New antiarrhythmic drugs for atrial fibrillation: Focus on dronedarone and vernakalant

The prevalence of atrial fibrillation (AF) is forecast to rise to 2–5% of the general population by 2050. Of the two fundamental treatment strategies for AF management, rhythm control is the approach which is generally preferred for active, symptomatic, and/or younger patients, whereas rate control is all that is found necessary in the more elderly, sedentary, asymptomatic individual. In many cases, at neither extreme, there remains a genuine choice of therapy, and for those patients, antiarrhythmic strategies would be preferred if effective and safe antiarrhythmic medications were available. Many new antiarrhythmic agents exploiting new mechanisms of action or novel combinations of established antiarrhythmic activity are currently being investigated. Agents which selectively inhibit ion channels specifically involved in atrial repolarization, so-called atrial repolarization delaying agents, are widely acknowledged as potentially ideal antiarrhythmic treatments, as they will probably be both effective and safe, at the very least (free of pro-arrhythmic effects at the ventricular level). Modified analogues of traditional antiarrhythmic drugs with different combinations of ion channel and receptor blocking effects, novel mechanisms of action, and less complicated metabolic profiles are also under development. Completely innovative antiarrhythmic agents with new antiarrhythmic mechanisms, such as stretch receptor antagonism, sodium calcium exchanger blockade, late sodium channel inhibition, and gap junction modulation are also being explored. In addition, there is increasing evidence in support of the antiarrhythmic action of non-antiarrhythmic drugs. Treatments with statins, omega-3 fatty acids, angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, and aldosterone antagonists are all potentially valuable, over and above any effect related to the treatment of underlying heart disease. Professor A. John Camm is a consultant to AstraZeneca, Cardiome, sanofi aventis, and Xention.     

ZP123可预防右美托咪定延长心肌复极时程所致的负性变频效应

目的探讨缝隙连接改造剂ZP123对右美托咪定诱发鼠离体心脏复极时程延长所致的负性变频效应。方法健康成年SD大鼠18只,雌雄不拘,体重(300±30)g,制备Langendorff离体心脏灌注模型,K-H液平衡灌注15min后,随机分为三组,每组6只:空白对照组(C组)继续灌注37℃K-H液30min;右美托咪定组(D组)灌注含50ng/ml右美托咪定的K-H液30min,右美托咪定+ZP123组(ZD组)灌注含50ng/ml右美托咪定+80nmol/L ZP123的K-H液30 min。于平衡灌注15 min(T_o)、继续灌注15 min(T_1)、30 min(T_2)时记录HR和左心室心肌单相动作电位(MAP),计算MAP复极50%、90%的时程(MAPD50、MAPD90)、单相动电位振幅(MAPA)和最大去极化速度(Vmax)。结果与T_0时比较,T_1、T_2时D组HR明显减慢(P0.05),T_1、T_2时D组HR明显慢于C组和ZD组(P0.05)。与T_0时比较,T_1、T_2时D组心肌MAPD50、MAPD90明显延长(P0.05);T_1、T_2时D组心肌MAPD50、MAPD90明显长于C组和ZD组(P0.05)。三组心肌内外两层膜MAPA和Vmax组间组内差异均无统计学意义。结论缝隙连接改造剂ZP123通过缩短心肌单相动作电位复极的时程从而拮抗右美托咪定诱发的鼠离体心脏的负性变频效应。     

罗替加肽抑制糖尿病大鼠胃平滑肌自主收缩运动的实验研究

目的　探讨罗替加肽对糖尿病大鼠胃平滑肌自主收缩运动的影响及机制。方法　以链脲佐菌素诱导制备糖尿病大鼠模型,实验分为正常对照组和模型组。离体肌条实验观察罗替加肽处理前后2组大鼠胃平滑肌自主收缩运动的变化;Western blot法检测正常对照组、模型组及模型组经罗替加肽处理后（模型+罗替加肽组）的胃平滑肌组织膜蛋白和浆蛋白中连接蛋白43（Cx43）、蛋白激酶C（PKCα）的表达以及膜蛋白中p-Cx43 Ser368及p-PKCα Thr497的表达。结果　与正常对照组比较,模型组胃平滑肌自主收缩运动的振幅和频率均降低（均P＜0.05）。正常对照组与罗替加肽处理后（正常对照+罗替加肽组）比较胃平滑肌自主收缩运动振幅和频率无变化;罗替加肽处理后（模型+罗替加肽组）的胃平滑肌自主收缩运动振幅和频率较处理前（模型组）降低（均P＜0.05）。与正常对照组比较,模型组膜蛋白Cx43含量增加,浆蛋白Cx43含量降低,Cx43的膜浆比与膜蛋白p-Cx43 Ser368含量均增加（均P＜0.05）;模型+罗替加肽组与模型组相比,膜蛋白Cx43含量降低,浆蛋白Cx43含量增加,Cx43的膜浆比降低（P＜0.05）。与正常对照组比较,模型组膜蛋白PKCα含量降低,浆蛋白PKCα含量增加,PKCα的膜浆比及膜蛋白p-PKCα Thr497含量均降低（P＜0.05）;模型+罗替加肽组与模型组相比,膜蛋白p-PKCα Thr497含量增加（P＜0.05）。结论　罗替加肽可通过PKCα-Cx43通路下调缝隙连接数量及缝隙连接半通道开放率,抑制糖尿病大鼠胃平滑肌自主收缩运动。     

