Analyses of the onset mechanisms of cardio-stimulatory action by aciclovir.

ABSTRACT

Cardio-stimulatory actions of aciclovir have been considered to primarily depend on the sympathetically-mediated reflex resulting from its hypotensive effect. To further clarify onset mechanisms of the cardio-stimulatory actions, we initially studied them using isoflurane-anesthetized dogs under thorough ß1-adrenoceptor blockade with atenolol (1 mg/kg, i.v.) (n = 4). Aciclovir (20 mg/kg/10 min, i.v.) decreased mean arterial blood pressure by 10 mmHg, whereas it increased heart rate by 10 bpm and maximum upstroke velocity of ventricular pressure by 928 mmHg/s, and shortened AH interval by 2 ms, indicating that cardio-stimulatory actions were not totally abolished by ß1-adrenoceptor blockade. Then, unknown mechanisms of cardio-stimulatory action were explored. Since aciclovir has a similar chemical structure to theophylline, in silico molecular docking simulation was performed, indicating aciclovir as well as theophylline possesses strong likelihood of interactions with phosphodiesterase 1A, 1C and 3A. Indeed, aciclovir inhibited phosphodiesterase 1A derived from the bovine heart (n = 4), moreover it exerted positive chronotropic action on the atrial tissue preparation of rats along with an increase of tissue cyclic AMP concentration (n = 4). These results indicate that cardio-stimulatory actions of aciclovir could result from not only hypotension-induced, reflex-mediated increase of sympathetic tone but also its inhibitory effects on phosphodiesterase in the heart.