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Direct evidence for in vivo NO formation from nitroglycerin (GTN) was obtained by measurements of exhaled nitric oxide in anaesthetized. Infusions of GTN (1-100 micrograms kg-1 min-1 i.v.) induced dose-dependent and biphasic increments in exhaled NO parallelled by reductions in systemic blood pressure. The NO detected during GTN infusion was unaffected by the nitric oxide synthase inhibitor L-NAME or acute i.v. administration of L-cysteine, N-acetyl-L-cysteine or glutathione. The present data demonstrate that NO is formed from GTN in vivo, and that tolerance in vivo is due to decreased formation of NO.

This study was undertaken to investigate the possible involvement of K+ channels in PGE1-mediated vasodilatation. The increase in coronary flow elicited by PGE1 in isolated working rat hearts was attenuated by phentolamine and glibenclamide, inhibitors of ATP-regulated K+ channels, whereas apamin and charybdotoxin, inhibitors of calcium-activated K+ channels, were ineffective. In the anaesthetized rat, the duration of the hypotensive action of PGE1 was markedly attenuated by glibenclamide. It is concluded that the vasodilatory action of PGE1 in the coronary and systemic circulation of the rat is, at least in part, mediated via an opening of ATP-sensitive K+ channels.

Large amount of nitric oxide (NO) are produced at sites of inflammation through the action of inducible nitric oxide synthase (iNOS) present in both infiltrating leucocytes and activated, resident tissue cells. However, the role of NO in inflammation remains unclear. NO is a vasodilator, which inhibits the adhesion of neutrophils to the vascular endothelium; it reduces the production of IL-6 by Kupffer cells and chondrocytes, and the production of gamma-IFN and TNF-alpha by splenocytes. The literature provides contradictory information on the effect of NO on vascular leakiness, chemotaxis, prostaglandin production and tissue damage. Increasingly, data suggest that NO is immunosuppressive. Inhibitors of NOS have potent prophylactic activity in several but not all, animal models of inflammatory disease. However, in rat adjuvant arthritis, therapeutic activity is weak. Whether inhibitors of iNOS will be therapeutically useful in human inflammatory diseases cannot be predicted on the basis of present information.

BIRM 270 was developed as a potent and enantioselective inhibitor of LTB4 biosynthesis by human neutrophils, and was also found to inhibit LTC4 production by human eosinophils and lung mast cells. BIRM 270 inhibited LTB4 synthesis in neutrophils by preventing arachidonate release from membrane phospholipids, and over the same concentration range, inhibited PAF biosynthesis. BIRM 270 did not directly inhibit acylhydrolases which have been implicated in eicosanoid and PAF biosynthesis, suggesting an indirect mode of action.

This study was performed to determine whether long-term treatment with organic nitrovasodilators exhibit pharmacological effects on the development of atherosclerotic lesions and endothelial dysfunction in the cholesterol fed rabbit. The major finding of this study is that PETN, but not ISMN, decreases the extent of aortic intimal lesions and the development of endothelial dysfunction. In addition, 15 weeks of feeding a diet enriched with either PETN or ISMN did not induce a measurable extent of vascular in-vitro tolerance to the vasodilator activity of these drugs.

Reactive hyperemia following 30 s of coronary occlusion in the isolated guinea pig heart is accompanied by a two-fold increase of nitric oxide (NO) and histamine release, which are significantly reduced in the presence of L-NAME, cimetidine and thioperamide, respectively. Great changes of histamine release occur during autoregulation. However, histamine seems much more important for metabolic dilation below the autoregulatory range. Inhibition of NO synthesis, but not blockade of histamine receptors, widens the autoregulatory range. Changes of the released NO and histamine under conditions employed in this study suggest a positive feed-back relationship between NO and histamine in the regulation of coronary circulation.

The potential role of endothelial dysfunction, defined by an imbalance in the production of endothelium-derived vasodilator and constrictor factors is discussed. Evidence is presented that increased endothelin-1 production plays an important role in the clinical and morphological manifestations of pulmonary hypertension, particularly in primary disease. As well, the potential contribution of a relative decrease in nitric oxide production to inappropriately elevated pulmonary vascular resistance in patients with secondary causes of pulmonary hypertension, particularly those with congestive heart failure is discussed.

The PACAPs have been shown to be potent vasodilators in different animal species. Data in humans are still lacking. Therefore we investigated the effects of PACAP 38, PACAP 27 and VIP on isolated human and porcine coronary arteries (HCA and PCA). Our data show, that the PACAPs are endothelium-independent vasorelaxants, which in HCA are slightly more potent than VIP. The N-terminal shortened peptides PACAP 6-38 and PACAP 6-27 also show relatively potent vasorelaxant effects, acting as partial agonists. Glibenclamide, a selective inhibitor of ATP-sensitive potassium channels, partially reverses the effects of the PACAPs, indicating an involvement of these channels in the mechanism of action.