The vasodilatory actions of insulin on resistance and terminal arterioles and their impact on muscle glucose uptake

Whether a discrete vascular action of insulin in skeletal muscle integrally participates in insulin-mediated glucose disposal has been extensively examined but remains a contentious issue. Here, we review some of the data both supporting and questioning the role of insulin-mediated increases in limb blood flow in glucose metabolism. We advance the hypothesis that controversy has arisen, at least in part, from a failure to recognize that insulin exerts at least three separate actions on the peripheral vasculature, each with its own characteristic dose and time responsiveness. We summarize how, viewed in this manner, certain points of contention can be resolved. We also advance the hypothesis that an action on the precapillary arteriole may play the dominant role in mediating perfusion-dependent effects of insulin on glucose metabolism in muscle.     

Development of stress-induced gastric lesions involves central adenosine A1-receptor stimulation

When rats were exposed to immobilization stress for 1-12 h, gastric lesions did not occur at 1-6 h but did at 12 h of immobilization. Exogenous adenosine increased stress-induced gastric lesions, and dipyridamole, a blocker of adenosine uptake, potentiated the action of adenosine. The selective adenosine A1-receptor stimulants N6-cyclohexyl adenosine (CHA) and N6-(L-phenylisopropyl) adenosine (L-PIA) produced gastric lesions even in non-stressed state and markedly potentiated in dose- and time-dependent manner in stressed state. The stimulatory effect of N6-(D-phenylisopropyl) adenosine (D-PIA) on ulceration was weaker than that of CHA or L-PIA. Furthermore, intracerebral ventricular (i.c.v.) injection of adenosine or adenosine analogues produced the most rapid and most potent exacerbation of stress-induced gastric lesions relative to those induced with subcutaneous (s.c.) injection. The stress lesions enhanced by CHA were not affected by phentolamine, yohimbine, prazosin, naloxone and cholecystokinin (CCK8) but were inhibited by caffeine, clonidine, morphine and beta-endorphin. The inhibitory effect of clonidine was not antagonized by yohimbine or prazosin. The inhibition by morphine was selectively antagonized by exogenous CCK8 as well as naloxone. These results suggest that endogenous adenosine is tonically active in stress lesion formation which is modulated by opiate systems. Clonidine as well as caffeine may function as a purinoceptor antagonist, and it seems unlikely that the inhibitory effect of clonidine on stress ulcer is due to activation of alpha-adrenoceptors.     

Central nervous system stimulants: basic pharmacology and relevance to anaesthesia and critical care

Central nervous system stimulants provoke cortical, brain stem and spinal cord excitation. They have a wide range of clinical uses and a strong potential for abuse. Central nervous system stimulants can be divided into three categories: (i) psychomotor stimulants; (ii) psychotomimetic stimulants; and (iii) respiratory stimulants/convulsants. Psychomotor stimulants produce excitement and euphoria, increase motor activity and reduce fatigue. Psychotomimetic stimulants alter mental function and affect perception and cognition. Respiratory stimulants and convulsants increase activity in the spinal cord and brainstem, leading to hyperreflexia, activation of the respiratory and vasomotor centres, and promotion of seizure activity.     

Effects of a xanthine derivative (BL 191) on insulin secretion in normal man

Summary A xanthine derivative, named BL-191, was administered iv in 8 healthy volunteers alone and in association with glucose (0.33 g/kg body weight iv) or glybenclamide (1 mg iv). BL-191 was infused iv at a constant rate in a dose of 200 mg during 45 minutes. Blood glucose, free fatty acids and immunoreactive insulin were measured during one hour. It was impossible to demonstrate neither a direct effect nor an enhancement of insulin secretion during drug administration; in another experiment (treatment F) a higher dosage of BL-191 (100 mg as a priming dose + 200 mg as infusion dose) was likely ineffective. It appears that some difference in insulin response may be present in the single subject (not evident in the mean), indicating a difference in the -cell cAMP-system sensitivity in individuals. These negative results allow some considerations on the importance of the -cell cAMP-system in healthy human beings.     

Effects of cholesterol depletion on compartmentalized cAMP responses in adult cardiac myocytes

β₁-Adrenergic receptors (β₁ARs) and E-type prostaglandin receptors (EPRs) both produce compartmentalized cAMP responses in cardiac myocytes. The role of cholesterol-dependent lipid rafts in producing these compartmentalized responses was investigated in adult rat ventricular myocytes. β₁ARs were found in lipid raft and non-lipid raft containing membrane fractions, while EPRs were only found in non-lipid raft fractions. Furthermore, β₁AR activation enhanced the L-type Ca²⁺ current, intracellular Ca²⁺ transient, and myocyte shortening, while EPR activation had no effect, consistent with the idea that these functional responses are regulated by cAMP produced by receptors found in lipid raft domains. Using methyl-β-cyclodextrin to disrupt lipid rafts by depleting membrane cholesterol did not eliminate compartmentalized behavior, but it did selectively alter specific receptor-mediated responses. Cholesterol depletion enhanced the sensitivity of functional responses produced by β₁ARs without having any effect on EPR activation. Changes in cAMP activity were also measured in intact cells using two different FRET-based biosensors: a type II PKA-based probe to monitor cAMP in subcellular compartments that include microdomains associated with caveolar lipid rafts and a freely diffusible Epac2-based probe to monitor total cytosolic cAMP. β₁AR and EPR activation elicited responses detected by both FRET probes. However, cholesterol depletion only affected β₁AR responses detected by the PKA probe. These results indicate that lipid rafts alone are not sufficient to explain the difference between β₁AR and EPR responses. They also suggest that β₁AR regulation of myocyte contraction involves the local production of cAMP by a subpopulation of receptors associated with caveolar lipid rafts.     

