缺血预处理改善心脏收缩功能的效应与腺苷关系的研究

本研究旨在证实缺血预处理改善心脏收缩功能的作用及其与血浆腺苷水平的关系。采用家兔在体缺血预处理模型，观察了缺血预处理对心脏收缩功能（ＬＶＳＰ，＋ｄｐ／ｄｔｍａｘ）的影响以及血浆腺苷的变化。结果发现，缺血预处理可显著改善缺血再灌注损伤后的收缩功能，预处理组再灌注期血浆腺苷浓度明显高于对照组，改善作用可被腺苷受体拮抗剂８－苯基茶碱阻断。说明腺苷及腺苷受体在缺血预处理中起重要作用     

腺苷预处理和缺血预处理心肌保护效果对比研究

目的探讨心肌腺苷预处理和缺血预处理对离体大鼠心脏缺血/再灌注后心肌功能的影响。方法采用离体大白鼠工作心脏模型,比较腺苷预处理和缺血预处理对心肌缺血再灌前、后左室收缩压(LVSP)、左室舒张末期压(LVDEP)、左心室内压上升及下降最大速率(±dp/dtmax)、主动脉压(AP)、冠脉流量(CF)、心输出量(CO)、每搏心输出量(SV)和冠脉流出液乳酸脱氢酶(LDH),心肌三磷酸腺苷(ATP)含量、超氧化物歧化酶(SOD)活性、脂质过氧化物(LPO)含量及自灌注停搏液至完全停搏的时间(AT)。结果3组大鼠AT间差异有显著性意义(P<0.05),且Control组与其他两组间差异均有显著性意义(P<0.05)。3组大鼠停搏前、复跳后30minAP、LVSP、LVDEP、±dp/dtmax、SV、CF、Co间差异均有显著性意义(P<0.05)。3组大鼠ATP、SOP、LPO、LDH间差异亦均有显著性意义(P<0.05)。结论腺苷预处理和缺血预处理后产生相似的心肌保护作用,明显促进心肌缺血再灌后心肌功能的恢复,增进心脏的收缩功能、心肌ATP含量和SOD活性的恢复,减少LDH的漏出。腺苷预处理对心脏模拟体外循环的缺血再灌注损伤具有保护作用,具有临床应用价值。     

超速心室起搏预处理介导心肌保护作用的实验研究

为探讨超速心室起搏 (ventricularoverdrivepacing,VOP)预处理的心肌保护作用及其可能机制。将 2 0只兔随机分为 4组 :①对照组 :右心室留置起搏电极 70min ,1h后结扎冠状动脉左前降支 6 0min ,再放松 90min ,造成缺血再灌注模型。②起搏组 :缺血再灌注前予 5 0 0次 /分起搏右心室 10min× 5次 ,每次间歇 5min。③起搏 +8 苯茶碱 (8 PT)组 :缺血再灌注前使用腺苷受体阻滞剂 8 PT并右心室起搏。④ 8 PT组 :缺血再灌注前静脉注射 8 PT。各组动物于起搏前后或相应时段及缺血再灌注期测定血流动力学和腺苷含量的变化 ;以氯代三苯四氮染色测量各组心肌梗死面积百分比。结果 :起搏组心肌梗死面积百分比较对照组减少 5 1.5 5 % ,P <0 .0 1;缺血再灌注期 ,左室收缩及舒张功能均较对照组改善。起搏 +8 PT组和 8 PT组与对照组比较 ,在梗死面积百分比、左室功能等方面无显著差异。起搏组血清腺苷含量于预处理时一过性增高 ,并在缺血期再度明显增高。结论 :VOP预处理能缩小心肌梗死面积并改善左室功能 ,腺苷可能是其保护作用的机制     

