The effect of calcium antagonists on histamine and leukotriene-induced tracheal microvascular permeability in the guinea pig

The effects of several calcium antagonists, i.e., nifedipine, verapamil and 8-[N,N-diethylamino]-octyl 3,4,5-trimethoxybenzoate hydrochloride (TMB-8), were evaluated in situ on agonist-induced increases in permeability of the airway microvasculature in anesthetized guinea pigs. Vascular permeability was measured as tracheal extravascular albumin content by using 125I-bovine serum albumin and the utilization of 51Cr labelled-erythrocytes to correct for blood volume. Intratracheal injections of histamine (1, 10 and 100 micrograms) or leukotriene (LT) D4 (1, 10 and 100 ng) produced dose-dependent increases in extravasated radiolabelled albumin in the trachea. Although histamine produced a greater maximal response than LTD4, the latter provocation was ten times more potent than the former. Nifedipine, a dihydropyridine calcium slow channel blocker, exhibited dose-dependent (30, 100 and 300 micrograms/kg) inhibitory activity against histamine-induced increases in extravascular albumin, while another calcium slow channel blocker, verapamil (100, 300 and 1000 micrograms/kg), exhibited much less activity. TMB-8, a purported intracellular calcium antagonist (1 and 10 mg/kg), was observed to have some inhibitory activity versus histamine. Similar doses of all three calcium antagonists failed to significantly inhibit increases in tracheal microvascular permeability evoked by LTD4. These results suggest that differences in mediator-induced microvascular permeability in the guinea pig trachea are evident depending upon the agonist selected and the pool of calcium utilized.     

The effect of calcium antagonists on histamine and leukotriene-induced tracheal microvascular permeability in the guine pig

The effects of several calcium antagonists, i.e., nifedipine, verapamil adn 8-[N,N-diethylamino]-octyl 3,4,5-trimethoxybenzoate hydrochloride (TMB-8), were evaluated on agonist-induced increases in permeability of the airway microvasculature in anesthetized guinea pigs. Vascular permeability was measured as tracheal extravascular albumin content by using ¹²⁵I-bovine serum albumin and the utilization of ⁵¹Cr labelled-erythrocytes to correct for blood volume. Intratracheal injections of histamine (1, 10 and 100 μg) or leukotriene (LT) D₄ (1, 10 and 100 ng) produced dose-dependent increases in extravasated radiolabelled albumin in the trachea. Although histamine produced a greater maximal response than LTD₄, the latter provocation was tent times more potent than the former. Nifedipine, a dihydropyridine calcium slow channel blocker, exhibited dose-dependent (30, 100 and 300 μg/kg) inhibitory activity against histamine-induced increases in extravascular albumin, while another calcium slow channel blocker, verapamil (100, 300 and 1000 μg/kg), exhibited much less activity. TMB-8, a purported intracellular calcium antagonist (1 and 10 mg/kg), was observed to have some inhibitory activity versus histamine. Similar doses of all three calcium antagonists failed to significantly inhibit increases in tracheal microvascular permeability evoked by LTD₄. These results suggest that differences in mediator-induced microvascular permeability in the guinea pig trachea are evident depending upon the agonist selected and the pool of calcium utilized.     

The effect of selenium and vitamin E on microvascular permeability of rat organs

The effects of dietary sodium selenite and vitamin E on the microvascular permeability of rat organs such as heart, brain, kidney, liver and eye were investigated by using the Evans blue leakage method. Combined deficiency of selenium and vitamin E caused an increase in the permeability of the heart and eye with respect to their controls while it had no considerable effect on the permeability of other organs. On the other hand, toxic levels of selenium (4.2 mg/kg) in diet decreased the permeabilities in kidney, liver, and eye whereas this parameter of brain increased in the same animal group. These results suggested that low or high sodium selenite and vitamin E contents in diet could alter the microvascular permeability of different organs in different manners. It might be important to give reasonable explanations for the pathophysiology of some diseases that are characterized with organ damage and /or disfunction originated from selenium deficiency or toxicity.     

The effect of synthetic polymers on the electrical and permeability properties of lipid membranes

1. The effect of two series of hydrophilic and hydrophobic polymers on the stability, conductivity and permeability towards water and leucine of black lipid membranes and liposomes is reported. 2. The changes in properties of these membrane preparations is related to bulk phase viscosity and dielectric measurements together with monolayer studies. 3. The hydrophobic polymers dramatically increase membrane stability, had no effect on conductivity, but increased the permeability coefficient of leucine. 4. The hydrophilic polymers produced minor, but significant changes to membrane properties. 5. It is concluded that not only basic polymers but also neutral and acidic macromolecules can interact strongly with lipid membranes.     