Pentoxifylline aggravates fatty liver in obese and diabetic ob/ob mice by increasing intestinal glucose absorption and activating hepatic lipogenesis

BACKGROUND AND PURPOSE

Pentoxifylline is in clinical trials for non-alcoholic fatty liver disease and diabetic nephropathy. Metabolic and hepatic effects of pentoxifylline were assessed in a murine model of obesity and type 2 diabetes.

EXPERIMENTAL APPROACH

Pentoxifylline (100 mg·kg⁻¹·day⁻¹) was administered for 4 days or 3 weeks in lean and obese/diabetic ob/ob mice. Plasma lipids, glucose, other metabolites and relevant enzymes were measured by standard assays. Hepatic lipids in vivo were assessed with magnetic resonance spectroscopy and by histology. Hepatic extracts were also analysed with RT-PCR and Western blotting.

KEY RESULTS

Four days of pentoxifylline treatment slightly increased liver lipids in ob/ob mice. After 3 weeks, pentoxifylline exacerbated fatty liver and plasma transaminases in ob/ob mice but did not induce liver steatosis in lean mice. Plasma glucose was highest in fed, but not fasted, ob/ob mice treated with pentoxifylline. During the first 10 min of an oral glucose tolerance test, blood glucose increased more rapidly in pentoxifylline-treated mice. Jejunal expression of glucose transporter 2 isoform was increased in pentoxifylline-treated obese mice. Hepatic activity of carbohydrate response element binding protein (ChREBP) increased after pentoxifylline in ob/ob, but not lean, mice. Hepatic expression of lipogenic enzymes was highest in pentoxifylline-treated ob/ob mice. However, pentoxifylline reduced markers of oxidative stress and inflammation in ob/ob liver.

CONCLUSION AND IMPLICATIONS

Pentoxifylline exacerbated fatty liver in ob/ob mice through enhanced intestinal glucose absorption, increased postprandial glycaemia and activation of hepatic lipogenesis. Long-term treatment with pentoxifylline could worsen fatty liver in some patients with pre-existing hyperglycaemia.     

早产儿呼吸暂停诊治进展

新生儿原发性呼吸暂停最主要的原因是早产,即早产儿呼吸暂停(AOP),也是目前新生儿重症监护中面临的主要临床问题之一。AOP的发病机制仍不清楚,目前多倾向于与早产儿呼吸中枢发育尚不完善有关,对低氧、高碳酸血症的呼吸反应不成熟,肺牵张反射过度抑制以及中枢神经介质在AOP的发生发展中起重要作用。而某些中枢神经系统和感染性疾病及早产儿行为状态可能诱发或加重呼吸暂停的发生。俯卧位、甲基黄嘌呤类药物和持续气道正压通气(CPAP)是治疗AOP的主要方法。其他治疗方法包括CO2吸入、输血以及触觉刺激等的临床应用仍需进一步研究。文章就新生儿呼吸暂停的发病机制以及治疗策略的最新研究进展进行综述。     

The Effects of Caffeine on Jumping Performance and Maximal Strength in Female Collegiate Athletes

Caffeine is often used in a variety of forms to enhance athletic performance; however, research regarding caffeine’s effects on strength and power in female athletes is lacking. Therefore, the purpose of this study was to analyze the acute effects of caffeine anhydrous (6 mg/kg of body mass) on jumping performance and maximal strength in female collegiate athletes. Eleven athletes (19.7 ± 0.9 yrs; 166.4 ± 10.2 cm, 67.7 ± 9.4 kg) performed two testing sessions separated by one week, and randomly received caffeine or placebo using a double-blind approach. Heart rate, blood pressure, and tympanic temperature were recorded before athletes received each condition, following 60 min of quiet sitting, and directly after performance testing. Athletes were assessed on unweighted and weighted squat jump height (SJH0, SJH20) and countermovement jump height (CMJH0, CMJH20), isometric mid-thigh pull peak force (IPF), and rate of force development from 0–200 ms (RFD200). Resting systolic blood pressure was significantly greater following caffeine administration compared to a placebo (p = 0.017). There were small, significant differences in SJH0 (p = 0.035, g = 0.35), SJH20 (p = 0.002, g = 0.49), CMJH0 (p = 0.015, g = 0.19), and CMJH20 (p < 0.001, g = 0.37) in favor of caffeine over placebo. However, there was no significant difference in IPF (p = 0.369, g = 0.12) and RFD200 (p = 0.235, g = 0.32) between conditions. Therefore, caffeine appears to enhance jumping performance, but not maximal strength in female collegiate athletes.