腺苷及缺血后处理对兔缺血再灌注心肌的保护作用

目的 探讨腺苷对缺血再灌注后心肌的保护作用,及其与缺血后处理的关系.方法 40只健康大耳白兔,随机分为对照组、拮抗剂组、缺血后处理组、腺苷治疗组4组,每组10只.制备在体兔心肌缺血再灌注模型,检测心肌收缩功能指标,测量心肌梗死范围,观察缺血再灌注即刻应用腺苷及缺血后处理对兔缺血再灌注后心肌的影响.结果 腺苷治疗组和缺血后处理组与对照组和拮抗剂组相比,再灌注之后左室内压峰值、左室内压最大上升速率和左室内压最大下降速率的恢复率差异有统计学意义(P＜0.05);梗死范围均明显低于对照组和腺苷受体拮抗剂组(P<0.01);心肌酶学LDH和CK含量较对照组和腺苷受体拮抗剂组明显降低(P<0.01).结论 腺苷/腺苷受体途径是缺血后处理的重要途径之一,能够减轻缺血再灌注损伤,保护心肌.     

盐酸法舒地尔预处理联合缺血后处理对离体大鼠心肌缺血/再灌注的影响

目的 探讨Rho激酶抑制剂盐酸法舒地尔预处理联合缺血后处理对离体大鼠心肌缺血/再灌注的影响.方法 60只雄性Wistar大鼠,取出心脏,随机分为对照（Control）组、缺血后处理（IPO）组、小剂量法舒地尔预处理（LF）组、大剂量法舒地尔预处理（HF）组、小剂量法舒地尔预处理联合缺血后处理（LF＋ IPO）组、大剂量法舒地尔预处理联合缺血后处理（HF＋ IPO）组,各10只.采用Langendorff离体心脏流灌装置,行缺血30 min,再灌注120min,制备心肌缺血/再灌注模型.缺血后处理采用6×10s的再灌注/缺血循环,法舒地尔预处理于缺血前15 min分别以含有1 μmol/L、10 μmol/L的法舒地尔KH液灌注.记录各组血流动力学指标,测定心肌梗死面积,测定冠状动脉（冠脉）灌流液中超氧化物歧化酶（SOD）、丙二醛（MDA）含量.结果 LF＋ IPO组和HF＋ IPO组缺血后心功能明显改善、心肌梗死范围缩小、SOD活性升高、MDA含量降低,与Control组相比,P均＜0.01;HF＋ IPO组的上述各指标与IPO组和HF组相比,P均＜0.05.结论 法舒地尔预处理联合缺血后处理可减轻离体大鼠心脏缺血/再灌注损伤,同时大剂量法舒地尔预处理与缺血后处理两者联合应用时对缺血再灌注心肌有协同保护作用,其作用机制可能与两者提高机体抗氧化应激损伤的能力有关.     

远隔预处理和后处理对兔急性心肌缺血再灌注损伤的作用

目的探讨远隔预处理和后处理是否具有减轻兔心肌缺血再灌注损伤的作用及其机制。方法新西兰大白兔40只，随机平均分为4组：对照组、心肌缺血预处理组、肢体缺血预处理组和肢体缺血后处理组，分组进行干预。测定血浆磷酸肌酸激酶（CK）和丙二醛（MDA）活性及心肌梗死面积并检测组织髓过氧化物酶（MPO）活性。结果心肌缺血预处理组、肢体缺血预处理组和肢体缺血后处理组心肌梗死面积、再灌注末MDA活性、缺血组织MPO活性均明显低于对照组（均P〈0．01）。结论远隔预处理和后处理均有显著的心脏保护作用，其作用可能与减轻活性氧的损伤及抗氧化作用加强有关。     

