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 β1-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 β1-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.
摘要:
阿昔洛韦的心血管刺激作用被认为主要取决于其降压作用引起的交感神经介导的反射。为了进一步阐明心脏刺激作用的起效机制,我们最初使用异氟醚麻醉的狗在彻底的β1-肾上腺素受体阻断与阿替洛尔(1mg/kg,i.v.)(n=4)。阿昔洛韦(20mg/kg/10分钟,i.v.)平均动脉血压降低10mmHg,而它使心率增加了10bpm,心室压力的最大上冲程速度增加了928mmHg/s,并将AH间隔缩短2ms,表明β1-肾上腺素受体阻滞剂并未完全消除心脏刺激作用。然后,研究了未知的心脏刺激作用机制.由于阿昔洛韦的化学结构与茶碱相似,进行了计算机分子对接模拟,表明阿昔洛韦以及茶碱具有与磷酸二酯酶1A相互作用的强烈可能性,1C和3A。的确,阿昔洛韦抑制来自牛心脏的磷酸二酯酶1A(n=4),此外,随着组织环AMP浓度的增加,它对大鼠心房组织的制备具有正变时作用(n=4)。这些结果表明,阿昔洛韦的心脏刺激作用可能不仅由低血压引起,反射介导的交感神经张力增加,但也对心脏磷酸二酯酶的抑制作用。