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An endogenous NO-release which exceeds the basal endogenous NO-release has a regulatory effect on capillary microvasculature in isolatedly perfused rat hearts. The basal NO-release in contrast has no effect on capillaries. The functional findings are corresponding to the endothelial distribution of NOS in coronary vessels, which displays a lack of NOS in capillary endothelium. An increase of coronary flow by exogenously administered NO-donors does not necessarily lead to a dilation of capillary microvasculature. Local differences in the release of unstable NO by SNP and GTN are responsible for variations in effects. We can conclude: NO influences the dilation of the capillary microvasculature independently of flow regulation.

The effects of PGE1, PGE0 and the stable PGE1-analogue SPM 206 on human epicardial coronary arteries were studied in vitro. The tension of the isolated arterial rings was measured isometrically. After precontraction, concentration-response curves with the compounds were performed. PGE1 and SPM 206 elicited concentration-dependent relaxations which are counteracted by a contractile action in higher concentrations. In PGE0, the contractile action occurred even in lower concentrations. This contraction was antagonized by the selective thromboxane A2 antagonist SQ 29,548, resulting in an equipotent relaxation for all three compounds.

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.

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.

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.

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.

Long-term exposure of platelets to prostacyclin or iloprost (100nM, 3hr) results in receptor desensitization measured as decrease in 3H-iloprost binding sites by 47 +/- 14%. Desensitized platelets respond with an increased adhesion to endothelial cells. The mechanism of increased adhesiveness was studied by measuring the expression of the adhesion molecule CD62p (p-selectin; GMP140) on washed human platelets by flowcytometry. In thrombin stimulated platelets CD62p expression was dose-dependently reduced by iloprost. In receptor desensitized platelets IC50 for iloprost inhibition of thrombin-induced CD62p expression increased from 0.48 +/- 0.10 to 2.4 +/- 0.7 nM.