两种血管性痴呆模型大鼠学习记忆能力与海马自由基代谢的比较

目的 观察两种拟血管性痴呆(VD)模型大鼠学习记忆能力及海马组织自由基代谢变化.方法 采用线栓法和双侧颈总动脉结扎法分别制备大脑中动脉梗死(MCAO)和慢性脑低灌注型(CCA)VD模型,Morris水迷宫检测痴呆大鼠的学习记忆功能,生化法检测模型大鼠海马组织中谷胱甘肽过氧化物酶(GSH-Px)、超氧化物歧化酶(SOD)、丙二醛(MDA)的含量变化.结果 在训练的1～4 d,MCAO模型和CCA模型大鼠逃避潜伏期和游泳路径延长(P＜0.05,P＜0.01),CCA模型出现逃避潜伏期和游泳路径延长的时间早于MCAO模型(P＜0.05,P ＜0.01);MCAO模型大鼠的dP/dT和穿环次数均明显减少(P＜0.05,P＜0.01);MCAO模型与CCA模型大鼠海马组织MDA含量明显增加,SOD、GSH-Px的含量则明显下降(P ＜0.05,P＜0.01),两种模型MDA、SOD、GSH-Px含量变化无显著差别.结论 CCA模型大鼠空间记忆能力下降明显,而MCAO模型记忆保持能力较差,MDA、SOD、GSH-Px代谢参与了MCAO和CCA所致血管性痴呆的病理过程.     

补肾活血方对血管性痴呆小鼠行为学及脑海马自由基代谢的影响

目的 探讨补肾活血方对血管性痴呆小鼠学习记忆能力及自由基代谢的影响.方法 采用脑缺血再灌注法复制血管性痴呆小鼠模型,对补肾活血方与补肾方、活血方三组及对照组、模型组小鼠水迷宫法行为学及脑海马超氧化物歧化酶(SOD)活性和丙二醛(MDA)含量的变化进行对比观察.结果 与对照组比较,模型组小鼠学习与记忆能力下降,表现为游全程时间延长,错误次数增加(P＜0.01),脑海马SOD活性明显降低,MDA含量明显升高(均P＜0.01);与模型组比较,各治疗组学习成绩和记忆成绩均有明显提高(P＜0.01),脑海马SOD活性明显升高,MDA含量明显降低(P＜0.05或P＜0.01);各治疗组比较,补肾活血组的学习成绩与记忆成绩以及改善SOD活性和MDA含量方面均优于其他治疗组(P＜0.05或P＜0.01).结论 补肾中药、活血中药、补肾活血中药均可促进自由基代谢,改善血管性痴呆小鼠学习与记忆能力,且补肾中药与活血中药具有协同作用,补肾活血方疗效显著.     

二苯乙烯苷对血管性痴呆大鼠室管膜细胞增殖的影响

目的探讨二苯乙烯苷(TSG)对血管性痴呆(VD)大鼠海马血流量和脑室管膜细胞变化的影响。方法实验分为假手术组、模型组、TSG组,后两组采用4血管阻断法(4-VO法)建立VD大鼠模型。假手术组麻醉及手术过程与模型组相同,但不电凝双侧椎动脉,不阻断双侧颈总动脉。水迷宫法评价行为学。应用氢清除法检测大鼠海马血流量。用5-溴脱氧尿核苷(Brd U)免疫荧光染色,显微镜下观察室管膜下区(SVZ)干细胞增殖。结果与假手术组比较,模型组大鼠学习与记忆能力下降,表现为游全程时间延长,错误次数增加(P<0.01)。手术后7 d,与模型组比较,TSG组海马血流量明显提高和脑室管膜Brd U免疫荧光染色阳性细胞明显增加(P<0.01)。结论 TSG可改善VD大鼠海马血流量和促进脑室管膜细胞增殖。     