蛋白激酶在微血管通透性中的作用

微血管内皮细胞层是一层半选择通透性屏障,可以调节血液中的液体、溶质和血浆蛋白进入组织间隙。在炎症刺激作用下,可通过旁细胞途径和跨细胞途径引起内皮通透性上升。旁细胞通路主要由内皮细胞间的紧密连接、黏附连接和细胞与外基质的黏着斑组成。炎症介质,如脂多糖和肿瘤坏死因子α可激活多种蛋白激酶。活化的蛋白激酶主要包括Rho相关的卷曲蛋白激酶、肌球蛋白轻链激酶、蛋白激酶C、酪氨酸激酶和丝裂原活化蛋白激酶等,参与引发内皮屏障生化和结构改变,旁细胞通路开放,导致通透性上升。该文对上述蛋白激酶在微血管通透性中作用机制的研究进展进行综述。     

Neutrophil-dependent mediation of microvascular permeability

Macromolecular extravasation induced by the chemoattractants N-formyl-methionylleucylphenylalanine (FMLP), complement fragment C5a, and leukotriene B4 (LTB4) has been reported to be neutrophil dependent. A review of experimental evidence argues against mechanical disruption of the endothelial barrier as a likely mechanism for enhanced microvascular permeability. Other proposed mechanisms attribute macromolecular efflux to extracellular liberation of granule constituents or granule-independent neutrophil release products (e.g., oxygen radicals) that can undermine vascular integrity by direct or indirect actions on endothelial cells or other components of vascular walls (glycocalyx, basement membrane). The cytotoxic potential of neutrophil-release products on endothelial cells prompts consideration of a transcellular pathway for macromolecular transport. Further studies are needed to clarify the precise nature of endothelial injury and its resolution to better understand the physiology behind the transient effects of these mediators on vascular permeability.     

Contraction of guinea pig uterus by synthetic leukotrienes

Synthetic leukotrienes (LT) C₄ and D₄ elicited concentration-dependent contractions of the guinea pig uterus between 10^?8-10^?6M, whereas LTE₄ appeared 1000-fold weaker. The potencies of LTC₄ and LTD₄ were similar to that of acetylcholine and PGF_2α but weaker than that of PGE₂. The maximal contractions elicited by LTC₄ and LTD₄ were 66.0 ± 2.1% and 63.8 ± 4.6% that elicited by acetylcholine. FPL 55712 (10^?5M) antagonized the uterine contractile activity of LTD₄, while meclofenamic acid at 10^?5M but not at 10^?6M also antagonized the LTD₄-induced contration. Radioimmunoassay of the uterine tissue bathing fluid following LTD₄ indicated the variable presence of low concentrations of PGE₂, PGF_2α and TXB₂. These results demonstrate the LTC₄ and LTD₄ possess significant uterine contractile activity, which may only partially be mediated indirectly via prostaglandin products.     

The effect of established infection on microvascular surgery

The success of microvascular anastomoses in the presence of staphylococcal infection was studied using rat femoral arteries. There was a spontaneous thrombosis rate of 19 percent in normal vessels that traversed the area of infection. Vessels with an anastomosis outside the area of infection had a similar thrombosis rate, but if the anastomotic site was within the infected area itself, the thrombosis rate increased to 75 percent. Inflammatory changes with subsequent fibrosis in the media and adventitia appeared responsible for the thrombosis. The intima was unaffected by the presence of infection. This study suggests that when a microvascular anastomosis is necessary in the presence of infection, the anastomosis should be placed outside the area of infection with a pedicle to traverse the infected area.     

Relationship between microvascular permeability and ultrastructure

This article attempts to review some of the advances made during the past few years in our understanding of the nature of the barrier presented by the endothelial cell wall and how it may contribute to the regulation of exchange between blood and tissues. It has concentrated on a small number of experimental techniques which have yielded information on the correlation between structure and function of the endothelial cell wall and which have emphasized the potentially dynamic characteristics of the barrier. Whilst there now seems to be little dispute as to the location of the fluid conducting channels across the endothelial cell wall, within the clefts, fenestrae and in inflammation the open cell junctions, it has proved difficult to identify the molecular filter which limits macromolecular exchange across these pathways. In fenestrated endothelium it has been suggested that the filter resides at the fenestral diaphragms or in the underlying basement membrane, while in continuous endothelium there is strong support in the literature that the filter is located within the intercellular cleft, at regions of closely apposed cell membranes, or in the case of a vesicular pathway, at the necks or diaphragms of the vesicle openings. Alternatively, there is a considerable and increasing body of experimental evidence that macromolecular movement is retarded by the endothelial cell coat which lines the whole of the endothelial cell surface and covers the openings of interendothelial cell clefts, fenestral diaphragms and vesicle openings. It is believed to comprise glycoproteins secreted and regulated by the endothelial cells themselves and to have associated with it plasma proteins, particularly serum albumin. Expression of this glycocalyx and its modification have been demonstrated in vivo and in cultures of isolated endothelial cells, in vitro. Experiments using single microvessels in which a correlation between structure and function can be most readily made, offer further evidence that the clefts between endothelial cells are quantitively more than sufficient in extent to accommodate the fluid fluxes measured in even the most highly permeable vessels. They further demonstrate that the dramatic increases in fluid flux seen in inflammation result from a modulation of endothelial cell shape to form interendothelial cell gaps by activation of intracellular contractile mechanisms, mediated by changes in intracellular calcium. Increases in macromolecular leakage may only be seen when gap formation is accompanied by extensive modulation of the intercellular cement substance, or glycocalyx filling those gaps.(ABSTRACT TRUNCATED AT 400 WORDS)     

