Delavirdine modifies action potential configuration via inhibition of IKr and Ito in canine ventricular myocytes

Abstract

Delavirdine is an anti-HIV agent with structural similarity (presence of methanesulfonamide group) to well-known rapid delayed rectifier potassium current (I_Kr) inhibitors like dofetilide and E-4031. In spite of this and the fact, that I_Kr blockade can lead to long QT syndrome with a risk of early afterdepolarization, cardiac arrhythmia and even sudden cardiac death development, there is no information on the cardiac electrophysiological effects of the delavirdine. Therefore, we examined the concentration-dependent acute effects of delavirdine on action potential morphology and on the underlying ion currents in enzymatically dispersed canine ventricular cardiomyocytes, as well as in a hERG-channel- and NaV1.5-expressing cell lines. Delavirdine application in the µM concentration range resulted in rapid, potent and reversible blockade of expressed hERG channels. NaV1.5 channels were slightly reduced by delavirdine. Moreover, APD increase, reduction of maximal rates of phases 1 and 3 and a small increase of Plateau20 amplitude were detected in canine left ventricular isolated cardiomyocytes in a concentration-dependent manner. Accordingly, the delavirdine-sensitive current contained an early and transient, as well as a late outward component corresponding to phases 1 and 3 of the AP. These results support the delavirdine-evoked inhibition of I_Kr, transient outward potassium current as well as sodium current. As these concentrations are similar to therapeutic plasma values (7–30 µM), delavirdine application might carry some risk of cardiac side effects especially in HIV-infected patients with altered cardiac function or patients with co-administration of drugs metabolized by certain cytochrome P450 isoforms.