Biomedical subjects

R Spriestersbach

Publications and source records attributed to R Spriestersbach.

5 recordsLinked to original sources

PubMed1997

Human endothelial cell activation and mediator release in response to the bacterial exotoxins Escherichia coli hemolysin and staphylococcal alpha-toxin.

Escherichia coli hemolysin (HlyA) and Staphylococcus aureus alpha-toxin are membrane-perturbating bacterial exotoxins that have been implicated as significant virulence factors in human diseases. We investigated the capacity of these toxins to cause cell activation and mediator release in human endothelial cells, compared with the efficacies of thrombin and the Ca2+ ionophore A23187. Concentration ranges tested were 1 to 1000 ng/ml (HlyA), 0.01 to 10 micro/ml (alpha-toxin), 0.01 to 10 U/ml (thrombin), and 0.01 to 10 microM (A23187). All stimuli caused dose-dependent generation of platelet-activating factor, nitric oxide, and prostaglandin I2. HlyA and thrombin effected time- and dose-dependent accumulation of large quantities of inositol phosphates, with maximum effects at 100 ng/ml and 1 U/ml, respectively. Corresponding time course and dose dependency were noted for HlyA-elicited diacylglycerol formation. In contrast, only the highest concentrations of alpha-toxin (10 microg/ml) and A23187 (10 microM) effected some moderate inositol phosphate accumulation, and this was suppressed in the presence of the platelet-activating factor antagonist WEB 2086. Metabolic and secretory responses elicited by alpha-toxin were dependent on the presence of extracellular Ca2+. We conclude that both HlyA and alpha-toxin are potent inductors of inflammatory and vasodilatory mediators in human endothelial cells. HlyA-elicited effects may proceed predominantly via activation of the phosphatidylinositol hydrolysis-related signal transduction pathway, whereas transmembrane Ca2+ flux appears to be the major event underlying the release of mediators in response to alpha-toxin. These toxin properties may contribute to vasoregulatory and inflammatory disturbances encountered in states of severe infection and sepsis.

Animals↗

PubMed1997

Efficiency of aerosolized nitric oxide donor drugs to achieve sustained pulmonary vasodilation.

Inhalation of nitric oxide (NO) causes selective pulmonary vasodilation, but demands continuous supply of the gaseous agent. We investigated the suitability of aerosolization of NO-donor drugs for achieving sustained reduction of pulmonary vascular tone. In buffer-perfused rabbit lungs, stable pulmonary hypertension was achieved by continuous infusion of the thromboxane-analogue U46619. The NO-donor drugs molsidomine, 3-morpholinosydnone-imine (SIN-1), sodium nitroprusside (SNP) and glyceryl-trinitrate reduced the pulmonary hypertension in a dose-dependent fashion, whether admixed to the perfusate or inhaled as alveolar-accessible aerosol particles (aerosolization time 3-6 min), with an efficiency ranking of SNP > SIN-1 >> molsidomine and glyceryl-trinitrate. Notably, nearly identical dose-response curves were obtained when corresponding molar quantities of the most potent agents, SNP and SIN-1, were applied either via transbronchial or via intravascular routes, with respect to rapidity of onset, extent (pressure reduction to near baseline) and duration (>90 min) of vasorelaxation. Appearance of sydnonimines in the perfusate after aerosolization and reduction of SIN-1 efficacy when nebulized in nonrecirculatingly perfused lungs demonstrated substantial entry of this prodrug into the vascular space after alveolar deposition. In contrast, undiminished vasodilatory efficacy of aerosolized SNP under conditions of non-recirculating perfusion suggested predominant efficacy via local NO release for this agent. We conclude that short aerosolization maneuvers of NO-donor drugs are suitable to achieve dose-dependent, extensive and sustained vasodilation in the pulmonary circulation, thus offering a new therapeutic approach in pulmonary hypertension.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1995

Effects of NADPH oxidase inhibitors on hypoxic vasoconstriction in buffer-perfused rabbit lungs.

