Agents and actions. Supplements最新文献

We tested classically used organic nitrovasodilators such as s-nitroso-n-acetyl-D,L-penicillamine, 3-morpholino-sydnonimine, pentaerythrityl-tetranitrate, isosorbide-dinitrate, isosorbide-mononitrate, glyceryl-trinitrate on different isolated conductive arterial and venous blood vessels of the same species (rabbit). We found an up to two orders of magnitude more pronounced venoselectivety in the systemic-circulation as compared to the lung-circulation. ISMN and PETN were most venoselective nitrovasodilators, with PETN being the most potent drug in all vessels studied.

Testosterone has been implicated as a risk factor for cardiovascular diseases and thromboxane A2 (TXA2) plays a role in these diseases. We tested the notion that testosterone regulates the expression of TXA2 receptors in platelets and vascular smooth muscle. Testosterone significantly increased the density of TXA2 receptors in cultured rat aortic smooth muscle and human erythroleukemia cells, a megakaryocyte-like cell. Treatment of rats with testosterone resulted in a significant increase in platelet and aortic TXA2 receptor density and increased responsiveness to TXA2 mimetics. We conclude that testosterone regulates the expression of TXA2 receptors.

The permeability influencing effect of nitric oxide was studied by means of an isolated perfused mesentery preparation in combination with a intravital/fluorescence microscopic set up. As a fluorescent marker served FITC-dextran mol wt 70,000 daltons. Tissue treatment was performed by application of NO-donors like SNP or GTN. Additionally the effects of bradykinin, L-nitroarginine or the combination of both were tested in regard to a permeability modulation. The results point out that NO-donors did not enhance microvascular permeability, whereas the permeability increasing effect of bradykinin is mediated by an NO-independent pathway.

Endothelins (ET) are a family of peptides with potent biological properties. Endothelial cells produce exclusively ET-1 while other tissues produce ET-2 and ET-3. The production of ET requires an increase in intracellular Ca2+. This increase can be induced by physical chemicals (i.e. hypoxia) or receptor-operated stimuli (i.e. thrombin, angiotensin II, arginine vasopressin, transforming growth factor beta 1, interleukin-1). Most of ET is released abluminally towards vascular smooth muscle and less luminally. The main vascular effect of ET are vasodilation (transient), profound and sustained vasoconstriction as well as proliferation of vascular smooth muscle. These biological effects are mediated by distinct receptors. Three ET receptors have been cloned, i.e. ETA-, ETB- and ETC-receptors. In vascular tissue ETA-receptors are expressed on vascular smooth muscle and responsible for vasoconstriction. ETB-receptors are expressed on endothelium and linked to nitric oxide and/or prostacyclin release. Activation of these receptors explains the transient vasodilation with intraluminal application of ET. Vascular smooth muscle cells can express ETB-receptors which contribute to ET-induced vasoconstriction particularly at lower concentrations. The role of the recently cloned ETC-receptor in the vasculature is still uncertain. ET production is increased (as judged from circulating plasma levels) in vascular disease and atherosclerosis in particular, in myocardial infarction and heart failure, pulmonary hypertension and renal disease. ET production is increased in arterial hypertension remains controversial. Non-peptidic ET antagonists have been developed which either block ETA- receptors or ETA- and ETB-receptors simultaneously. The advantage of ETA-receptors is that they leave the endothelium-dependent vasodilation to ET (via ETB-receptor) intact. However, ETB-mediated contraction remains unaffected by these antagonists. In contrast ETA-/ETB-antagonists fully prevent ET-induced vasoconstriction, however, they also inhibit the endothelial effects of the peptide. ET antagonists interfere with the effects of ET in isolated vascular tissue (including that obtained from humans) as well as in vivo. In humans, ETA as well as ETA-/ETB-antagonists inhibit endothelin-induced vasoconstriction. Hence in summary ET are a family of potent peptides with profound effects in the vasculature. Several studies suggest a role of ET in cardiovascular disease. The newly developed ET-antagonists are potent and selective tools to delineate the (patho-)physiological roles of ET and may become a new class of cardiovascular drugs.

F2-isoprostanes are free radical catalyzed prostaglandin F2 isomers formed from arachidonic acid in an enzyme independent manner (1). Analogous families of other prostaglandin isomers have also been described. Detection of these compounds in vivo has been postulated to represent an approach to the quantitative assessment of free radical generation in humans (2). Additionally, the 8-iso analogues of PGF2 alpha and PGE2 have been shown to induce vasoconstriction, a response which is prevented by pharmacological antagonists of the thromboxane receptor (3). Consequently, it is conceivable that these particular isomers might exhibit an autacoidal function. We chose to explore the factors which regulate the biosynthesis of one of these compounds, 8-iso-PGF2 alpha, in vivo and by human platelets in vitro, to understand more clearly how the discovery of these compounds might be exploited to further our understanding of free radical catalyzed processes in vivo.

Protein kinase C plays a central role in the cellular signaling pathway for the lipophilic second messenger sn-1,2-diacylglycerol, which is involved in many biological responses, including tumor promotion and inflammation. A major effort has been directed at understanding diversity within this system in order to develop strategies for selective inhibition. Two classes of ligands for the regulatory domain of protein kinase C have been identified which, although they function in vitro as activators of the enzyme, paradoxically behave in vivo as partial antagonists. Identification of targets for the phorbol esters distinct from protein kinase C argues that antagonists acting on the regulatory and catalytic domains of protein kinase C will have different spectra of action.

Cell-impermeable inhibitors of phospholipase A2 were prepared by linking inhibiting molecules to macromolecular carriers which prevent the inhibitor's internalization. These preparations inhibit the release of oxygen reactive species from neutrophils and cell death induced by inflammatory agents, as well as bleomycin-induced lung injury.

The eosinophil is the predominant inflammatory cell which accumulates in the asthmatic lung. There is considerable circumstantial evidence linking these cells to lung dysfunction, but the precise cause and effect relationship is controversial. The defensive role of the eosinophil appears to be concerned largely with eliminating helminth parasites which do not normally present a constant threat. Thus, unlike the neutrophil whose defensive role against microbes is essential, the eosinophil presents a target for therapeutic intervention which is potentially applicable to long-term treatment. Several approaches to suppressing eosinophil accumulation are possible, based on the multiple steps involved in their appearance and activation in the lung (for review see [1]). One approach is to block the receptor(s) to the important endogenous eosinophil chemoattractants generated in the asthmatic lung, offering the potential for selective leukocyte-type suppression. A first step in this pursuit is the identification of such chemoattractants. This article describes recent attempts in this direction, with the long-term goal of producing chemoattractant receptor antagonists.