健脑口服液对血管性痴呆大鼠学习记忆及脑组织SOD、MDA和AchE活性的影响

目的观察健脑口服液对双侧颈总动脉结扎致痴呆大鼠学习记忆能力及脑组织中超氧化物歧化酶(SOD)、丙二醛(MDA)和乙酰胆碱酯酶(AchE)含量的影响。方法大鼠双侧颈总动脉反复夹闭再灌注同时腹腔注射硝普钠降压法建立血管痴呆(VD)大鼠模型,考察痴呆大鼠在水迷宫中学习、记忆成绩,测定脑组织SOD、MDA和AchE活性。结果与假手术组比较,痴呆模型组大鼠记忆成绩明显下降(P0.01),脑组织SOD含量下降(P0.01),MDA、AchE含量增加(P0.05);与痴呆模型组大鼠比较,健脑口服液中、高剂量组学习记忆成绩明显上升,脑组织SOD含量升高,MDA、AchE含量下降(P0.01)。结论健脑口服液升高VD大鼠脑组织SOD和AchE含量,降低MDA活性,增强VD大鼠学习记忆能力。     

竹节参总皂苷对血管痴呆大鼠递质氨基酸及自由基代谢的影响

目的观察竹节参总皂苷(TSPJ)对血管性痴呆大鼠学习记忆功能和递质氨基酸、自由基代谢的影响。方法双侧颈总动脉结扎制备血管性痴呆大鼠模型;Morris水迷宫检测各组大鼠学习记忆能力;ELISA法测定海马组织谷氨酸(Glu)及γ-氨基丁酸(GABA)的含量;生化方法检测海马组织谷胱甘肽过氧化物酶(GSH-Px)、超氧化物歧化酶(SOD)及丙二醛(MDA)的含量。结果 TSPJ可明显改善血管性痴呆大鼠学习记忆功能,提高海马组织GABA含量,降低Glu/GABA的比值,并可增加海马组织抗氧化酶GSH-Px、SOD活性,降低MDA含量。结论 TSPJ改善血管性痴呆大鼠学习记忆能力与调节脑Glu和GABA含量,改善自由基代谢有关。     

首乌益智灵对血管性痴呆模型大鼠脑组织SOD活性、MDA含量的影响

目的观察首乌益智灵对血管性痴呆(VD)模型大鼠脑组织SOD活性、MDA含量的影响,并探讨其对血管性痴呆的干预机理。方法用改良Pulsinelli四血管阻断(4-VO)法制造血管性痴呆大鼠模型,设首乌益智灵组、脑复康组、模型组、假手术组,分别测定干预后各组大鼠脑组织中的超氧化物歧化酶(SOD)活性、丙二醛(MDA)含量。结果灌胃20 d后,首乌益智灵组大鼠脑组织中的SOD活性显著提高、MDA含量显著降低,与模型组和脑复康组相比有显著差异(P<0.05,P<0.01)。结论首乌益智灵具有提高VD大鼠脑组织中的SOD活性、降低MDA含量的作用,这可能是其治疗血管性痴呆的主要作用机制之一。     

美满霉素增强血管性痴呆大鼠自由基清除

目的 观察美满霉素(minocycline)对血管性痴呆(VD)大鼠脑组织和血清SOD、MDA、GSH-Px、LPO表达的影响,探讨其对血管性痴呆脑保护作用机制.方法 Wistar大鼠随机分组:正常组、假手术组、痴呆模型组、美满霉素治疗组.采用生物化学法检测大鼠脑组织和血清SOD、MDA、GSH-Px、LPO表达水平.结果 美满霉素组MDA、GSH-Px、LPO表达较模型组降低(P＜0.05),美满霉素组SOD表达较模型组增高(P＜0.05);美满霉素组SOD、MDA、GSH-Px、LPO表达较正常组和假手术组增高(P＜0.01);模型组SOD、MDA、GSH-Px、LPO表达较正常组和假手术组显著增高(P＜0.01).结论 美满霉素能降低VD大鼠脑组织和血清MDA、GSH-Px、LPO水平、增强SOD表达,通过清除VD大鼠自由基、抑制氧化应激效应发挥其脑保护作用.     