非心脏缺血预处理对未成熟心肌和心肌间质保护作用的研究

目的 :研究非心脏缺血预处理对未成熟心肌和心肌间质的保护作用。方法 :建立动物离体心脏 L angendorff灌注模型 ,分为 4组 :1缺血 /再灌注 （I/R,n=6 ） ,离体心灌注 15 min转为工作心 15 min;2心脏缺血预处理组 （IPC,n=6 ） ,离体灌注 15 min转为工作心 15 m in,缺血 5 m in/再灌 5 min各 2次 ;3双下肢缺血预处理组 （DL- IPC,n=6 ） ,反复 3次阻断双下肢血流 5 min/松开 5 m in,建立离体心脏 L angendorff灌注模型 ,灌注 15 min转为工作心 15min;4肾缺血预处理组 （K- IPC,n=6 ） ,反复 3次阻断左肾动脉 5 m in/放开 5 min,建立离体心脏 L angendorff灌注模型 ,灌注 15 min转为工作心 15 min。然后各组全心缺血 45 min,恢复灌注 15 m in改为工作心 30 m in。以左室功能恢复、心肌含水量、血清肌酸激酶 （CK）和乳酸脱氢酶 （L DH）漏出率、心肌组织 ATP和丙二醛 （MDA）含量、超氧化物歧化酶 （SOD）活性、心肌羟脯氨酸 （HP）含量及血清内皮素 （ET）含量作为观察指标。结果 :IPC,DL- IPC及 K-IPC组左室功能恢复优于 I/R组 （P<0 .0 5 ） ,ATP含量、SOD活性、HP含量均优于 I/R组 （P<0 .0 1） ,心肌含水量低于 I/R组 （P<0 .0 5 ） ,MDA含量 ,CK,L DH漏出率及 ET含量均低于 I/R组 （P<0 .0 1）。结论 :非心脏缺血预处理与心脏缺     

腺苷预处理及后处理对兔窦房结缺血再灌注损伤致心律失常的影响

目的通过建立兔右冠状动脉缺血再灌注损伤模型,研究腺苷预处理和后处理对窦房结缺血再灌注所致心律失常的影响,探讨腺苷抗心律失常的心肌保护机理。方法家兔60只,随机分为:假手术组、缺血再灌注组、腺苷预处理组、腺苷后处理组,每组15只。通过结扎及放松右冠状动脉起始部建立在体兔窦房结缺血再灌注损伤模型,同步记录体表心电图,全程心电监护并分析心律演变情况,行心律失常评分。结果无论在缺血期还是再灌注期,腺苷预处理和后处理组心律失常评分较缺血再灌注组心律失常评分明显下降,但是预处理和后处理之间比较无显著差异。同时组织学检测亦观察到腺苷预处理及后处理后窦房结细胞损伤较缺血再灌注组轻。结论腺苷预处理及后处理皆可以降低缺血再灌注心律失常的发生,是减少心肌缺血再灌注损伤的机理之一。     

异氟烷预处理对离体大鼠心肌缺血再灌注损伤的影响

目的:采用Langendorff离体心脏灌注模型,研究异氟烷预处理对离体大鼠心肌缺血再灌注损伤的影响。方法:24只SD大鼠随机分为4组,每组6只,分别为缺血再灌注损伤组(IR组)、异氟烷预处理1组(IsoP 1组)、异氟烷预处理2组(IsoP 2组)和异氟烷预处理3组(IsoP 3组)。监测复灌后心功能恢复情况、冠脉流出液中磷酸肌酸激酶(CK)、乳酸脱氨酶(LDH)的释放量和心肌存活面积的变化。结果:复灌期间3组IsoP心脏各对应时间点的LVEDP均显著低于对照组(P<0.05~<0.01);再灌注30 min时IsoP各组LVDP的恢复均高于IR组(P<0.05),IsoP3组±dp／dtmax在再灌注30 min时的恢复百分比均高于IR组(P<0.05),IsoP1组+dp／dt max高于IR组(P<0.05);复灌后异氟烷预处理组各时间点的CK、LDH释放量均低于IR组(P<0.01);IsoP2组、IsoP1组和IsoP3组心肌存活面积百分比均高于IR组(P<0.01);预处理各组之间比较无显著性差异(P>0.05)。结论:IsoP对大鼠离体缺血再灌注心肌有保护作用,可以显著减轻心肌细胞的损伤,改善心功能,增加心肌存活面积。     

