Interactions between imidazoline compounds and sulphonylureas in the regulation of insulin secretion

1. Imidazoline α₂-antagonist drugs such as efaroxan have been shown to increase the insulin secretory response to sulphonylureas from rat pancreatic B-cells. We have investigated whether this reflects binding to an islet imidazoline receptor or whether α₂-adrenoceptor antagonism is involved.
2. Administration of (±)-efaroxan or glibenclamide to Wistar rats was associated with a transient increase in plasma insulin. When both drugs were administered together, the resultant increase in insulin levels was much greater than that obtained with either drug alone.
3. Use of the resolved enantiomers of efaroxan revealed that the ability of the compound to enhance the insulin secretory response to glibenclamide resided only in the α₂-selective-(+)-enantiomer; the imidazoline receptor-selective-(−)-enantiomer was ineffective.
4. In vitro, (+)-efaroxan increased the insulin secretory response to glibenclamide in rat freshly isolated and cultured islets of Langerhans, whereas (−)-efaroxan was inactive. By contrast, (+)-efaroxan did not potentiate glucose-induced insulin secretion but (−)-efaroxan induced a marked increase in insulin secretion from islets incubated in the presence of 6 mM glucose.
5. Incubation of rat islets under conditions designed to minimize the extent of α₂-adrenoceptor signalling (by receptor blockade with phenoxybenzamine; receptor down-regulation or treatment with pertussis toxin) abolished the capacity of (+)-and (±)-efaroxan to enhance the insulin secretory response to glibenclamide. However, these manoeuvres did not alter the ability of (±)-efaroxan to potentiate glucose-induced insulin secretion.
6. The results indicate that the enantiomers of efaroxan exert differential effects on insulin secretion which may result from binding to effector sites having opposite stereoselectivity. Binding of (−)-efaroxan (presumably to imidazoline receptors) results in potentiation of glucose-induced insulin secretion, whereas interaction of (+)-efaroxan with a second site leads to selective enhancement of sulphonylurea-induced insulin release.

     

Coronary microcirculation: autoregulation and metabolic control

The majority of studies axamining the regulation of coronary blood flow and vascular resistance have considered the coronary circulation as being composed of large conduit vessels and resistance vessels. Recently, it has become apparent that regulation of coronary microvascular resistance is not distributed uniformly, but varies across different segments or microdomains of the vasculature. Generally, small arterioles, those less than 100 m in diameter, respond differently than larger arterioles and small arteries. There are major differences in the level of autoregulatory control, myogenic control, endothelial modulation and control by metabolic factors across these various microvascular domains. There are also transmural variations which may account for some of the differences in coronary blood observed between epicardial and endocardial regions. In addition, interactions between these various regulatory mechanisms further complicate the understanding of coronary microvascular regulation. Importantly however, it may be these complex interactions and heterogeneous regulatory mechanisms which allow for adequate perfusion of the myocardium under an extreme range of metabolic conditions. This segmental distribution of regulation suggests an integrative hypothesis of regulation whereby a variety of mechanisms play a role in the overall response.Invited Contributions to the Symposium Regulation of coronary blood flow, held at the XV. World Congress of the International Society for Heart Research in Prague 1995     

微血管舒张功能障碍及体外反搏的改善作用

目的：通过测定微血管血流灌注来反映微血管的舒张功能,同时观察体外反搏治疗改善冠心病患者微血管舒张功能障碍的效果。方法：应用激光多普勒血流量计（ＬＤＦ） ,测量５８ 个被观察者的前臂皮肤在反应性充血前后微血管血流灌注增加比值,评价血流介导的微血管舒张功能。结果：冠心病组、高胆固醇血症组及吸烟组微血管舒张功能明显低于对照组,比值分别为１．８３±０．３７、２．６３±０．５１、３．１９ ±０．５６ 比３．５６±０．３６ ;Ｐ分别＜ ０．０１,＜０．０１,＜ ０．０５。冠心病组反搏治疗前后比,其微血管的舒张功能明显提高,比值为１．８３±０．３７ 比２．５４±０．４３; Ｐ＜０．０１。结论：ＬＤＦ可检测冠心病患者明显的微血管舒张功能障碍及高胆固醇血症者和吸烟者微血管功能的异常;体外反搏治疗可改善冠心病患者的微血管舒张功能。     