Modulation of solute permeability in microvascular endothelium

Modulation of macromolecular permeability involves creation of venular leaks in response to receptor-operated mechanisms in the endothelial cell membrane elicited by various autacoids (histamine, serotonin, bradykinin). Reversible modulations may occur within seconds in response to specific agents, which indicates receptor-mediated events that act via the endothelial cells' contractile apparatus, leading to subtle changes in junctional microtopography and allowing faster passage of small solutes. This mechanism probably involves activation of the actin-myosin system in endothelial cells. Ca2+ is an important signal substance, as reflected in the permeability-increasing effect of calcium ionophores. The junctional control system may share functional similarities with the contractile system in various types of muscle cells, in particular, smooth muscle. This suggests a function for the extensive vesicular invaginations of the plasmalemmal membrane present in endothelial cells. Rather than being a system to carry macromolecules across the endothelium, its physiological role may be to regulate free cytosolic calcium concentration. It is reminiscent of similar membrane invaginations found in muscle cells. Thus intracellular free calcium may be regulated by a combination of energy-requiring extrusion and passive influx through receptor-operated calcium channels located in the invaginated vesicular membranes, with short diffusion distances to the actin-myosin filaments in the cytoplasm.     

The leukotrienes

This paper reviews the leukotrienes, a new group of biologically active compounds in the metabolism of eicosapolyenoic acids. The leukotrienes are acyclic eicosanoids that arise through the 5-lipoxygenase pathway from eicosatrienoic, eicosatetraenoic, and eicosapentaenoic acid. Of these eicosatetraenoic acid, arachidonic acid, is the most important source of leukotrienes. Leukotriene B4 (LTB4), a dihydroxy metabolite, has been shown to exert marked chemotactic effect in many different animal species. LTB4 probably plays a role in inflammatory responses, and has been detected in several pathologic conditions. Reaction of LTA4, another lipoxygenase metabolite of arachidonic acid, with glutathione yields peptidolipid leukotrienes, LTC4, LTD4, and LTE4; these are components of slow reacting substance (SRS and SRS-A). The peptidolipid leukotrienes are potent bronchoconstrictors and enhance mucus production in the lungs. Furthermore, they constrict coronary arteries and have a negative inotropic effect. They probably play an important role in asthma and anaphylaxis. LTB4 and the peptidolipid leukotrienes may be important in several other organs, too, e.g., the skin and the eye. They may exert effects on a variety of smooth muscles and have neuronal and immunological effects.     

肺微血管内皮细胞通透性调控的信号转导机制

肺微血管内皮细胞通透性增加是急性呼吸窘迫综合征等疾病的病理基础,多种信号转导系统参与其通透性调控,如细胞内Ca2 、蛋白激酶C、环磷酸腺苷、丝裂原激活蛋白激酶、小G蛋白.这些信号转导系统的激活和调控机制各异,并且相互关联组成复杂的信号网络.肺微血管内皮细胞中信号转导的相互作用将是研究方向之一.     

Homocysteine in microvascular endothelial cell barrier permeability

Redox stress activates the endothelium and upregulates matrix metalloproteinases (MMPs), which degrade the matrix and lead to blood-endothelial barrier leakage. Interestingly, elevated levels of plasma homocysteine (Hcy) are associated with vascular dementia, seizure, stroke, and Alzheimer disease. Hcy competes with the γ-aminobutyric acid (GABA)-A/B receptors and behave like an excitatory neurotransmitter. GABA stimulates the inhibitory neurotransmitter GABA-A/B receptor and decreases arterial blood pressure. However, the neural mechanisms of microvascular remodeling in hyperhomocysteinemia are unclear. This review addresses the idea that Hcy induces microvascular permeability by attenuating the GABA-A/B receptors and increasing redox stress, which activates a disintegrin and metalloproteinase that suppresses tissue inhibitors of metalloproteinase. This process causes disruption of the matrix in the blood-brain barrier. Understanding the mechanism of Hcy-mediated changes in permeability of the blood-brain barrier and extracellular matrix that can alter the neuronal environment in cerebral-vascular dementia is of great importance in developing treatments for this disease.