缺血预处理限制心肌梗塞范围的作用与腺苷受体的关系

本实验采用家兔在体缺血预处理模型(5分钟冠脉阻塞,10分钟再灌注后,30分钟冠脉阻塞,120分钟再灌注),观察了其对心肌梗塞范围的影响以及腺苷受体在缺血预处理机制中的作用.结果表明,缺血预处理可显著降低心肌梗塞范围(14.1%与对照组36.6%比较,P<0.01),而这一效应可被非特异性腺苷受体拮抗剂8-苯基茶碱所阻断(梗塞范围32.1%,P<0.01).提示缺血预处理的心肌保护作用与腺苷受体密切相关.     

Cellular Uptake and Intracellular Phosphorylation of GS-441524: Implications for Its Effectiveness against COVID-19

GS-441524 is an adenosine analog and the parent nucleoside of the prodrug remdesivir, which has received emergency approval for treatment of COVID-19. Recently, GS-441524 has been proposed to be effective in the treatment of COVID-19, perhaps even being superior to remdesivir for treatment of this disease. Evaluation of the clinical effectiveness of GS-441524 requires understanding of its uptake and intracellular conversion to GS-441524 triphosphate, the active antiviral substance. We here discuss the potential impact of these pharmacokinetic steps of GS-441524 on the formation of its active antiviral substance and effectiveness for treatment of COVID-19. Available protein expression data suggest that several adenosine transporters are expressed at only low levels in the epithelial cells lining the alveoli in the lungs, i.e., the alveolar cells or pneumocytes from healthy lungs. This may limit uptake of GS-441524. Importantly, cellular uptake of GS-441524 may be reduced during hypoxia and inflammation due to decreased expression of adenosine transporters. Similarly, hypoxia and inflammation may lead to reduced expression of adenosine kinase, which is believed to convert GS-441524 to GS-441524 monophosphate, the perceived rate-limiting step in the intracellular formation of GS-441524 triphosphate. Moreover, increases in extracellular and intracellular levels of adenosine, which may occur during critical illnesses, has the potential to competitively decrease cellular uptake and phosphorylation of GS-441524. Taken together, tissue hypoxia and severe inflammation in COVID-19 may lead to reduced uptake and phosphorylation of GS-441524 with lowered therapeutic effectiveness as a potential outcome. Hypoxia may be particularly critical to the ability of GS-441524 to eliminate SARS-CoV-2 from tissues with low basal expression of adenosine transporters, such as alveolar cells. This knowledge may also be relevant to treatments with other antiviral adenosine analogs and anticancer adenosine analogs as well.     

Adenosine triphosphate and adenosine: perspectives in the acute management of paroxysmal supraventricular tachycardia

Adenosine triphosphate (ATP) and adenosine exert strong and transient depressant effects on the sinoatrial and atrioventricular (AV) nodes of the human heart. The AV nodal effects of these drugs explain their high efficacy in either terminating AV re-entrant supraventricular tachycardia or in slowing ventricular rate during atrial tachyarrhythmias. Their very short half-life enables repeated administration of increased doses without reaching toxic effects and explains the transient character of their frequent but benign side effects. These agents represent a good alternative to verapamil in the acute management of paroxysmal supraventricular tachycardia both in infants and adults.     