不同时间电针对血管性痴呆小鼠学习记忆能力与海马氧自由基的影响

目的通过观察不同时间电针对血管性痴呆(VD)模型小鼠行为学与海马超氧化物歧化酶(SOD)活性及丙二醛(MDA)、一氧化氮合酶(NOS)的含量变化,探讨电针干预对VD的治疗效应及可能的作用机制。方法采用颈总动脉结扎缺血再灌注的方法复制VD模型,将小鼠随机分为两批,第1批于造模当日给予电针干预,第2批于造模第3天给予电针干预,并设假手术组、模型组进行对照。电针组选取双侧"足三里"、"膈俞"及"百会"、"大椎",针刺得气后接通电针仪,采用疏密波,频率2/80 Hz,每次治疗10 min,连续15 d,观察比较各组小鼠行为学与海马SOD活性及MDA、NOS含量的变化。结果与假手术组比较,各模型组学习和记忆成绩均显著下降(P0.01),海马SOD活性均明显降低(P0.01),MDA、NOS含量均显著升高(P0.01);与模型组比较,各电针组学习和记忆成绩均显著提高(P0.01),海马SOD活性均明显升高(P0.01),MDA、NOS含量均显著降低(P0.01),并且造模第3天治疗效果优于造模当日(P0.05或P0.01)。结论电针能够提高VD小鼠的学习记忆能力,其作用机制与对抗脑缺血损伤后氧化损伤有关,并初步发现介入干预时间不同,其治疗效应存在差异。     

灯盏花素对血管性痴呆大鼠学习与记忆能力的干预作用

目的 探讨灯盏花素对血管性痴呆(VD)大鼠学习与记忆能力的影响.方法 采用双侧颈总动脉结扎法建立VD样学习记忆障碍的大鼠模型.实验大鼠随机分为假手术组、模型组、灯盏花素治疗组和他克林治疗组4组,采用用Morris试验如定位航行和空间探索试验测定大鼠的空间学习记忆功能,观察造模后大鼠血清中超氧化物歧化酶(SOD)活性和丙二醛(MDA)含量.结果 VD大鼠定位航行试验的逃避潜伏期明显延长;空间探索试验的跨越平台次数减少,SOD活性降低和MDA含量增高,与假手术组比较有显著性差异(P<0.05);灯盏花素治疗后,VD大鼠定位航行试验的逃避潜伏期缩短;空间探索试验的跨越平台次数增加(P<0.05),SOD活性升高和MDA含量降低(P<0.05).结论 灯盏花素能明显改善VD大鼠的空间记忆,其可能机制是通过抑制氧化应激而发挥作用的.     

血管性痴呆大鼠海马胆碱乙酰基转移酶的动态变化

目的 观察血管性痴呆(VD)模型大鼠海马组织胆碱乙酰转移酶(ChAT)与学习记忆功能的动态变化,探讨VD发病的可能机制.方法 采用双侧颈总动脉反复夹闭再灌注,同时腹腔注射硝普钠建立VD大鼠模型,在7、15 d、1、2、4个月等时间点,采用水迷宫检测大鼠学习记忆能力的变化,HE染色和免疫组化染色观察大鼠海马神经元的形态学改变及ChAT表达的变化.结果 模型组大鼠各时间点的逃逸潜伏期(EL)比假手术组均明显延长(P＜0.01);海马区锥体细胞数比假手术组明显减少(P＜0.01);免疫组织化学观察海马ChAT阳性神经元表达均显著少于假手术组(P＜0.01).而且随造模手术后时间的延长,以上变化逐渐加重,与水迷宫EL呈负相关(r=-0.937,P＜0.05).结论 缺血再灌注后,海马胆碱能神经元进行性缺失与ChAT活性降低可能是VD大鼠学习记忆障碍的重要机制之一.     

硫氧还蛋白-1通过调控IRE1-JNK信号通路改善血管性痴呆大鼠认知功能和神经损伤

目的研究慢病毒介导的硫氧还蛋白(Trx)-1过表达对血管性痴呆(VD)大鼠认知功能和神经损伤的改善作用及机制。方法按体重将SD大鼠随机分成假手术组(Sham组)、模型组(VD组)、Trx-1过表达空载慢病毒干预组(VD/Lv-NC组)、Trx-1过表达慢病毒干预组(VD/Lv-Trx-1组)及肌醇酶(IRE)-1抑制剂KIRA6干预组(VD/KIRA6组)各10只。各干预组及模型组以双侧颈总动脉夹闭再通法建立VD模型。VD/Lv-NC及VD/Lv-Trx-1组在造模前24 h侧脑注射对应慢病毒溶液0.2 ml;VD/KIRA6组在造模前2 h侧脑注射KIRA6溶液(剂量10 mg/kg);Sham及VD组则注射等量生理盐水。在造模24 h后,采用Morris水迷宫测试认知能力;取海马组织,原位末端标记技术(TUNEL)检测神经细胞凋亡情况;Western印迹检测磷酸化肌醇酶(p-IRE)1及磷酸化c-Jun氨基末端激酶(p-JNK)蛋白的表达水平。结果造模24 h后,VD组较Sham组逃避潜伏期显著延长、跨越原平台次数显著减少(均P<0.01);与VD组比较,VD/Lv-Trx-1组及VD/KIRA6组逃避潜伏期显著缩短、跨越原平台次数显著增多(均P<0.01)。与Sham组比较,VD组Trx-1显著降低、p-IRE1和p-JNK显著增多(均P<0.01);与VD组比较VD/Lv-Trx-1组、VD/KIRA6组Trx-显著增多、p-IRE1和p-JNK显著降低(均P<0.05)。结论过表达Trx-1可能通过抑制IRE1-JNK信号通路的激活发挥抗神经元凋亡作用,从而改善VD大鼠海马区损伤及认知能力。     

