Intracellular Calcium Dynamics,Shortened Action Potential Duration,and Late‐Phase 3 Early Afterdepolarization in Langendorff‐Perfused Rabbit Ventricles

Calcium Dynamics, APD Shortening, and Late‐Phase 3 EAD. Introduction: To elucidate the mechanism of late‐phase 3 early after depolarization (EAD) in ventricular arrhythmogenesis, we hypothesized that intracellular calcium (Ca_i) overloading and action potential duration (APD) shortening may promote late‐phase 3 EAD and triggered activity, leading to development of ventricular fibrillation (VF). Methods and Results: In isolated rabbit hearts, we performed microelectrode recording and simultaneous dual optical mapping of transmembrane potential (V_m) and Ca_i transient on left ventricular endocardium. An I_KATP channel opener, pinacidil, was used to abbreviate APD. Rapid pacing was then performed. Upon abrupt cessation of rapid pacing with cycle lengths of 60–200 milliseconds, there were APD₉₀ prolongation and the corresponding Ca_i overloading in the first postpacing beats. The duration of Ca_i transient recovered to 50% (DCaT₅₀) and 90% (DCaT₉₀) in the first postpacing beats was significantly longer than baseline. Abnormal Ca_i elevation coupled with shortened APD produced late‐phase 3 EAD induced triggered activity and VF. In additional 6 preparations, the heart tissues were treated with BAPTA‐AM, a calcium chelator. BAPTA‐AM significantly reduced the maximal Ca_i amplitude (26.4 ± 3.5% of the control; P < 0.001) and the duration of Ca_i transients in the mapped region, preventing the development of EAD and triggered activity that initiated VF. Conclusions: I _KATP channel activation along with Ca_i overloading are associated with the development of late‐phase 3 EAD and VF. Because acute myocardial ischemia activates the I_KATP channel, late‐phase 3 EADs may be a mechanism for VF initiation during acute myocardial ischemia. (J Cardiovasc Electrophysiol, Vol. 23, pp. 1364‐1371, December 2012)     

贝伐单抗联合放射方案的实验研究

Objective To evaluate the impact of the hypoxia induced by bevacizumab on the antitumor effect in combining with irradiation in CNI-H441 xenografts in mice. Methods Bevacizumab of 5 mg/kg mouse for groups of control, bevacizumab alone, irradiation alone, earlier combination (EC), and later combination (LC) were initially injected peritoneally. Single irradiation of 14 Gy (122Sc γ-ray) was given at the 4th hour for the group of irradiation alone, 24th hour for EC group, and 72nd hour for LC group after the initial injection. Tumor hypoxia, micro vessels density and permeability of tumor vasculature,pathological responses, apoptosis, and tumor growth delay curve were evaluated after using bevacizumab and/or irradiation. Results Although it was lower than the control at the 24 hr after using bevacizumab (3. 1 × 106: 6.1 × 106 ;t = - 1.73 ,P > 0. 05), the HIF-1α rapidly increased to 3 - 4 times and 2 - 3 times of the control at day 3 (7.4 × 106: 20. 4 × 106; t = 2. 36, P < 0. 05) and lasted until day 10, which was consistent with the changes of tumor function vessels count. The count of residual micro vessel density count in LC group was higher than that in groups of EC and irradiation at day 3 after irradiation (9. 33: 3. 17;t =- 2. 43, P < 0. 05). The apoptotic count of tumor cells was lower in LC group than that in EC group (23.33: 43.83; t= 2.54, P< 0.05, at day 3 after radiation). Tumor growth delay time of LC groupwas shorter than that of EC groups (10. 5 days vs. 23. 0 days , t = 2. 67 , P < 0. 05) . Conclusions Hypoxia level induced by bevacizumab decreases the antitumor effect in later combination of bevacizumab and irradiaion. It shows a time window that determines whether the combination of bevacizumab and irradiation will be benefit or diverse.