial flutter (Afl) or fibrillation (AF), programmed atrial stimulation was carried out prior to and during intravenous acetylcholine (ACh) infusion at a dosage rate of 2.7 mg/min. Atrial repolarization was measured at 30, 50, and 90% of total MAP duration. Results - Two main types of atrial MAPs were distinguished: MAPs originated from high atrial regions showing a prominent notch and longer duration and MAPs recorded from the lower atrium displaying a much slower slope of phase I repolarization and shorter duration. Control stimulation did not elicit any significant atrial tachyarrhythmias. After ACh all animals developed reproducibly induced sustained and non-sustained whole Afl or AF during programmed stimulation. A total of 40 sustained arrhythmia episodes were selected for evaluation: fourteen episodes of primary AF and 26 episodes of Afl. Whole Afl and AF in all animals were associated with MAPs of almost regular morphology in lower parts of atrium and disorganized activation in higher atrial regions. ACh significantly reduced (P < 0.001) both high and low atrial effective refractory periods as well as MAP duration determined at 30, 50, and 90% repolarization. Conclusions - ACh facilitated the induction of Afl more than AF in this experimental model. MAPs recorded from high atrial regions revealed discordant repolarization during Afl or AF, whereas low atrial MAPs maintained their baseline regular morphology. These findings may help expand knowledge about mechanisms underlying instability and perpetuation of these arrhythmias

Dose-related shortening of ventricular tachycardia cycle length after administration of the KATP channel opener bimakalim in a 4-day-old chronic infarct anesthetized pig model

Potassium channel openers are known to act on potassium ATP-dependent channels in cardiac tissue. Such agents may exacerbate acceleration of acute ischemia-induced ventricular repolarization and aggravate arrhythmias. To test whether activation of KATP channels during the healing period of myocardial infarction (MI) can still influence the electrophysiologic properties and the type of inducible arrhythmias, we investigated the effects of bimakalim (BIM) on sustained ventricular tachycardia (VT) 4 days after ligation of the left anterior descending (LAD) coronary artery in pigs. Programmed stimulation was performed to elicit VT prior to and after intravenous (IV) BIM. Combination monophasic action potential (MAP)/PACING catheters were used to enable simultaneous ventricular MAP recording and pacing. Ventricular effective refractory period (ERP) and MAP duration determined at 50% and 90% repolarization were measured prior to and after BIM. After completion of baseline measurements, BIM was consecutively given at 0.5, 1, and 3 mg/kg bolus followed by 0.025, 0.05, and 0.1 mg/kg per minute maintenance infusion, respectively. From a total of 23 pigs subjected to LAD ligation, 4 animals succumbed to infarction and the remaining 19 animals were studied by programmed stimulation. Only animals that exhibited reproducible and hemodynamically stable monomorphic VTs during control stimulation were selected for evaluation (n = 14). After the first, second, and third dose of BIM, the mean VT rate was increased by 6%, 14% (P &amp;lt;. 01), and 47% (P &amp;lt;.001) compared to control values, respectively. Ventricular ERP and repolarization were significantly shortened only by the second and third dose of BIM. Of 14 pigs receiving the highest BIM dosage, 3 revealed polymorphic VTs degenerating into ventricular fibrillation (VF). Our data suggest that high BIM doses may lead to faster and more aggressive pacing-induced reentrant VTs after subacute MI. This is consistent with the drug-induced acceleration of ventricular repolarization with shortening of MAP duration and refractoriness

Electrophysiological and mechanical properties of isolated rabbit heart papillary muscles and their correlation with nitric oxide (NO) and oxygen free radicals in hypovolemic shock blood plasma

We investigated the electrophysiological and contractile responses of isolated rabbit heart papillary muscles, to plasma from the blood of rabbits suffering severe hypovolemic shock (SP) and compared the production of oxygen free radicals and nitric oxide (NO) released as a result of the hypovolemic shock. Papillary muscles removed from the right heart ventricle of 11 rabbits, superfused in an organ bath with oxygenated (95% O-2 + 5% CO2) Tyrode solution at 37 degrees C were stimulated at a constant rate (1 Hz). The action potentials (APs) and contractions of papillary muscles were simultaneously recorded on a storage oscilloscope and photographed. SP exerted an intense negative inotropic effect on the papillary muscles accompanied by depression of the +V-max and prolongation of the fast and slow action potential duration. The effects of SP were reversible, to a large extent, when the extracellular calcium concentration was increased from 1.8 to 3.6 and 5.4 mM, or after washout. The recovery was completed within 15 min. Furthermore, NO levels increased by 50 times and SP antioxidant capacity declined by 50%. These results indicate that SP contained humoral factors that promoted the production of oxygen free radicals and NO in hypovolemic shock. The neutralisation of NO by superoxide (O-2(-)) leads to the formation of the noxious oxidant peroxynitrite (ONOO-) that may be responsible for the observed excitation-contraction uncoupling

Mechanisms of the action of zoledronic acid on human MG-63 osteosarcoma cells

The aim of our study was to analyze the action of zoledronic acid on MG-63 human osteosarcoma cells. The proliferation of MG-63 cells was inhibited by either continuous or pulsatile exposures of zoledronic acid in a dose-dependent manner (10-250 μM). Zoledronic acid did not produce evidence of MG-63 cell death when administered at 100 mM for 48 hours, but only after exposure of 96 hours. Zoledronic acid (100 μM) increased the distribution of MG-63 cells in G0/G1 phase, however, it did not increase the adriamycin-induced apoptosis. In addition, zoledronic acid action was partially neutralized by exogenous administration of geranylgeranyl pyrophosphate (GGPP), but not by farnesyl pyrophosphate (FPP). Furthermore, zoledronic acid resulted in the attenuation of the prenylated form of Ras. Zoledronic acid and EDTA increased fluorescence of Fluo-3 loaded MG-63 cells in a similar pattern. This increase was owing to the release of Ca2+ from intracellular stores since zoledronic acid failed to reveal such a change to intracellular Ca2+ when cells were previously treated with 1 mM caffeine. Moreover, zoledronic acid significantly decreased the expression of estrogen receptor α (ERα) whereas it did not change significantly the expression of estrogen receptor β (ERβ) in MG-63 cells. These data suggest that zoledronic acid can control the proliferation and the differentiation of osteosarcoma-like cells. © Georg Thieme Verlag KG Stuttgart