心室纤颤时心肌缝隙连接蛋白Cx43的变化

目的 观察心室纤颤(室颤)发生后缝隙连接蛋白Cx43的表达以及缝隙连接改造剂ZP123对Cx43表达的影响.方法 按照随机数字表法将30只家猪分为假手术组、模型组和ZP123干预组,每组10只.以80 V电压持续刺激动物5 s诱发室颤;致颤前15 min ZP123组给予ZP123 1μg/kg静脉推注+ZP12310μg·kg-1·h-1微量泵泵入;模型组泵入生理盐水50 ml;假手术组动物不致颤也不补液.室颤持续8 min后开胸取左心室游离壁心肌,用免疫荧光结合激光共聚焦显微镜技术检测Cx43的分布及水平,用蛋白质免疫印迹法(Western blotting)定量检测Cx43蛋白表达.结果 假手术组Cx43荧光信号强,分布均匀;模型组Cx43荧光信号弱,呈不均一分布;ZP123干预组Cx43荧光信号增强,不均一分布减轻.与假手术组比较,模型组心室肌组织Cx43荧光信号面积百分比、积分吸光度(A)值及蛋白表达均明显下降[面积百分比:(0.64±0.36)%比(1.27±0.19)%,积分A值:15 201±2 613比30 634±4 975,Cx43蛋白表达:0.72±0.08比0.97±0.07,均P＜0.05];与模型组比较,ZP123干预组Cx43表达[面积百分比(0.96±0.16)%,积分A值22 100±4 404,Cx43蛋白表达0.82±0.04]均明显升高(均P＜0.05).结论 室颤发生时心肌组织Cx43表达减少;应用ZP123可减少或逆转Cx43的降解.     

Discontinued drugs in 2008: cardiovascular drugs

This perspective is part of an annual series of papers discussing drugs dropped from clinical development in the previous year. Specifically, this paper focuses on the 16 cardiovascular drugs discontinued in 2008. Information for this perspective was derived from a search of the Pharmaprojects database for drugs discontinued after reaching Phase I – III clinical trials.     

Identification of ischemia-regulated phosphorylation sites in connexin43: A possible target for the antiarrhythmic peptide analogue rotigaptide (ZP123)

Previous studies suggest that dephosphorylation of connexin43 (Cx43) is related to uncoupling of gap junction communication, which plays an important role in the genesis of ischemia-induced ventricular tachycardia. We studied changes in Cx43 phosphorylation during global ischemia in the absence and presence of the antiarrhythmic peptide analogue rotigaptide (formerly known as ZP123). Phosphorylation analysis was performed on Cx43 purified from isolated perfused rat hearts using matrix-assisted laser desorption/ionization mass spectrometry and liquid chromatography electrospray ionization tandem mass spectrometry. Thirteen different serine phosphorylation sites were identified in Cx43 during non-ischemic conditions, three of which had not previously been described. Within the first 7 min of ischemia, Ser306 became fully dephosphorylated whereas Ser330 became phosphorylated. Between 15 and 30 min of ischemia, the critical time interval where gap junction uncoupling occurs, Ser297 and Ser368 also became fully dephosphorylated. During the same time period, all untreated hearts developed asystole. Treatment with rotigaptide significantly increased the time to ischemia-induced asystole and suppressed dephosphorylation of Ser297 and Ser368 at 30 min of ischemia. Our results suggest that phosphorylation of Ser297 and Ser368 may be involved in functional gating of Cx43 during ischemia and may be possible downstream targets for rotigaptide signaling.