ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITORS AND KININ METABOLISM: EVIDENCE THAT ACE INHIBITORS MAY INHIBIT A KININASE OTHER THAN ACE

1. Angiotensin converting enzyme (ACE) converts angiotensin I to angiotensin II, and also metabolizes bradykinin-(1–9) to bradykinin-(1–7) and bradykinin-(1–7) to bradykinin-(1–5). Increases in endogenous kinin levels may contribute to the therapeutic effects of ACE inhibitors. 2. ACE inhibitors increase vascular levels of both bradykinin-(1–9) and its ACE cleavage product bradykinin-(1–7), at doses below the threshold for ACE inhibition, leading to the proposal that ACE inhibitors may also inhibit a non-ACE kininase which cleaves both kinin peptides; this non-ACE kininase may be the major pathway of kinin metabolism in the vasculature and some other tissues. 3. In support of this proposal, ACE inhibitors potentiate bradykinin-(1–9) effects at doses which have little or no effect on ACE activity, as indicated by angiotensin I conversion to angiotensin II. ACE inhibitors also potentiate the actions of ACE-resistant kinin analogues, which may be susceptible to metabolism by a non-ACE kininase. 4. Identification and characterization of the putative non-ACE kininase which is inhibited by ACE inhibitors may reveal novel approaches to the tissue-specific modulation of kinin levels.     

Disposition of antipyrine in patients with extensive metastatic liver disease

Summary In the present study the effect of metastatic liver disease on hepatic drug metabolism has been examined by studying the pharmacokinetics of antipyrine and the urinary excretion of antipyrine and its three major metabolites (4-hydroxyantipyrine, norantipyrine, and 3-hydroxymethylantipyrine) in 12 patients with extensive metastatic liver disease, and in 12 matched healthy controls.In the patients total liver volume, the volume of the liver parenchyma, and the volume of the liver metastases were determined by computed tomography. The volume of liver metastases always exceeded 35% of the total liver volume.There were no significant differences between the patients and controls in plasma half-life, plasma clearance, or apparent volume of distribution of antipyrine.The cumulative urinary excretion of antipyrine and its three major metabolites was significantly lower in patients [44 (18)%] than in controls [71 (8)%]. The excretion of antipyrine itself was unchanged and the decrease in cumulative excretion was due to reduced excretion of the three metabolites.The results show that the activity of the hepatic mixed function oxidases was not impaired even in patients with extensive metastatic liver disease. This may be because liver metastases do not cause a corresponding reduction in the volume of normal hepatic parenchyma. The decreased urinary excretion of the three major metabolites of antipyrine, which are mainly glucuronidated, may have been due to an alteration in the process of conjugation.     

继发性骨质疏松防治的研究

目的总结继发性骨质疏松预防与治疗的经验及提出见解.方法用钙代谢平衡的方法研究了钙代谢的基本情况,比较了补钙与不补钙在若干种生理状态对骨密度的影响,总结继发性骨质疏松的病因及对其采取不同方法的治疗经验.结果中国人膳食含钙量属于正常范围低水平状态,与适宜摄入量(AI)比较是不足的,在一定的生理状态下应予补钙.缺钙是原发性骨质疏松与继发性骨质疏松的不利因素.氟中毒骨病、糖尿病、性腺功能减退、肿瘤、糖皮质激素过多和甲亢均有其各别的病理生理,导致继发性骨质疏松,防治方法各异.结论从胚胎至老年都应防治骨质疏松.不同情况采取方法各异,但有效.     

