These results may provide a clue to better understanding the physiological as well as the pathophysiological regulation of sphingosine 1-phosphate in the heart.
The purpose of this study was to assess the cardiovascular effects of an ultra-short-acting beta-blocker, ONO-1101, by using halothane-anesthetized beagle dogs in comparison with esmolol. ONO-1101 (n = 6) or esmolol (n = 6) was administered at four infusion rates of 0.3, 3, 30, and 300 microg/ kg/min. Each infusion was performed over a 30-min period, and the parameters were measured at 20-30 min after the start of each infusion. ONO-1101 significantly decreased the heart rate, rate-pressure product, left ventricular contraction, cardiac output, and relative refractory period of the right ventricle, suppressed the AV nodal conduction, and increased the effective refractory period of the right ventricle, whereas no significant change was observed in the preload and afterload of the left ventricle, intrinsic sinus nodal automaticity, His-Purkinje-ventricular conduction, and the monophasic action-potential duration of the right ventricle. The cardiovascular effects of esmolol were comparable to those of ONO-1101, except that the preload of the left ventricle was significantly increased, and the ventricular repolarization phase was shortened by 300 microg/kg/min of esmolol infusion. Meanwhile, ONO-1101 as well as esmolol significantly reduced the isoproterenol-induced increase in heart rate and ventricular contraction, but the inhibitory action of ONO-1101 was 6-8 times greater than that of esmolol. These results suggest that the suppressive effects of ONO-1101 on cardiovascular performance are significantly less potent than those of esmolol at equipotent beta-blocking doses.
ABSTRACT-The present study was designed to investigate what kinds of adaptation occurred in the canine chronic AV block model, which has been used to study torsade de pointes (TdP). Dogs at 7 -10 days (acute phase) and 28 -56 days (chronic phase) after AV block were assessed. Ventricular effective refractory period and monophasic action potential duration were prolonged in chronic animals compared with acute animals; moreover the electrically vulnerable period was prolonged in chronic animals. Non-specific IKr channel blocker cisapride (1 and 10 mg /kg, p.o.) was administered without anesthesia to estimate the feasibility of QT prolongation. In chronic animals, QT prolongation followed by TdP was induced in one dog by the low dose and in all by the high dose, which was not observed in acute animals. MR images indicated increases of diameter and wall thickness of both ventricles in chronic animals. The degree of hypertrophy was prominent in the right ventricular wall and septal wall. Heart weight of the chronic animals was 1.7 times greater than that of normal control subjects. Photo-and electron-micrograph analyses showed myocardial cell hypertrophy with parallel increases of collagen fiber and extracellular space in chronic animals. These electrophysiological, anatomical and histological adaptations may predispose the chronic AV block heart to drug-induced QT prolongation with enhanced risk of re-entry and early afterdepolarization, leading to the onset of TdP.Keywords: Long QT syndrome, AV block, Monophasic action potential, Holter ECG, MR image Since drug-induced prolongation of the QT interval is often associated with the onset of torsade de pointes (TdP), the interest in animal models of TdP arrhythmias has considerably increased (1, 2). The dog with chronic AV block has been used as a very suitable large-animal model for the study of TdP, both under conscious (3) and anesthetized circumstances (4 -10). Previous studies revealed that the functional adaptations predispose the canine AV block heart to acquired TdP (4, 6, 8 -10). Namely, QT interval and ventricular endocardial monophasic action potential (MAP) duration are much longer than expected from the bradycardia alone largely because of the reduction of IKs and IKr (4 -6). Moreover, early afterdepolarization and interventricular dispersion of repolarization have been suggested to play major roles in the genesis of acquired TdP (8 -10). However, it is still difficult to correlate the premature depolarization (trigger) and the dispersion of repolarization (substrate) to the occurrence of TdP.The present study was designed to investigate electrophysiological, anatomical and histological adaptation possibly related to the facilitated occurrence of TdP in the AV block heart. For this purpose, we first examined the local changes of the final repolarization phase of the action potential, since the spatial proarrhythmic substrates should locate in adjoining sites involved in the perpetuation of the arrhythmias (11). AV block was induced in dogs using a recently...