三磷酸腺苷对房室结前向传导的影响与房室结前传功能的相关性研究

目的　评价三磷酸腺苷 (ATP)对房室结前向传导的影响与房室结前传功能的相关性。方法　选择 19例预激综合征行射频消融术后且房室结前传文氏点等于或大于 15 0次/分的患者 ,测量房室结前传功能 (前传文氏点、2 :1点)和有效不应期 ,在心房起搏时静脉推注ATP,直至 0 .3 0mg/kg或出现房室前传阻断。结果　房室结前传文氏点平均为 (3 0 5 .79± 4 5 .0 1)ms,前传 2 :1点平均为(2 62 .63±2 4 .5 5 )ms,房室结前传有效不应期平均为(2 3 5 .78± 5 9.2 4 )ms,阻断房室结前传所需ATP平均剂量为(0 .16±0 .0 5 7)mg/kg,总量平均为 (11.4±4 .5 3 )mg。房室结前传文氏点、2 :1点 (ms)与阻断其前向传导所需ATP剂量呈负相关 (r=- 0 .797,P <0 .0 1;r=- 0 .699,P <0 .0 1)。房室结前传有效不应期与阻断其传导所需ATP剂量呈负相关(r=- 0 .4 65 ,P <0 .0 5 )。结论　阻断房室结前向传导所需ATP与房室结前传功能、房室结前传有效不应期有明显相关性 ,房室结前传功能越好 ,房室结前传有效不应期越短 ,阻断房室结前传所需ATP剂量越大。     

Comparison of adenosine effects on atrioventricular node reentry and atrioventricular reciprocating tachycardias

Background: Adenosine is an established first line therapy for the treatment of narrow complex tachycardias. The two most common etiologies of paroxysmal supraventricular tachycardia (SVT) are atrioventricular node reentry tachycardia (AVNRT) and atrioventricular reciprocating tachycardia (AVRT). Hypothesis: We postulated that adenosine might have different effects on the termination of AVNRT vs. AVRT, and that these differences might assist in the noninvasive differentiation between these diagnoses. Methods: Fifty-nine patients referred for the diagnosis and treatment of SVT were included in the study. All patients had SVT induced during electrophysiology testing, and each patient received adenosine during SVT. The adenosine dose, time to tachycardia termination, and site of tachycardia termination were recorded. Seventeen patients required isoproterenol administration to initiate SVT. This subset of patients was compared with those not requiring isoproterenol. Results: There was no statistically significant difference in the adenosine dose or time to tachycardia termination when comparing patients with AVNRT with those with AVRT. All patients with AVNRT had termination of tachycardia in the antegrade direction with final activation in the atria. Patients requiring isoproterenol for tachycardia initiation experienced tachycardia termination significantly faster than those not requiring isoproterenol, although there was no difference in the dose of adenosine required for termination. Conclusion: These data demonstrate that patients with dual AV node physiology and AVNRT do not have altered sensitivity to adenosine compared with patients with AVRT and normal AV nodes. Further investigation will be required to determine the clinical utility of the significantly shorter time to tachycardia termination for patients receiving isoproterenol.     

Effects of adenosine and xanthine derivatives on breathing during acute hypoxia in the anesthetized newborn piglet

Neonates of animals and humans exhibit a paradoxical ventilatory response to hypoxia characterized by an initial increase in minute ventilation followed by a late, sustained decrease. Exogenous adenosine analogues cause respiratory depression, and the xanthine derivative aminophylline, a competitive inhibitor of adenosine receptors, decreases the amount of hypoxic ventilatory depression in the newborn piglet. Other xanthine derivative such as enprofylline are weak adenosine antagonists. The purpose of this report is to test the hypothesis that enprofylline would not reverse ventilatory depression caused by hypoxia, supporting the suggestion that adenosine contributes to hypoxic ventilatory depression. To confirm the weak adenosine antagonism of enprofylline, L-N6-(phenylisopropyl)adenosine (PIA) was administered to six newborn piglets until respiratory depression was achieved. Either aminophylline or enprofylline was then administered. Aminophylline, but not enprofylline, reversed the respiratory depression caused by PIA. In seven additional piglets, respiratory depression was first produced by 10% oxygen breathing and the ability of saline, aminophylline, and enprofylline to reverse the decrease in ventilation was evaluated. The administration of either saline or enprofylline produced little change in minute ventilation (9.8% +/- 3.7% and -11.7% +/- 7.7%, respectively), whereas aminophylline consistently produced an increase (43.5% +/- 7.3% [P less than 0.001]). Both aminophylline and enprofylline increased heart rate (P less than 0.01), whereas saline produced no significant change. Blood pressure was increased by enprofylline but not by aminophylline or saline. These findings suggest that, in the anesthetized newborn piglet, adenosine contributes to ventilatory depression caused by hypoxia.     