脑通胶囊对VD大鼠海马组织NMDA受体1亚基和2B亚基mRNA表达的影响

目的观察脑通胶囊对血管性痴呆(VD)模型大鼠学习记忆、海马组织N-甲基-D-天冬氨酸(NMDA)受体1亚基和2B亚基mRNA表达的影响。方法采用改良的四血管法(14-VO)制备VD模型,Morris水迷宫测定大鼠学习、记忆能力,实时荧光定量PCR检测NMDA受体1亚基和2B亚基mRNA的表达情况。结果与模型组比较,脑通胶囊大、中剂量组逃避潜伏期缩短,穿越原平台次数增加,NMDA受体1亚基mRNA表达降低,NMDA受体2B亚基mRNA表达升高(P<0.05,P<0.01)。结论脑通胶囊可降低NMDA受体1亚基mRNA的表达,提高NMDA受体2B亚基mRNA的表达,从而改善VD大鼠学习、记忆能力。     

电针改善血管性痴呆大鼠学习记忆及其与海马神经细胞谷氨酸、NMDAR表达的关系

目的 观察电针对血管性痴呆(VD)大鼠学习记忆功能和海马谷氨酸及其NMDA受体表达的影响,探讨电针的治疗作用机制.方法SD大鼠,随机分为正常对照组、假手术组、模型组、电针组.在建立VD大鼠模型后,电针“百会”、“大椎”穴,水迷宫观察大鼠学习记忆能力,免疫组织化学染色技术观察脑组织海马谷氨酸及其NMDA受体染色结果.结果 与模型组比较,经电针治疗后水迷宫潜伏期明显缩短(P＜0.01),相同时间内在原平台象限跨越相应平台次数明显增多(P＜0.01);谷氨酸及其NMDA受体免疫阳性细胞积分光密度显著增加(P＜0.01).结论 电针大鼠“白会”、“大椎”穴能改善大鼠学习记忆能力,其机制可能与提高海马谷氨酸及其NMDA受体表达有关.     

依达拉奉对血管性痴呆大鼠海马线粒体COX活性及基因表达的影响

目的 探讨依达拉奉对血管性痴呆(VD)大鼠海马组织的细胞色素C氧化酶(COX)活性及基因表达的影响.方法 采用双侧颈总动脉永久结扎法制备慢性前脑缺血大鼠模型,分依达拉奉治疗组(皮下注射,每日1次,3 mg/kg体重),甲磺酸阿米三嗪(都可喜,灌胃,每日1次,20 mg/kg体重)组和模型组,另取正常大鼠为正常对照组.自手术7 d起给药,共20 d后,各组分别取1及2个月为时间点,处死取脑,测定大鼠海马组织COX活性及基因表达并进行基因突变分析.结果 提取各组大鼠海马组织线粒体后,COX活性检测结果显示:术后1、2个月依达拉奉治疗组COX活性明显高于相应时间点模型组(P＜0.05),并有高于都可喜组趋势.依达拉奉治疗组COX表达量高于模型组(P＜0.05),与都可喜组无差异.依达拉奉组COX基因新出现3处基因突变,比正常组少3个突变位点,与模型组比新出现3处基因突变,少3处突变位点.COX基因依达拉奉组没有模型组的突变位点,也没有对照组突变位点,都可喜组突变频率较高既有正常对照组的突变位点,也有模型组的突变位点.结论 依达拉奉可以使VD大鼠海马组织COX活性升高,COX基因突变率减少,提示依达拉奉可以减轻自由基对mtDNA的氧化损伤,保护VD大鼠的神经功能.     