The sodium-calcium exchange (NCX) plays a pivotal role in regulating contractility and electrical activity in the heart. However, the effects of NCX blockers on ventricular arrhythmias are still controversial. We examined the effects of KB-R7943 (KBR) and SEA0400 (SEA), two NCX blockers, on aconitine-induced arrhythmias in guinea pigs using the ECG recordings and the current-clamp method. Using Luo's and Rudy's computer model (1991 Circ Res 68:1501-1526) for ventricular myocytes, we simulated abnormal membrane activity produced by NCX inhibition. In the whole-animal model, KBR in a dose range of 1 to 30 mg/kg (intravenous) suppressed aconitine-induced arrhythmias dose-dependently, but 10 mg/kg of SEA did not suppress these arrhythmias. There was a difference in isolated ventricular myocytes also. KBR (10 M) suppressed abnormal electrical activity induced by aconitine, but SEA (100 M) did not show such effects. KBR (10 M) significantly changed the shape of the action potential configurations (action potential duration at 50% repolarization), but SEA (1-100 M) did not change these configurations. In the computer simulation study, the aconitine-induced abnormal electrical activity was mimicked by a negative shift of the kinetics of Na ϩ channels, and this was followed by additional suppression of NCX activity by 90% (mimicking the effect of NCX inhibitors), which enhanced abnormal membrane activity. Our results indicate that the inhibition of aconitine-induced arrhythmias by KBR, not by SEA, might result from a mechanism other than the inhibition of NCX, and thus the involvement of the NCX system plays an insignificant role in the aconitine-induced arrhythmias.
The Na + -Ca 2+ exchange (NCX) system plays a pivotal role in regulating intracellular Ca 2+ concentration in cardiomyocytes, neuronal cells, kidney and a variety of other cells. It performs a particularly important function in regulating cardiac contractility and electrical activity. One of the leading NCX inhibitors is KB-R9743 (KBR) that appears to exhibit selectivity for Ca 2+ -influx-mode NCX activity (reverse mode of NCX). In this article we reviewed pharmacology of KBR and provide a brief summary of studies with other NCX inhibitors, such as SEA0400 (SEA) and SN-6 (SN). Potential clinical usefulness of KBR and other NCX inhibitors is still controversial but the reviewed findings may be helpful in designing more selective and clinically useful NCX inhibitors for the treatment of cardiac, neuronal and kidney diseases. the electrogenic movement of 3 Na + ions into and one Ca 2+ ion out of the cells (52,92), thus transporting net one positive charge (inward current) inside the cell per cycle. This movement is called the forward mode or Ca 2+ exit mode or Ca 2+ efflux mode operation of NCX.Under ischemic conditions, however, oxidative phosphorylation rapidly ceases, while anaerobic glycolysis, the net products of which are lactate and protons, is accelerating. This process leads to acidosis that decreases intracellular pH (pH i ). This intracellular acidosis increases [Na + ] i through the Na + -H + exchange (NHE) system or other sources of Na + entry (11). A rise in [Na + ] i , from whatever source, affects NCX by decreasing the driving force for Ca 2+ exit and/or increasing the driving force for Ca 2+ entry. This, in turn, leads to an increases in [Ca 2+ ] i favoring the entry of one Ca 2+ in exchange for 3 Na + ions out of the cells, thus moving net one positive charge (outward current) out of the cells per cycle. This process is called reverse mode, or Ca 2+ entry mode, or Ca 2+ influx mode of the NCX. This process of accumulation of Ca 2+ inside the cells leads to Ca 2+ overload that is observed with ischemia-reperfusion, ouabain-, veratridine-, or aconitine-induced arrhythmias and simulated ischemia in the whole animals, multi-cellular preparations and isolated myocytes of heart, brain or kidney (2)(3)(4)10,15,19,28,33,35,72,91,113,117,123). KBR is regarded as selective inhibitor of reverse mode of NCX. The role of NCX and the effects of KBR in each organ are described in respective sections.The purpose of the present review is to survey the recent progress in the research on a new class of drugs known as NCX inhibitors. KBR is the leading member of this class. This review article covers recent advances in the development and activity of KBR and briefly describes other NCX inhibitors, such as SEA0400 and SN-6. Additional information on NCX and KBR can be found in other reports (10,13,15,21,28,35,85,94,113,116).
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