胆固醇酯转运蛋白基因多态性在多囊卵巢综合征中的初步研究

目的:探讨胆固醇酯转运蛋白(CETP)在PCOS患者中的基因多态性和血脂、性激素的关系,以进一步认识PCOS脂代谢的特点。方法:应用PCR酶切方法检测108例PCOS患者及60例对照组的CETPTaqIB位点基因多态性。结果:CETPTaqIB基因频率及基因型分布在两组间分布差异无显著性。结论:CETPTaqIB基因多态性影响PCOS患者的HDLC水平,该基因在PCOS患者分布与正常人群分布无差异性。     

Cholesterol reduction and death from noncoronary causes: evidence from randomised controlled trials*

An overview of randomised trials of cholesterol reduction (26 trials, 50,000 patients, net cholesterol reduction ?10%) provides clear evidence of a reduction in the incidence of coronary heart disease (CHD) after just a few years of treatment. Overall, the observed reduction in CHD death (9%± 3) was only half as large as the reduction in non-fatal myocardial infarction (19%±4), although both were statistically significant (2p <0.005). In these trials, 60% of all deaths were from CHD, and since treatment reduced these by about 9%, the expected reduction in total deaths was about 5–6%. This expected reduction falls within the 95% confidence interval of the observed effect of cholesterol reduction on total mortality in these trials. There were small excesses of deaths from cancer and deaths from trauma among patients allocated active treatment. However, in no single trial, nor in the trials collectively, were these increases individually statistically significant. Furthermore, the increases did not appear to be specific to any one agent nor were the increases consistent between trials of the same agent. These observations suggest that the small excesses of noncoronary deaths observed in the cholesterol reduction trials may have occurred by chance. Evidence from ongoing longer-term studies of treatments producing larger cholesterol reductions will be useful in further delineating the effects, if any, of such treatments on non-coronary mortality.     

Scopolamine abolishes cerebral blood flow response to somatosensory stimulation in anesthetized cats: PET study

The effect of the cholinergic blocker, scopolamine on the cerebral blood flow (CBF) response to vibrotactile stimulation of a fore paw was studied using high-resolution positron emission tomography and H₂¹⁵O in 5 pentobarbital-anesthetized cats. Before scopolamine injection, the CBF response to the stimulation was found in the contralateral somatosensory cortex (mean ratio (contralateral/ipsilateral) control: stimulated1.02 ± 0.02: 1.17 ± 0.05; P < 0.01). After intravenous injection of scopolamine (0.35 mg/kg), the CBF response was abolished. However, the cerebral metabolic rate of glucose (CMRGlu) response to the same stimulation was unchanged after scopolamine injection in the same cats. We concluded that scopolamine abolishes the CBF response but not neuronal response to stimulation. We suggest that cholinergic mechanisms may play an important role for mediating CBF coupling to neuronal activity during physiological stimulation.     

维生素K4、维生素D2对绝经妇女骨折早期骨代谢的影响

为探讨不同剂量水平的维生素K4及维生素D对绝经妇女骨折早期骨代谢的影响。选择年龄60~84岁(72.17±1.216岁),绝经女性骨折病人35例,随机分为4组,分别给予不同剂量的维生素K4及维生素D口服,实验进行20天。通过观察患者服药前后血清钙、血清磷、血清碱性磷酸酶、血清凝血酶原时间及血清骨钙素值的变化,综合评价维生素K、维生素D对老年妇女骨折早期骨代谢的影响。结果显示,不同剂量水平维生素K4、维生素D对绝经妇女骨折早期骨代谢的影响不同,有统计学意义。维生素K4对骨代谢的影响作用超过维生素D,并随剂量水平不同而差异有显著性。但维生素K4、维生素D对骨代谢的影响无交互作用。表明维生素D、维生素K4能促进骨折早期骨代谢,对骨折愈合有一定促进作用,且维生素K的作用强于维生素D。     

Anthracycline-induced cardiotoxicity: Overview of studies examining the roles of oxidative stress and free cellular iron