Cardio-ankle vascular index is a candidate predictor of coronary atherosclerosis.

BACKGROUND: Recently, arterial stiffness parameter called cardio-ankle vascular index (CAVI) has been developed. In the current study, using coronary angiographic (CAG) findings, the usefulness of CAVI as a marker of the severity of coronary atherosclerosis was compared with that of carotid atherosclerosis parameters obtained from high-resolution B-mode ultrasonography. METHOD AND RESULT: A total of 109 participants who underwent CAG were enrolled in the current study. They were divided into 4 groups according to the number of stenotic vessels on CAG; no lesion (0VD), 1-vessel (1VD), 2-vessel (2VD) and 3-vessel (3VD) groups. CAVI was significantly higher in 1VD group compared with the 0VD group (p<0.05), and was significantly higher in 2VD and 3VD group compared with the 1VD group. In single regression analysis, CAVI correlated positively with maximum intima-media thickness (IMT) (p<0.01) and plaque score (p<0.0001). A stepwise ordinal logistic regression analysis using mean IMT, maximum IMT, plaque score and CAVI as independent variables identified only CAVI as positively related to the severity of coronary atherosclerosis. The area under the receiver operating characteristic curve defined by CAVI was the greatest. CONCLUSION: CAVI might be more useful for discriminating the probability of coronary atherosclerosis than findings of carotid atherosclerosis by high-resolution B-mode ultrasonography.     

Development of aortic valve sclerosis or stenosis in rabbits: role of cholesterol and calcium

BACKGROUND AND AIM OF THE STUDY: Aortic valve sclerosis is fairly common and is currently seen as a marker of systemic atherosclerosis. For unclear reasons only a minority of those sclerotic valves will evolve to become stenotic suggesting that atherogenic factors alone are insufficient to explain the development of valve stenosis. We had reported in a model of cholesterol fed rabbits that a combination of high cholesterol with vitamin D supplementation was necessary to induce valve stenosis and significant calcium deposition whereas high cholesterol alone only induced a sclerosis of the valve. In this study, we further evaluated the role of vitamin D treatment in the development of aortic valve disease (sclerosis or stenosis) in this rabbit model. METHODS: Rabbits were divided in 4 groups followed for 12 weeks: 1) no treatment; 2) cholesterol-enriched diet, 3) cholesterol-enriched diet + vitamin D2 (VD; 50000IU, daily) 4) VD alone for 12 weeks. Echocardiographic assessment of the aortic valve was done at baseline, and every 4 weeks thereafter. Aortic valve area, maximal and mean transvalvular gradients were recorded and compared over time. Immunohistological study of the valves of AS rabbits was also realized for several classical atherosclerosis markers. RESULTS: Vitamin D2 treated animal did not develop any stenosis of the valve despite increased echogenicity due to diffuse calcium deposits on the leaflets without any atherosclerotic lesions. Only the combination of high cholesterol with VD resulted in a decrease of aortic valve area. Immunohistological analysis of aortic valves from VD rabbits showed the presence of calcium deposits, T-cell infiltration in addition to positive labeling for alpha-smooth muscle cell actin. We did not observe macrophage infiltration in aortic valve leaflets of VD rabbits. CONCLUSION: Hypercholesterolemia or vitamin D supplements alone could not induce aortic valve stenosis in our animal model whereas the combination resulted in a decreased aortic valve area. These findings support the hypothesis that a combination of atherosclerotic and calcifying factors is necessary to induce aortic valve stenosis in this model.     

Dipyridamole electrocardiography test for the assessment of the severity of coronary artery disease.