The effect of separate red blood cells on capillary tissue oxygenation calculated with a numerical model

Author to whom correspondence should be addressed In simplified models that describe large quantities of capillariesthe capillary content is considered to be homogeneous for oxygentransport; but, in reality, the capillaries contain discretered blood cells (RBCs), and this discreteness will affect oxygentransport from the capillary to the tissue. This was previouslyinvestigated with an analytical model, where RBCs were modelledas point-like sources. A numerical approach is used in thisinvestigation, and the results are compared with the analyticalmodel. In both models the effect of the particulate nature ofblood depends on the haematocrit and on the RBC velocity. Thereis only a minor difference between the two models. For rat hearts,the correction factor used in this study, the extraction pressure,can be up to 3 kPa (23 mmHg).     

胰腺癌的临床表现

胰腺的临床表现因病变而异。腹痛、黄疸及体重减轻是胰腺癌的主要临床表现。部分病人同时可表现为发热、焦虑、抑郁、胆囊肿大及血栓性静脉炎等。     

降纤酶对血栓形成和光化学诱导大鼠脑缺血的影响

目的:探讨降纤酶对血栓形成和光化学诱导大鼠脑缺血的影响。方法:①对血栓形成的影响:10只大鼠分为生理氯化钠溶液对照组及降纤酶治疗组(每组各5只),采用微循环方法观察降纤酶治疗后肠系膜血栓溶解情况,分别在光照后1,2,5,10min记录对照组及治疗组血栓体积及占管腔体积比。②对光化学诱导大鼠脑缺血的影响:72只大鼠以光化学法制成左顶叶皮层缺血模型,治疗组于缺血后1,3,6,9,12,24h由尾静脉注射降纤酶8U·kg~(-1)),对照组按相同时间点用等量生理氯化钠溶液尾静脉注射。进行神经功能评分,缺血48h后处死,标本用HE及TTC染色,观察梗死灶病理改变及测定梗死灶体积。结果:①对血栓形成的影响:降纤酶治疗组血栓体积明显减小,占管腔体积百分比减少,与对照组相比有显著性差异(P<0.05)。②对光化学诱导大鼠脑缺血影响:缺血1,3,6h治疗组神经功能评分改善,脑梗死体积明显减小,与对照组相比有极显著性差异(P<0.01),相应时间点病理改变轻于对照组。缺血9h给药组神经功能评分有改善,脑梗死体积亦较对照组小,统计学有显著差异(P<0.05)。12和24h治疗组与对照组相比无显著差异(P>0.05)。结论:降纤酶能有效溶解肠系膜血栓并减小光化学诱导大鼠脑梗死体积。     

2340例胰腺癌临床病例分析

目的 探讨提高胰腺癌治愈性切除相关因素和获得更佳疗效。方法 中国抗癌协会胰腺癌专业委员会回顾性分析了8省2市14大医院的1990年-2000年诊治的2340例胰腺病例。多因素生存分析采用Cox比例风险模型找出可能影响胰腺癌病人预后的独立因素。单因素生存分析用寿命表法计算,以生存曲线描述生存率,并进行Gehan比分检验。结果 COX单因素分析表明在a=0.05水平上有意义的有年龄、职业、病程、肿瘤部位、手术方式、术后胰瘘、术后肝衰、化疗、TNM分期、免疫治疗、有无肝转移、肠系膜上血管有无侵犯等变量。COX多因素分析表明在a=0.05水平上有意义的有患者年龄、手术方式、术后胰瘘、术后肝衰、化疗、免疫治疗等变量,这些变量为影响胰腺癌预后的独立因素。根治性手术者相对于未手术者,以及化疗、免疫治疗均为保护性因素。其中40岁以上的占了92.91％,40岁以下的仅占7.09％。胰头癌根治性手术组中位生存时间为 17.11个月,1年、3年和5年生存率分别为54.36％、13.47％、8.47％。结论 有必要将40岁以上的人群视为高危人群,能及时发现早期病例。各种综合治疗措施的结合都将有助于改善胰腺癌患者的生活质量和延长生存期。     

