Effects of dofetilide on cardiovascular tissues from normo- and hypertensive rats

Abstract

The aim was to test whether dofetilide has some potential for use in the treatment of heart failure. Dofetilide at ≤3 times 10−5 M had no effect on the quiescent Wistar Kyoto (WKY) rat aorta, mesenteric and intralobar arteries, or the spontaneous contractions of the WKY rat portal vein. Dofetilide at 10−6 to 3 times 10−5 M relaxed the KCl-contracted aorta. Dofetilide at 10−9-10−7 M augmented the force of contraction of left ventricle strips from 12- and 18-month-old WKY rats at 2 Hz. Spontaneously hypertensive rats (SHRs) at 12 and 17–21 months of age are models of cardiac hypertrophy and failure, respectively. The augmentation of force at 2 Hz with dofetilide was similar on 12-and 18-month-old WKY rats and 12-month-old SHRs but reduced on the 18-month-old SHR left ventricle. At a higher more physiological frequency, 4 Hz, the threshold concentration of dofetilide required to augment the force responses of 21-month-old SHR left ventricles was markedly increased and the maximum augmenting effect was decreased. Dofetilide at 10−7-10−5 M reduced the rate of the 17-month-old WKY rat right atrium, and had a similar effect on age-matched SHR right atrium. In summary, dofetilide is a positive inotrope and negative chronotrope in the rat. However, as the positive inotropic effect is not observed with clinically relevant concentrations at a physiological rate in heart failure, dofetilide is unlikely to be useful as a positive inotrope in the treatment of heart failure.