The purpose of this study was to investigate the relationship of dipyridamole-induced ST changes to the severity of coronary artery disease. The subjects were 100 patients without myocardial infarction who underwent coronary arteriography for the diagnosis of coronary artery disease. The dipyridamole injection test (D) (0.568 mg/kg/4 min), and symptom-limited treadmill exercise test (T) were performed separately. Body surface electrocardiographic mapping of 87 leads was performed in both tests. The incidences of significant ST depression greater than or equal to 0.10 mV, number of leads showing significant ST depression (nST) and the maximal voltage of ST depression (maxST) in D and T were compared to the number of diseased coronary arteries. In patients without significant coronary stenosis (0VD group), the incidence of ST depression in the dipyridamole test was significantly lower than that in the treadmill test (D 9% vs T 47%, p less than 0.01). While, in one vessel disease (1VD), two vessel disease (2VD), and three vessel disease (3VD) groups, there was no significant difference in the incidence of ST depression between the dipyridamole test and the treadmill test (in 1VD, D 44% vs. T 65%; in 2VD, D 67% vs. T 93%; and in 3VD, D 93% vs. T 96%). In the dipyridamole test, nST was 0.6 +/- 2.4 in 0VD, 4.5 +/- 6.9 in 1VD, 4.1 +/- 4.5 in 2VD, and 10.6 +/- 8.1 in 3VD. Significant differences were found between 0VD and 1VD (P less than 0.05), 0VD and 3VD (P less than 0.01), 1VD and 3VD (P less than 0.01), and 2VD and 3VD (p less than 0.01). The maxST in the dipyridamole test was 0.02 +/- 0.04 mV in 0VD, 0.10 +/- 0.12 mV in 1VD, 0.13 +/- 0.11 mV in 2VD, and 0.22 +/- 0.11 mV in 3VD. Significant differences were found between 0VD and 1VD (p less than 0.01), 0VD and 2VD (p less than 0.01), 0VD and 3VD (p less than 0.01), 1VD and 3VD (p less than 0.01), and 2VD and 3VD (P less than 0.01). For the diagnosis of 3VD, the dipyridamole ECG test had as high a sensitivity (93% vs 96%), higher specificity (68% vs 38%, p less than 0.01), and higher predictive accuracy (75% vs 54%, p less than 0.01) than the treadmill test.(ABSTRACT TRUNCATED AT 400 WORDS)     

血管性痴呆大鼠海马神经元凋亡与乙酰胆碱含量变化

目的 探讨血管性痴呆(VD)大鼠海马神经元凋亡和乙酰胆碱(ACh)含量变化在VD发病过程中的作用.方法 将90只大鼠随机分为模型组、假手术组和正常组,每组30只.再将各组的30只大鼠根据造模后断头取脑时间随机分为3小组,即7、14、21 d组,每组10只大鼠.采用反复大鼠双侧颈动脉缺血再灌注,加剪尾放血法制备VD大鼠模型;用TUNEL法检测海马组织的凋亡细胞,用生化法检测ACh含量.结果 模型组大鼠海马组织在第7、14、21天均有大量凋亡神经元,且ACh含量持续降低,与假手术组及正常组相比差异显著(P<0.01).结论 脑海马组织神经元的大量凋亡和ACh含量持续降低可能在VD发病过程中起重要作用.     

Down regulation of the L-type Ca2+ channel, GRK2, and phosphorylated phospholamban: protective mechanisms for the denervated failing heart

We previously found that a canine model of selective surgical ventricular denervation (VD), which does not permit increased sympathetic tone during the pathogenesis of heart failure (HF), tolerated the development of HF better than controls. To investigate the cellular mechanisms, we examined cellular contraction and L-type Ca(2+) channel currents (I(Ca)) and their responses to beta-adrenergic receptor (beta-AR) stimulation in left ventricular myocytes from 1) control, 2) VD, 3) HF induced by rapid pacing, and 4) HF induced in VD (VD-HF) dogs. The magnitude of myocyte contraction and rate of relaxation in VD were similar to control but were depressed in both HF and VD-HF. These changes were associated with reduced protein expression of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a) and protein kinase A phosphorylated phospholamban (PLB), which was reduced in HF, but essentially abolished in VD-HF. beta-AR kinase (GRK2) was increased in HF but reduced in VD-HF. Basal I(Ca) density did not differ among control, VD, and HF groups, but VD-HF myocytes showed a markedly reduced I(Ca) density (approximately 40%). Compared to controls, the sensitivity of I(Ca) to isoproterenol (ISO), was significantly higher in VD, but reduced in HF. While I(Ca) responses to ISO in VD-HF were maintained at control levels, the amplitude of the ISO-stimulated I(Ca) was significantly smaller (approximately 50%) compared with HF myocytes. The relative decrease in Ca(2+) influx due to downregulation of I(Ca) density may contribute to the cardioprotective effects in VD-HF hearts by preventing Ca(2+) overload during the development of HF. These findings, in combination with the virtual abolition of phosphorylated PLB in VD-HF and the decrease in GRK2, may explain, in part, why VD dogs tolerate the development of HF better than control dogs.