Modulation of 5-fluorouracil with methotrexate and low-dose N-(phosphon-acetyl)-L-aspartate (PALA) is inactive in advanced pancreatic carcinoma

Purpose: To evaluate the effect of biochemical modulation by PALA and methotrexate on the therapeutic activity of 5-fluorouracil (5-FU) in patients with advanced pancreatic adenocarcinoma.Patients and methods: The treatment protocol consisted of phosphonacetyl-L-aspartate (PALA) 250 mg/m² i.v. 15-minute infusion followed by methotrexate 200 mg/m² i.v. 30-minute infusion on day 1 and 5-FU 600 mg/m² i.v. push on day 2. Folinic acid was given at 15 mg/m² p.o. every six hours for eight doses, starting 24 hours after methotrexate infusion. Cycles were repeated every two weeks.Results: Thirty patients with advanced chemotherapy-naive pancreatic cancer were included; 26 had measurable disease. Median age 56 years (27–72); median PS 1 (0–2). One PR (3.9%) was achieved; nine patients had stable disease. Median time to progression was 91 days. Median survival was 177 days and one year survival was 13.3% (4 of 30 patients). Treatment was well tolerated; diarrhea WHO grade 2 or 3 occurred in six patients; stomatitis WHO grade 2 and 3 in nine patients.Conclusions: Modulation of 5-FU by PALA and MTX given in this dose and schedule appears to be ineffective in patients with advanced pancreatic adenocarcinoma.     

Hypoglycémie hyperinsulinémique persistante du nouveau-né et du nourrisson

Persistent hyperinsulinemic hypoglycaemia of infancy (PHHI) is the most frequent cause of hypoglycaemia in infancy. Clinical presentation is heterogeneous, with variable onset of hypoglycaemia and response to diazoxide, and presence of sporadic or familial forms. Underlying histopathological lesions can be focal or diffuse. Focal lesions are characterised by focal hyperplasia of pancreatic islet-like cells, whereas diffuse lesions implicate the whole pancreas. The distinction between the two forms is important because surgical treatment and genetic counselling are radically different. Focal lesions correspond to somatic defects which are totally cured by limited pancreatic resection, whereas diffuse lesions require a subtotal pancreatectomy exposing to high risk of diabetes mellitus. Diffuse lesions are due to functional abnormalities involving several genes and different transmission forms. Recessively inherited PHHI have been attributed to homozygote mutations for the beta-cell sulfonylurea receptor (SUR1) or the inward-rectifying potassium-channel (Kir6.2) genes. Dominantly inherited PHHI can implicate the glucokinase gene, particularly when PHHI is associated with diabetes, the glutamate dehydrogenase gene when hyperammonaemia is associated, or another locus.     

Impaired coronary microvascular function in diabetics

Global and regional myocardial uptake was determined with technetium-99m tetrofosmin and a 4 hour exercise (370 MBq i.v.) and rest (740 MBq i.v.) protocol, in 24 patients with non-insulin dependent diabetes mellitus and in 22 control subjects. The purpose of this study was to evaluate impaired coronary microvascular function in diabetics by measurement of % uptake increase in myocardial counts. The parameter of % uptake increase (deltaMTU) was calculated as the ratio of exercise counts to rest myocardial counts with correction of myocardial uptake for dose administered and physical decay between the exercise study and the rest study. Global deltaMTU was significantly lower in the diabetics than in control subjects (14.4 +/- 5.4% vs. 21.7 +/- 8.5%, p < 0.01). Regional deltaMTU in each of 4 left ventricular regions (anterior, septal, inferior, posterolateral) was significantly lower in the diabetic group than in the control group (p < 0.01) respectively, but there were no significant differences between deltaMTU in the 4 left ventricular regions in the same group. deltaMTU was useful as a non-invasive means of evaluating impaired coronary microvascular function in diabetics.