On the Mechanism of Action of Theophylline and Caffeine

ABSTRACT Important developments in our understanding of the mechanism of action of methylxan-thines have taken place in the last 10 years. A brief overview of these developments is provided below and the author concludes that the common view that theophylline (and caffeine) acts by raising the levels of cyclic AMP is generally untenable. Instead, many of the actions of the methylxanthines can be explained on the basis of their being antagonists of endogenous adenosine. However the mechanism behind the antiasthmatic effects of xanthines still remains unknown and further research is necessary.     

Dose and Rate-Dependent Effects of Adenosine on Atrial Action Potential Duration in Humans

Adenosine provokes atrial fibrillation (AF) in some patients withparoxysmal supraventricular tachycardia (PSVT). Which patients are moresusceptible to develop atrial fibrillation after the administration ofadenosine to terminate PSVT is unknown. We prospectively measured atrialaction potential duration (APD) at incremental doses of 3, 6, and 12 mg ofadenosine at paced cycle lengths (CLs) of 600, 500, and 400 ms in 25patients. Bolus injection of adenosine decreased APD at 90%repolarization in a dose- and rate-dependent manner. During paced CLs of600, 500, and 400 ms, decreases of 8%, 13%, and 19% (p< 0.05), respectively, were found after bolus administration of 3 mg ofadenosine. After 6 mg of adenosine, the APD shortened by 12%, 19%, (p 0.05),and 27% (p < 0.01), respectively. After 12 mg of adenosine, the APDshortened by 15%, 27% (p < 0.05), and 38% (p < 0.01), respectively.Transient AF occurred in 4 of 25 (16%) patients, all during paced CLs of 400ms, and after adenosine 6 mg in one patient and 12 mg in three patients.Adenosine shortens atrial action potential duration in a dose- andrate-dependent manner. Whether patients with faster rates during PSVT andthose given higher doses of adenosine are more prone to develop atrialfibrillation remains to be determined.     

Adenosine: trigger and mediator of cardioprotection

Adenosine, a purine nucleoside, is ubiquitous in the body, and is a critical component of ATP. Its concentration jumps 100-fold during periods of oxygen depletion and ischemia. There are four adenosine receptors: A₁ and A₃ coupled to G_i/o and the high-affinity A_2A and low-affinity A_2B coupled to G_s. Adenosine is one of three autacoids released by ischemic tissue which are important triggers of ischemic preconditioning (IPC). It is the A₁ and to some extent A₃ receptors which participate in the intracellular signaling that triggers cardioprotection. Unlike bradykinin and opioids, the other two autacoids, adenosine is not dependent on opening of mitochondrial K_ATP channels or release of reactive oxygen species (ROS), but rather activates phospholipase C and/or protein kinase C (PKC) directly. Another signaling cascade at reperfusion involves activated PKC which initiates binding to and activation of an A₂ adenosine receptor that we believe is the A_2B. Although the latter is the low-affinity receptor, its interaction with PKC increases its affinity and makes it responsive to the accumulated tissue adenosine. A_2B agonists, but not adenosine or A₁ agonists, infused at reperfusion can initiate this second signaling cascade and mimic preconditioning’s protection. The same A_2B receptors are critical for postconditioning’s protection. Thus adenosine is both an important trigger and a mediator of cardioprotection. Returned for 1. revision: 17 September 2007 1. Revision received: 4 October 2007 Returned for 2. revision: 11 October 2007 2. Revision received: 16 October 2007