异搏定(verapamil)对急性低压缺氧复合失血性休克狗的心血管功能和氧运送的影响

本文观察了Ca~(2+)通道阻断剂-异搏定(verapamil)对急性低压缺氧复合失血性休克狗的心血管功能和氧运送的影响。13只健康雄性家犬,在模拟4 000m(61.2kPa)高原低压舱内,复制失血性休克,低血压(5.33kPa)维持90min,然后把失血全部输回,比较异搏定对mAP、CI、LVWI、TPR、HR、LVSP及±dp/dt max以及DO_2、VO_2和MVO_2的影响。实验结果表明,急性低压缺氧复合失血性休克,异搏定对心血管功能的改善没有明显作用,但可提高全身和心肌耗氧量改善细胞代谢和减轻酸中毒,这可能与异搏定能减轻细胞线粒体内Ca~(2+)过负荷有关。     

Diltiazem or verapamil prevents haloperidol-induced apomorphine supersensitivity in mice

Summary Chronic thioridazine treatment in animals has been reported to produce less dopaminergic supersensitivity than other neuroleptics. This difference may be due to the potent calcium channel inhibitory effect of thioridazine. To test this hypothesis Swiss-Webster mice were treated chronically (28 d) with calcium channel inhibitors (CCI's) — diltiazem, nifedipine or verapamil — with or without haloperidol. Following three days of drug withdrawal, mice were tested for amphetamine-induced locomotion and apomorphine-induced cage climbing. Co-administration of diltiazem or verapamil (but not nifedipine) prevented the development of haloperidol-induced behavioral supersensitivity to apomorphine. Co-administration of CCI's with haloperidol did not affect the development of amphetamine supersensitivity. These data support the hypothesis that coadministration of haloperidol and a CCI (verapamil or diltiazem, but not nifedipine) would mimic the effects of thioridazine treatment alone.     

Identification of <Emphasis Type="Italic">I</Emphasis><Subscript>Kr</Subscript> Kinetics and Drug Binding in Native Myocytes

Determining the effect of a compound on I _Kr is a standard screen for drug safety. Often the effect is described using a single IC₅₀ value, which is unable to capture complex effects of a drug. Using verapamil as an example, we present a method for using recordings from native myocytes at several drug doses along with qualitative features of I _Kr from published studies of HERG current to estimate parameters in a mathematical model of the drug effect on I _Kr. I _Kr was recorded from canine left ventricular myocytes using ruptured patch techniques. A voltage command protocol was used to record tail currents at voltages from −70 to −20 mV, following activating pulses over a wide range of voltages and pulse durations. Model equations were taken from a published I _Kr Markov model and the drug was modeled as binding to the open state. Parameters were estimated using a combined global and local optimization algorithm based on collected data with two additional constraints on I _Kr I–V relation and I _Kr inactivation. The method produced models that quantitatively reproduce both the control I _Kr kinetics and dose dependent changes in the current. In addition, the model exhibited use and rate dependence. The results suggest that: (1) the technique proposed here has the practical potential to develop data-driven models that quantitatively reproduce channel behavior in native myocytes; (2) the method can capture important drug effects that cannot be reproduced by the IC₅₀ method. Although the method was developed for I _Kr, the same strategy can be applied to other ion channels, once appropriate channel-specific voltage protocols and qualitative features are identified. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

静脉注射钙拮抗剂对大鼠胰岛B细胞功能影响的实验观察

目的观察不同钙拮抗剂对Sprague Dawley（SD）大鼠胰岛B细胞功能的作用。方法将正常成年SD大鼠随机分成4组（每组8只）：对照组、维拉帕米组、地尔硫卓组及尼卡地平组。利用静脉糖耐量实验技术（intravenous glucose tolerance test,IVGTT）观察静脉注射不同钙拮抗剂对大鼠胰岛B细胞分泌功能的影响。结果与对照组相比,钙拮抗剂维拉帕米、地尔硫卓和尼卡地平组的＋血糖升高,早期时相的胰岛素分泌下降。结论静脉给予钙拮抗剂降压可能影响胰岛B细胞的分泌功能。     

Cardiomyocyte Ca<Superscript>2+</Superscript> overload in atrial tachycardia: is blockade of L-type Ca<Superscript>2+</Superscript> channels a promising approach to prevent electrical remodeling and arrhythmogenesis?