The involvement of NADPH oxidase in hypoxic pulmonary vasoconstriction (HPV) was investigated in buffer-perfused rabbit lungs, employing the inhibitors diphenyleneiodonium (DPI) and apocynin. Responses to the vasoconstrictors U-46619 and angiotensin II (ANG II) were used to test specificity. Lung nitric oxide (NO) generation was assessed by on-line monitoring of NO exhalation (chemiluminescence), and the efficacy of DPI and apocynin on the NADPH oxidase-dependent O2- generation was quantified in alveolar macrophages by fluorescent-activated cell sorter technique. In a concentration range between 1 and 5 mM, apocynin inhibited macrophage respiratory burst and HPV but similarly suppressed U-46619-induced vasoconstrictor responses. DPI inhibited macrophage O2- generation in concentrations > or = 0.5 microM. At doses between 0.5 and 1.5 microM, DPI blocked lung NO generation, thereby increasing HPV. At higher doses (4 microM), in contrast, DPI fully blocked the hypoxia-induced pressor responses, whereas the vasoconstrictor responses to U-46619 and [Asn1, Val5] ANG II were not diminished. In the presence of NG-monomethyl-L-arginine, used to block lung NO generation throughout, DPI exhibited only the monophasic selective inhibition of HPV. We conclude that apocynin lacks specificity for HPV, but DPI, in addition to inhibiting lung NO generation, causes selective blockade of the hypoxia-induced vasoconstriction. This finding supports the hypothesis that an NADPH oxidase is involved in hypoxia sensing or specific signal transduction events underlying HPV.

Acetophenones↗

PubMed1995

On-line measurement of nitric oxide generation in buffer-perfused rabbit lungs.

In buffer-perfused rabbit lungs, the mixed expired gas was continuously analyzed for nitric oxide (NO) by chemiluminescence detection, and recovery data in dependency of the alveolar O2 tension were established. A small aliquot of the lung effluent was continuously forwarded to a reaction vessel in which the NO decomposition products nitrite, peroxynitrite, and nitrate [summarized as NOx; acidic vanadium (III) chloride reagent] or nitrite (acidic sodium iodide reagent) were quantitatively reduced back to NO, which was then transferred to a second chemiluminescence detector. Under baseline conditions, the perfused lungs continuously released 2.2 +/- 0.21 nmol/min of NO (n = 10) into the gas space. NO was permanently liberated into the intravascular compartment at 7.0 +/- 0.3 nmol/min (n = 4). According to a very low buffer-gas partition coefficient of NO (estimated to be 0.0292 +/- 0.005 in separate equilibration experiments), NO aerated into the prelung perfusate largely escaped into the alveolar space within one lung passage, whereas only low percentages of inhaled NO were detected as NOx in the buffer medium. Immediate increase of lung NO generation in response to A-23187 challenge and inhibition by NG-monomethyl-L-arginine were demonstrated. In conclusion, in buffer-perfused lungs, total NO generation may be monitored by continuous analysis of NO exhalation and perfusate NOx accumulation.

Animals↗

PubMed1995

Nitric oxide generation and hypoxic vasoconstriction in buffer-perfused rabbit lungs.

Nitric oxide generation and hypoxic vasoconstriction in buffer-perfused rabbit lungs. J. Appl. Physiol. 78(4): 1509-1515, 1995.--We investigated the role of nitric oxide (NO) generation in hypoxic pulmonary vasoconstriction in buffer-perfused rabbit lungs. Exhaled NO was detected by chemiluminescence, and intravascular NO release was quantified as perfusate accumulation of nitrite, peroxynitrite, and nitrate (NOx). Under baseline conditions, exhaled NO was 45.3 +/- 4.1 parts per billion (1.8 +/- 0.2 nmol/min), and lung NOx release into the perfusate was 4.1 +/- 0.4 nmol/min. Alveolar hypoxia (alveolar PO2 of approximately 23 Torr) induced readily reproducible pressor responses preceded by a sharp drop in exhaled NO concentration. In contrast, perfusate NOx accumulation was not affected. Vasoconstrictor responses to U-46619 and angiotensin II were not accompanied by a decrease in NO exhalation. NG-monomethyl-L-arginine dose-dependently suppressed NO exhalation and amplified pressor responses to hypoxia > U-46619 and angiotensin II. In conclusion, portions of baseline NO generation originating from sites with ready access to the gaseous space sharply decrease in response to alveolar hypoxia, whereas the intravascular release of NO is unchanged. Such differential regulation of lung NO synthesis in response to hypoxia may suggest a complex role in the regulation or modulation of hypoxic pulmonary vasoconstriction.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