Lys-[Leu8,des-Arg9]-bradykinin blocks lipopolysaccharide-induced SHR aorta hyperpolarization by inhibition of Ca(++)- and ATP-dependent K+ channels

The mediators involved in the hyperpolarizing effects of lipopolysaccharide and of the bradykinin B1 receptor agonist des-Arg9-bradykinin on the rat aorta were investigated by comparing the responses of aortic rings of spontaneously hypertensive and normotensive Wistar rats. Endothelized rings from hypertensive rats were hyperpolarized by des-Arg9-bradykinin and lipopolysaccharide, whereas de-endothelized rings responded to lipopolysaccharide but not to des-Arg9-bradykinin. In endothelized preparations, the responses to des-Arg9-bradykinin were inhibited by Nomega-nitro-L-arginine and iberiotoxin. De-endothelized ring responses to lipopolysaccharide were inhibited by iberiotoxin, glibenclamide and B1 antagonist Lys-[Leu8,des-Arg9]-bradykinin. This antagonist also inhibited hyperpolarization by des-Arg9-bradykinin and by the á2-adrenoceptor agonist, brimonidine. Our results indicate that Ca(2+)-sensitive K+ channels are the final mediators of the responses to des-Arg9-bradykinin, whereas both Ca(2+)- and ATP-sensitive K+ channels mediate the responses to lipopolysaccharide. The inhibitory effects of Lys-[Leu8,des-Arg9]-bradykinin is due to a direct action on Ca(2+)- and ATP-sensitive potassium channels.     

An evaluation of extubation failure predictors in mechanically ventilated infants and children

OBJECTIVE: To assess the accuracy of traditional weaning indices in predicting extubation failure, and to compare their accuracy when indices are measured at the onset of a breathing trial (SBT) and at the end of the SBT before extubation. DESIGN: Prospective study. SETTING: Medical-surgical intensive care unit at a tertiary care hospital. PATIENTS: Four hundred eighteen consecutive infants and children who received mechanical ventilation for at least 48 h and were deemed ready to undergo a SBT by their primary physician. INTERVENTIONS: Respiratory frequency (RR), tidal volume (V(T)), maximal inspiratory pressure (P(imax)) and frequency-to-tidal volume ratio (f/V(T)) were obtained within the first 5 min of breathing through a T-piece. The primary physicians were unaware of those measurements and the decision to extubate a patient was made by them. RR, V(T), f/V(T) were remeasured before extubation by the respiratory therapists. Extubation failure was defined as needing re intubation within 48 h after extubation. The area under the receiver operating characteristic (ROC) curve was calculated for each index as a measure of the accuracy in predicting extubation outcome. MEASUREMENTS AND MAIN RESULTS: Three hundred twenty-three patients successfully underwent the SBT and were extubated, but 48 of them (14%) required re-intubation. The ROC curve for V(T), RR, P(imax) and f/V(T) measured within the first 5 min of breathing were 0.54, 0.56, 0.57 and 0.57, respectively. The ROC curve did not increase significantly when the above indices were remeasured before extubation. CONCLUSIONS: In a population which had passed SBT, the ability of the traditional weaning indices to discriminate between children successfully extubated and children re-intubated is very poor.     

Characterization of alpha2-adrenoceptors in smooth muscles of the spontaneously hypertensive rat aorta

Previous works have shown that the alpha(2)-adrenoceptor agonist UK 14,304 induced the relaxation and hyperpolarization of the rat aorta, mediated by alpha(2)-adrenoceptors present in the smooth muscles, through small-conductance, ATP-sensitive K(+) channels. We now report that in spontaneously hypertensive rat (SHR) aortic rings, UK 14,304 induced concentration-dependent hyperpolarizing responses, which were inhibited by yohimbine, an alpha(2)-adrenoceptor inhibitor, and by glibenclamide, a specific inhibitor of small-conductance, ATP-sensitive K(+) channels. The responses were also partially inhibited by iberiotoxin and by apamin. Treatment with N(omega)-nitro-L-arginine (L-NNA) did not affect the response to UK 14,304. These results indicate that alpha(2)-adrenoceptors are present in SHR aortic smooth muscle cell membranes, but differ from those of normotensive animals regarding the K(+) channels involved in their responses. Moreover, the resting membrane potential (RMP) was significantly more negative in SHR than in normotensive rats. This relative hyperpolarized state is probably due to Ca(2+)-dependent K(+) channels being constitutively open in SHR, since the addition of iberiotoxin caused a significant depolarization of the aortic smooth muscle membranes in this strain.     

Corpus callosum: microsurgical anatomy and MRI

The anatomy of the corpus callosum has received renewed interest during recent years due to the increasing number of callosotomies performed to treat intraventricular lesions, as well as some forms of generalized epilepsy. We have previously reported on the microsurgical anatomy of the corpus callosum and identified specific anatomical reference landmarks that can be used during surgery. In the present study we have continued the anatomical aspect of this earlier work in a larger number of cases, with in vitro observations (brain out of skull) being compared with the corresponding in vivo features seen in sagittal MRI slices. Fifty-three in vitro microsurgical callosotomies was performed and the data collected compared with a series of 57 in vivo normal MR callosal images. Callosal dimensions were measured on both the anatomical and MRI material, thus overcoming the problems associated with in vitro callosal deformation. Of the anatomical landmarks studied the distance from the genu of the corpus callosum to the bifurcation of the columns of the fornix was found to be useful for the intraoperative evaluation of the extent of rostral callosotomy, as it is not significantly changed in in vitro. The main microsurgical features of rostral callosotomy are presented.     