Electrical remodeling paradigm has important implications for the understanding of atrial fibrillation (AF) and improvement of current treatment. Cardiomyocyte Ca²⁺ overload is generally accepted as the initiating signal for the tachycardia-induced changes in atrial electrical properties (electrical remodeling). The precise role of cardiomyocyte Ca²⁺ overload in AF-related ion channel alterations that contribute to AF maintenance is not fully understood. Clinically, patients with AF are often treated with Ca²⁺ channel blockers such as verapamil to control their ventricular rate and to improve the success rate of cardioversion procedures. However, verapamil may produce an increased L-type Ca²⁺ channel current (I_Ca,L) that may reinforce Ca²⁺ overload thereby promoting AF in the atrium. Ca²⁺ channel blockers which target T-type Ca²⁺ channels in addition to I_Ca,L (for instance, efonidipine) may be more efficient at preventing Ca²⁺ overload and arrhythmogenic electrical remodeling, but the potential benefits of these drugs have usually been tested in experimental models where drug administration preceded the initiation of electrical remodeling. Studies in animal models with established atrial tachycardia remodeling and in patients with AF are clearly warranted to prove the efficacy of Ca²⁺ channel blockers that additionally target T-type Ca²⁺ channels.     

维拉帕米对缺血再灌注损伤心肌保护机制的探讨

目的 :探讨维拉帕米对缺血再灌注损伤心肌的保护作用及其机制。方法 :①建立家兔心肌缺血再灌注模型。将 2 4只家兔按再灌注时限的不同及是否给予维拉帕米 (0 .2mg/kg静脉注射 )干预分为 4组 (A1、A2、B1、B2 ) ,测定各组的心肌梗死范围 ,并在电镜下对缺血再灌注心肌进行超微结构观察。②根据心肌缺血再灌注不同时限对 33只家兔进行分组 ,采用免疫组化法检测同一剂量维拉帕米 (0 .2mg/kg静脉注射 )对缺血再灌注不同时限心肌组织bcl 2蛋白的表达情况。结果 :①与 0 .85 %氯化钠组比较 ,维拉帕米组可明显减小心肌梗死范围(P <0 .0 1) ,改善其超微结构的变化。②与假手术对照组和 0 .85 %氯化钠组比较 ,维拉帕米组能显著上调缺血再灌注心肌bcl 2蛋白的表达 (P <0 .0 1)。结论 :维拉帕米可明显减轻心肌缺血再灌注损伤 ,其心肌保护机制可能是通过其促进缺血再灌注心肌组织bcl 2蛋白的表达来实现的     

Molecular interactions, internal structure and drug release kinetics of rationally developed polymer–lipid hybrid nanoparticles

This paper presents the first study of molecular interactions of ingredients and internal nanostructure in relation to drug loading and release mechanisms/kinetics of rationally designed solid polymer–lipid hybrid nanoparticles (PLN). The PLN were prepared by using a rationally selected composition that was found in our previous work to provide optimized interactions of verapamil hydrochloride (VRP) with dextran sulfate sodium (DS) and then the VRP–DS complex with dodecanoic acid (DA). The solid-state properties of the components, their molecular interactions and the morphology, particle size and internal structure of PLN were determined by use of differential scanning calorimetry, powder X-ray diffraction, ¹³C nuclear magnetic resonance, Fourier transform infrared spectroscopy, transmission electron microscopy (TEM) and dynamic light scattering. The distribution of VRP in PLN was examined by TEM imaging using a cationic gold tracer. Drug release studies were conducted in various media. Drug loading as high as 36% and loading efficiencies up to 99% were achieved in the rationally formulated PLN. Hydrogen bonding between drug, polymer and lipid and a uniform distribution of amorphous VRP within the solid lipid matrix were evident. Sustained drug release from the PLN was mainly controlled by ion exchange and diffusion processes. The results demonstrated that strong molecular interactions among the drug, the polymer and the lipid in the optimized formulation were responsible for the improved drug loading and release performance of the PLN.