Although parenteral administration of As(2)O(3) is highly effective in the treatment of acute promyelocytic leukemia, cardiac toxicity has been reported. This study employed Langendorff perfusion to ...determine the direct effects of As(2)O(3) in the electrophysiological properties of rabbit hearts after acute or chronic As(2)O(3) treatment (0.2 mg/kg/day iv for 30 days). Tissue accumulations of arsenicals and pathological changes as well as the reversibility of chronic As(2)O(3) effects were assessed. We found that cardiac conduction and repolarization were not altered whatsoever after acute As(2)O(3) treatment at clinically relevant (1, 3, and 10 microM) and higher (30 microM) doses. Nevertheless, an extremely high concentration of As(2)O(3) (300 microM) prolonged the corrected QT interval. Subsequent to chronic As(2)O(3) administration and with 30 microM As(2)O(3) via Langendorff perfusion, polymorphic ventricular tachycardia was observed (1/7, 14%). Corrected QT interval was prolonged, while basic cycle length was shortened. Significant accumulation of arsenicals in the cardiac tissue was found, but without any pathological changes. After As(2)O(3) was discontinued for 30 days, the chronic As(2)O(3) -induced electrophysiological changes improved, no ventricular arrhythmia was noted, and the tissue concentration of arsenicals decreased considerably. We therefore conclude that, although no immediate cardiac effects were discemable at clinically relevant doses, an extremely high concentration of As(2)O(3) could prolong ventricular repolarization. Chronic As(2)O(3) treatment resulted in a prolonged ventricular repolarization, in association with arsenicals accumulation and with risk of ventricular tachycardia. These chronic cardiac toxicities and the tissue accumulation of arsenicals were, however, partially reversible after cessation of As(2)O(3).
Parenteral administration of arsenic trioxide has recently been recognized as an effective antineoplastic therapy, especially for the treatment of acute promyelocytic leukemia. Its efficacy and ...toxicity are concentration-dependent and are related to the fractions of different arsenic species and the degree of methylation. In this study, arsenic trioxide was given parenterally to rabbits as a single dose or as a daily dose (0.2, 0.6, and 1.5 mg/kg) for 30 days. The blood and organ concentrations of the arsenic species, including As(III), dimethylarsinic acid (DMA), and monomethylarsonic acid (MMA), were studied on day 1 (single-dose study), day 30 (multiple dosing study), and day 60 (reversibility study). As(III) was the major detectable arsenic species in the blood. The pharmacokinetic parameters (total clearance, area under the curve, etc.) for As(III) indicated a limit for the capacity to eliminate As(III) at the dose of 1.5 mg/kg, and were quite the same after a single dose or chronic multiple dosing. In tissues, DMA was found to be the major metabolite and the concentrations of DMA, As(III), and MMA in general increased with the dose, with the increase most significant at a dose of 1.5 mg/kg. However, normalized tissue distribution of As(III) in the kidney on day 1, but not on day 30, was nonlinear. Along with decreased levels of As(III) and increased levels of DMA, an inducible capacity for methylating As(III) to DMA after chronic dosing in kidney was suggested. The tissue concentration of DMA was highest in lung and liver, and the normalized tissue distributions in liver on day 30 were nonlinear, suggesting a limit in eliminating DMA after a chronic high load of As(III). Tissue concentrations of As(III), DMA, and MMA in bladder increased dramatically after chronic dosing. However, after washout for 30 days, As(III), DMA, and MMA were all undetectable in bladder and liver. However, As(III) in hair and low levels of DMA in lung, kidney, heart and hair were still detected. In conclusion, in rabbits we found a similar pharmacological profile after a single dose or chronic multiple dosing of parenteral arsenic trioxide, with a limiting metabolizing capacity at a dose of 1.5 mg/kg. Tissue accumulation of arsenic species, mainly DMA, and its reversibility after washout were tissue-selective. The potential for late toxicities of arsenic trioxide in organs with a significant tendency for arsenic accumulation with low reversibility should be closely monitored.
Although cisapride is widely used to treat gastrointestinal motility disorders, it has been associated with QT prolongation, torsades de pointes, and cardiac arrest. Only in children, however, has ...atrioventricular (AV) block after cisapride been reported. This study used Langendorff perfusion to determine the direct effects of cisapride (0.03, 0.1, 0.3, and 1 microM) on the conduction properties of neonatal (<7 d) and adult (>3 mo) rabbit hearts. At a clinically relevant dose (0.03 microM), cisapride slowed the recovery of the His-Purkinje system. At 0.1 microM, the refractoriness of the His-Purkinje system and conduction through this system were prolonged. Corrected QT intervals and the ventricular refractory period were also lengthened. These parameters were significantly more prolonged in neonates than in adults. The level of AV block at rapid atrial pacing shifted from the AV node to the His-Purkinje system, with an ED(50) of 0.06 and 0.52 microM in the neonate and the adult, respectively. In the neonate, cisapride even resulted in infranodal AV block rhythm (ED50 = 0.12 microM), but this was not the case in the adult. Polymorphic ventricular tachycardia after cisapride was induced in one in seven neonates (14%;, 0.1 microM) and in one in seven adults (14%; 0.03 microM). It is concluded that cisapride may affect the refractoriness of cardiac tissue and that the His-Purkinje system seems to be the most sensitive. In neonatal hearts, this modification may, in fact, progress to infranodal AV block. Such susceptibility to cisapride strongly indicates that the therapeutic safety range used for the young heart should be narrowed.
