Paradoxical Effect of Dofetilide on Action Potential Duration and Calcium Transient Amplitude in Newborn Rabbit Ventricular Myocytes

Abstract

The Na+-Ca2+ exchanger (NCX) is up-regulated in the neonatal rabbit heart. Because the duration of membrane depolarization is an important determinant of calcium entry via NCX, pharmacological agents that lengthen the action potential (AP) may significantly increase the amount of activator calcium in newborns. We tested this potentially novel therapeutic strategy by using action potential voltage clamp steps or using dofetilide, a blocker of IKr, to prolong the action potential duration (APD). The effects of changing APD on calcium transients were determined in ventricular myocytes at different developmental stages: newborn (1-4 days), juvenile (9-10 days), and adult ventricular myocytes (35 degrees C; 1 Hz). Calcium transient amplitude in neonatal myocytes increased substantially with clamping with longer APs. In contrast, exposure to dofetilide (0.1, 1, and 10 microM) under current clamp conditions increased APD in a concentration-dependent manner but had no significant effect on calcium transient amplitude in either neonates or adults. When the AP was held constant under voltage clamp conditions, dofetilide decreased the calcium transient amplitude in neonates. This effect is likely related to inhibition of sodium-calcium exchanger and L-type Ca2+ currents (ICa), as observed in separate experiments. These results suggest that dofetilide has a paradoxical effect on APD and calcium transients in the newborn heart.

The Teratogenic Effect of Dofetilide during Rat Limb Development and Association with Drug‐Induced Bradycardia and Hypoxia in the Embryo

“…Category D in Australia means drugs that have caused, are suspected to have caused—or may be expected to cause—an increased incidence of human fetal malformations or irreversible damage. Dofetilide selectively inhibits I Kr in the adult human heart and has been associated with QT interval prolongation when used therapeutically (Ficker etal., ; Srivastava etal., ).…”

Dofetilide Enhances the Contractility of Rat Ventricular Myocytes via Augmentation of Na+–Ca2+ Exchange

“…During a single twitch of a cell, a series of time frames of the contracting cell were accumulated on the CCD detector, digitized and transferred to a PC with a TILLvision 4.0 program for analysis. Cell shortening amplitude (μm) was calculated as the longest length of the cell while it was relaxing subtracted the shortest length when the cell was contracting [30][31][32].…”

Generation of a Homozygous Transgenic Rat Strain Stably Expressing a Calcium Sensor Protein for Direct Examination of Calcium Signaling

“…Disruption of the calcium homeostasis by pharmacological agents or pathological conditions correlate with various conditions, including prolonged QT intervals and arrhythmias in the heart 2 3 , or ischemic kidney injuries resulting in poor outcome for kidney transplantations 4 . In fact, several drugs with various mechanisms of action had to be withdrawn from the market because of side effects caused by disruption of the calcium homeostasis, including Clobutinol, a cough suppressant 5 , Dofetilide, an antiarrhythmic agent 6 , Grepafloxacin and Sparfloxacin, antibacterial agents 7 , Terfenadine, an antihistamine 8 , or Terodiline, a spasmolytic agent 9 . All these findings suggest that in the process of drug discovery an early prediction of toxicity requires the direct examination of the drug effects on cellular calcium homeostasis and signaling in different target tissues, especially in the heart.…”