Hyperlipidaemia induced by a high-cholesterol diet leads to the deterioration of guanosine-3′,5′-cyclic monophosphate/protein kinase G-dependent cardioprotection in rats

Background and purpose:

Hyperlipidaemia interferes with cardioprotective mechanisms, but the cause of this phenomenon is largely unknown, although hyperlipidaemia impairs the cardioprotective NO–cGMP system. However, it is not known if natriuretic peptide–cGMP–protein kinase G (PKG) signalling is affected by hyperlipidaemia. Therefore, we investigated the cardioprotective efficacy of cGMP-elevating agents in hearts from normal and hyperlipidaemic rats.

Experimental approach:

Male Wistar rats were rendered hyperlipidaemic by feeding with 2% cholesterol-enriched chow for 12 weeks. Hearts isolated from normal and hyperlipidaemic rats were perfused (Langendorff mode) and subjected to 30 min occlusion of the left main coronary artery, followed by 120 min reperfusion. 8-Br-cGMP (CG, 10 nM), B-type natriuretic peptide-32 (BNP, 10 nM), S-nitroso-N-acetyl-penicillamine (SNAP, 1 µM) were perfused from 10 min prior to coronary occlusion until the 15th min of reperfusion. Infarct size (% of ischaemic risk zone) was determined by triphenyltetrazolium staining.

Key results:

Treatment with CG, SNAP or BNP decreased infarct size significantly in normal hearts from its control value of 41.6 ± 2.9% to 15.5 ± 2.4%, 23.3 ± 3.0% and 25.3 ± 4.6%, respectively (P < 0.05). Protection by BNP was abolished by co-perfusion of PKG inhibitors KT5823 (600 nM) or Rp-8pCPT-PET-cGMPs (1 µM), confirming its PKG dependence. In hearts from hyperlipidaemic rats, CG, SNAP or BNP failed to decrease infarct size. Hyperlipidaemia did not alter basal myocardial PKG content, but decreased its activity as assessed by phosphorylation of cardiac troponin I.

Conclusions and implications:

This is the first demonstration that defects in the cardioprotective cGMP–PKG system could be a critical biochemical anomaly in hyperlipidaemia.     

盐酸维拉帕米渗透泵片溶出度与人体生物利用度研究

溶出度按Weibull's分布处理得T_d=5.76 h,T₅₀=3.9 h,零级溶出速度常数K_t=9.9450,平均体外溶解时间MDT=5.391 h。测定8名健康受试者,单剂量口服,得C_max=76.2±16.7 ng/ml,T_amx=8.0 h,t_1/2=9.75 h,MRT=19.41 h,MAT=5.34 h,与Knoll公司SR片相比,F_rel=101.71%;与市售普通片相比,F_rel=96.16%。多剂量口服,得C_max=121.47±34.5 ng/ml,T_max=7.14 h。按Loo-Riegelman方程处理表明体内外显著相关。理论值与实测值基本相符。     

沙尘天气大气颗粒物对学龄儿童最大呼气流速的影响

目的 研究沙尘天气颗粒物浓度与学龄儿童最大呼气流速(PEFR)之间的关系.探讨沙尘天气颗粒物对儿童肺功能的影响.方法 于2006年4月27日-6月5日连续40d对内蒙古包头市1所小学107名四年级小学生进行每日3次PEFR的测定,同时监测和收集每日大气PM2.5、PM1O、NO2和SO2浓度以及气温和相对湿度,通过问卷调查了解儿童年龄、性别、身高、体重、哮喘病史、慢性呼吸系统疾病家族史、被动吸烟等情况.应用线性混合效应模型,在控制了个体特征、气象因素的情况下估计PM2.5和PM10对儿童PEFR的影响.结果 单污染物模型和多污染物模型均显示,PM2.5和PM10的日均浓度与沙尘天气当日及之后3 d内儿童的PEFR日均值都存在明显的负相关(P<0.01),其中以滞后1 d的效应最强.在多污染物模型中调整了NO2和SO2的影响之后,PM2.5和PM10的日均浓度每增加10μg/m3,儿童PEFR在沙尘天气1 d之后的日均值就分别降低0.245和0.121 L/min,有统计学意义(P<0.01).结论 学龄儿童PEFR日均值下降与包头市沙尘天气颗粒物浓度的升高有关.