The risk of cardiotoxicity is the most serious drawback to the clinical usefulness of anthracycline antineoplastic antibiotics, which include doxorubicin (adriamycin), daunorubicin or epirubicin. Nevertheless, these compounds remain among the most widely used anticancer drugs. The molecular pathogenesis of anthracycline cardiotoxicity remains highly controversial, although the oxidative stress-based hypothesis involving intramyocardial production of reactive oxygen species (ROS) has gained the widest acceptance. Anthracyclines may promote the formation of ROS through redox cycling of their aglycones as well as their anthracycline-iron complexes. This proposed mechanism has become particularly popular in light of the high cardioprotective efficacy of dexrazoxane (ICRF-187). The mechanism of action of this drug has been attributed to its hydrolytic transformation into the iron-chelating metabolite ADR-925, which may act by displacing iron from anthracycline-iron complexes or by chelating free or loosely bound cellular iron, thus preventing site-specific iron-catalyzed ROS damage. However, during the last decade, calls for the critical reassessment of this “ROS and iron” hypothesis have emerged. Numerous antioxidants, although efficient in cellular or acute animal experiments, have failed to alleviate anthracycline cardiotoxicity in clinically relevant chronic animal models or clinical trials. In addition, studies with chelators that are stronger and more selective for iron than ADR-925 have also yielded negative or, at best, mixed outcomes. Hence, several lines of evidence suggest that mechanisms other than the traditionally emphasized “ROS and iron” hypothesis are involved in anthracycline-induced cardiotoxicity and that these alternative mechanisms may be better bases for designing approaches to achieve efficient and safe cardioprotection.     

Effects of complete heart block on myocardial function, morphology, and energy metabolism in the rat.

AIMS: Severe sustained bradycardia may cause acute and possibly chronic congestive heart failure (CHF). The aim of this study was to investigate acute and chronic effects of complete heart block (CHB) on cardiac function, morphology, and creatine (Cr) metabolism. METHODS AND RESULTS: CHB was induced in male Sprague-Dawley rats (approximately 250 g, n = 11) by means of electrocautery applied to the region of AV node and were compared with controls (n = 15). The rats were investigated at 1, 3, and 12 weeks after CHB induction with transthoracic echocardiography. Invasive haemodynamic assessment of left and right ventricular pressures was performed at 12 weeks. After the sacrifice, the hearts were freeze-clamped for analysis of myocardial Cr, and high energy phosphometabolites. The efficacy of operative procedure was 54%. The peri-operative mortality rate was 20%. Heart rate (HR) decreased by approximately 50% (P < 0.01) while stroke volume (SV) increased 2.5 times (P < 0.01) in the CHB rats. Cardiac index remained unchanged. The rats with CHB grew normally and were in no apparent distress. Filling pressures in left and right ventricles were normal. The CHB rats developed marked cardiomegaly with biventricular dilatation and eccentric left ventricular hypertrophy (P < 0.01). There was no change in the myocardial content of Cr and high energy phosphometabolites. CONCLUSION: Rats with CHB are compensating for reduction in HR with increased SV without haemodynamic and biochemical characteristics of CHF. This model may be useful to study the effects of CHB and bradycardia on myocardial structure, function, electrophysiology, and metabolism as well as for studies of cell therapy for reparation of AV conductance.     

Cardiovascular risk factor profile on a population basis: Results from the Lipid Study Leipzig (LSL)

Population-based lipid screening studies were initiated in the city of Leipzig, Germany, and included more than 30,000 subjects. The objectives of the Lipid Study Leipzig (LSL) were to evaluate the cardiovascular risk factor profile and its dependence on age, nutrition and social factors. In addition, the study results were compared with those of other population-based studies, and the development of cardiovascular risk factors over a 10-year period was evaluated. LSL data were obtained from subjects recruited at community centres, work sites, schools and the University of Leipzig, Germany. Capillary blood cholesterol and high-density lipoprotein-cholesterol levels were measured using the Reflotron dry-chemistry system (Roche Diagnostics, Germany). Study data also included blood pressure, body mass index, waist-to-hip ratio, and the evaluation of dietary and lifestyle factors. The results of LSL show an age-dependent increase in cardiovascular risk, which may have been partly preventable. Furthermore, LSL showed an improvement in cardiovascular risk, with respect to plasma cholesterol, over the past 10 years in men and women older than 30 and 50 years, respectively. The known age dependence of total cholesterol and non-high-density lipoprotein-cholesterol is less pronounced for those following a healthy lifestyle and for vegetarians. This suggests that the age-dependent rise of these parameters is partly preventable.