Although parenteral administration of As
2O
3 is highly effective in the treatment of acute promyelocytic leukemia, cardiac toxicity has been reported. This study employed Langendorff perfusion to ...determine the direct effects of As
2O
3 in the electrophysiological properties of rabbit hearts after acute or chronic As
2O
3 treatment (0.2 mg/kg/day iv for 30 days). Tissue accumulations of arsenicals and pathological changes as well as the reversibility of chronic As
2O
3 effects were assessed. We found that cardiac conduction and repolarization were not altered whatsoever after acute As
2O
3 treatment at clinically relevant (1, 3, and 10 μM) and higher (30 μM) doses. Nevertheless, an extremely high concentration of As
2O
3 (300 μM) prolonged the corrected QT interval. Subsequent to chronic As
2O
3 administration and with 30 μM As
2O
3 via Langendorff perfusion, polymorphic ventricular tachycardia was observed (1/7, 14%). Corrected QT interval was prolonged, while basic cycle length was shortened. Significant accumulation of arsenicals in the cardiac tissue was found, but without any pathological changes. After As
2O
3 was discontinued for 30 days, the chronic As
2O
3 -induced electrophysiological changes improved, no ventricular arrhythmia was noted, and the tissue concentration of arsenicals decreased considerably. We therefore conclude that, although no immediate cardiac effects were discemable at clinically relevant doses, an extremely high concentration of As
2O
3 could prolong ventricular repolarization. Chronic As
2O
3 treatment resulted in a prolonged ventricular repolarization, in association with arsenicals accumulation and with risk of ventricular tachycardia. These chronic cardiac toxicities and the tissue accumulation of arsenicals were, however, partially reversible after cessation of As
2O
3.
We compared the direct effects of propofol on the conduction system of neonatal (< 7 days) and adult (> 3 mo) rabbit hearts using intracardiac recording/ stimulation in Langendorff-perfusion and ...autonomic blockade. At a low concentration (3 microM), propofol caused a slight but significant lengthening of the atrio-ventricular (AV) conduction interval of the adult hearts, but not of neonatal hearts. At a higher concentration (10 microM and above), propofol significantly prolonged the AV conduction interval in a frequency-dependent manner in both neonates and adults. The AV Wenckebach cycle length was also lengthened, with the change more significant in the adults. However, with concentrations of propofol up to 100 microM, the neonatal hearts frequently (9 of 13 experiments) progressed to complete AV block, which was not observed in the adults. Conduction through the atrial tissue (SA interval) and the His-Purkinje system (HV interval), as well as the spontaneous heart rate, were all slowed by propofol at 30 microM or above. However, the lengthening of SA interval was more pronounced in the neonates, and only in the neonate was the atrial refractory period prolonged by propofol at 10 microM and above. We conclude that 3 microM propofol produces no significant direct effects on the neonatal cardiac electrophysiological properties, although AV conduction of the adult heart may be suppressed at this concentration of propofol. At higher concentrations, age-related propofol effects were demonstrated in the AV node and the atrial tissue.
The pharmacological effects of HA-22 (2-(4'methoxyphenylmethyl)-3,4-dimethylpyrano2,3-cpyrazol- 6(2H)-one) and HA-23 (2-(2'-thienylmethyl)-3,4-dimethylpyrano2,3-cpyrazol-6(2H) -one) on rat isolated ...thoracic aorta have been examined. In high potassium medium (60 mM), Ca2+ (0.03-3 mM)-induced vasoconstriction was inhibited by HA-22 and HA-23 (10-100 micrograms mL-1). Cromakalim-relaxed aortic rings precontracted with 15 mM but not 60 mM K+. However, HA-22, HA-23 and verapamil produced a greater relaxation in 60 mM than in 15 mM K(+)-induced contraction. The tonic contractions elicited by KCl (60 mM) and Bay K 8644 (10(-7)M) were also relaxed by the addition of HA-22 and HA-23. The phenylephrine concentration-response curves displayed antagonism by HA-22 and HA-23 (10-100 micrograms mL-1) in a non-competitive manner. The caffeine (10 mM)-induced contraction and cAMP or cGMP levels were not affected by HA-22 or HA-23. It is concluded that HA-22 and HA-23 relaxed the rat aorta by suppressing the Ca2+ influx through both voltage-dependent and receptor-operated Ca2+ channels.
PDF