Demonstration of inhibitory effect of oral shark cartilage on basic fibroblast growth factor-induced angiogenesis in the rabbit cornea

Several angiogenic inhibitors have been obtained from shark cartilage, some of these are currently in clinical trials for assessment of safety and therapeutic efficacy in humans. Still, shark cartilage taken orally is commonly used in alternative and complimentary medicine for various ailments including serious diseases such as cancer. However, only few studies of oral shark cartilage have demonstrated pharmacological effects in experimental animals or patients, to indicate safe doses with sufficient bioavailability. In the present study we demonstrated the antiangiogenic properties of oral shark cartilage in the rabbit cornea model. Slow-release, polymethylmetacrylate pellets containing basic fibroblast growth factor (bFGF) were surgically implanted in the rabbit cornea to stimulate neovascularization scored by stereo microscopy. Powdered shark cartilage (PSC; commercial product) was tested orally along with a water-soluble fraction (WSF) of this cartilage product which was tested by local application. Animals were treated with oral dosages of 100 mg/kg PSC or 200 mg/kg thalidomide as positive control. Pellets containing WSF (50, 100 or 200 microg/pellet) or bFGF-inhibitor pentosan polysulfate were implanted adjacent to the bFGF pellet. Oral shark cartilage inhibited bFGF-induced angiogenesis, as did oral thalidomide, in this in vivo model. WSF and pentosan polysulfate was shown to block neovascularization in the cornea when applied locally. This study demonstrates that in the rabbit, oral shark cartilage appears to produce systemic levels of angiogenesis inhibitors that can exert their effect at the cornea.     

Local opiate receptors in the sinoatrial node moderate vagal bradycardia

Met-enkephalin-arg-phe (MEAP) interrupts vagal bradycardia when infused into the systemic circulation. This study was designed to locate the opiate receptors functionally responsible for this inhibition. Previous observations suggested that the receptors were most likely located in either intracardiac parasympathetic ganglia or the pre-junctional nerve terminals innervating the sinoatrial node. In this study 10 dogs were instrumented with a microdialysis probe inserted into the sinoatrial node. The functional position of the probe was tested by briefly introducing norepinephrine into the probe producing an increase in heart rate of more than 30 beats/min. Vagal stimulations were conducted at 0.5, 1.2 and 4 Hz during vehicle infusion (saline ascorbate). Cardiovascular responses during vagal stimulation were recorded on-line. MEAP was infused directly into the sinoatrial node via the microdialysis probe. The evaluation of vagal bradycardia was repeated during the nodal application of MEAP, diprenorphine (opiate antagonist), and diprenorphine co-infused with MEAP. MEAP introduced into the sinoatrial node via the microdialysis probe reduced vagal bradycardia by more than half. Simultaneous local nodal blockade of these receptors with the opiate antagonist, diprenorphine, eliminated the effect of MEAP demonstrating the participation by opiate receptors. Systemic infusions of MEAP produced a reduction in vagal bradycardia nearly identical to that observed during nodal administration. When local nodal opiate receptors were blocked with diprenorphine, the systemic effect of MEAP was eliminated. These data lead us to suggest that the opiate receptors responsible for the inhibition of vagal bradycardia are located within the sinoatrial node with few, if any, participating extra-nodal or ganglionic receptors.     

Plasma metalloproteinase activity is enhanced in the euglobulin fraction of breast and lung cancer patients

Matrix metalloproteinases (MMP) have been implicated in tumor invasion and metastasis. We verified, by gelatin zymography, MMP activity in the euglobulin plasma fraction of 82 healthy controls, 66 patients with benign diseases and 149 patients with breast, lung, colon or brain cancer. The euglobulin fractions assayed showed 4 gelatinolytic bands of 62, 92, 120 and 200 kDa. The median (Md) value for 92 kDa-MMP activity was significantly increased in breast (Md 1.34 arbitrary units [AU]/ml plasma, range 0.0-7.2) and lung cancer patients (Md 1.43 AU/ml, range 0.0-3.6) compared with the controls (Md 0.48 AU/ml, range 0.0-1.8). Patients with colon cancer or gliomas presented values of MMP-9 similar to those of the healthy population. Multivariate analysis indicated that plasma MMP-9 activity was not predicted by the known clinicopathological parameters such as age, stage, tumor size, number of positive lymph nodes, histologic grade, histologic type, nuclear grade or mitotic index. Lung cancer patients also presented high values of MMP-9 (Md 1.43, range 0.0-3.6 [n = 26]), without association with tumor stage or histologic type. The levels of 92 kDa-MMP activity in the plasma euglobulin fraction could be a potentially useful tumor marker in breast and lung cancer.     

新缩瞳剂包公藤甲素人工合成研究

包公藤甲素是从包公藤(Erycibe obtusifolia Benth.)茎中提得的一个新莨菪烷生物碱,具有强烈的缩瞳作用,临床用于治疗青光眼。本文报道用合成的6β-乙酰氧基托品酮为原料,经卤代、水解、还原和N-去甲基化等反应合成包甲素(8)。经光谱测定证实8与天然包甲素的结构完全一致。合成品系外消旋体,其作用机理与天然品相同,而强度则减半。