| Autor: |
Kalinichenko, Vladimir V., Gusarova, Galina A., Il-Man Kim, Galina A., Shin, Brian, Yoder, Helena M., Clark, Jean, Sapozhnikov, Alexander M., Whitsett, Jeffrey A., Costa, Robert H. |
| Předmět: |
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| Zdroj: |
American Journal of Physiology: Lung Cellular & Molecular Physiology; Mar2004, Vol. 30 Issue 3, pL521-L530, 10p, 12 Color Photographs, 14 Black and White Photographs, 1 Chart |
| Abstrakt: |
The anorectic agent dextenfluramine (dex) causes the development of primary pulmonary hypertension in susceptible patients by an unknown mechanism. We compared the effects of dex with those of its major metabolite, nordexfenfluamine (nordex), in the isolated perfused rat lung and in isolated rings of resistance pulmonary arteries. Nordex caused a dose-dependent and more intense vasoconstriction, which can be inhibited by the nonspecific 5-hydroxytryptamine type 2 (5-HT2) blocker ketanserin. Similarly a rise in cytosolic calcium concentration ([Ca2+]i) in dispersed pulmonary artery smooth muscle cells (PASMCs) induced by nordex could be prevented by ketanserin. Unlike prior observations with dex, nordex did not inhibit K+ current or cause depolarization in PASMCs. Removal of Ca2+ from the tissue bath or addition of nifedipine (1 µM) reduced ring contraction to nordex by 60 ± 9 and 63 ± 4%, respectively. The addition of 2-aminoethoxydiphenyl borate (2-APB), a blocker of store-operated channels and the inositol 1,4,5-trisphosphate receptor, caused a dosedependent decrease in the ring contraction elicited by nordex. The combination of 2-APB (10 µM) and nifedipine (1 µM) completely ablated the nordex contraction. Likewise the release of Ca2+ from the sarcoplasmic reticulum by cyclopiazonic acid markedly reduced the nordex contraction while leaving the KCl contraction unchanged. We conclude that nordex may be responsible for much of the vasoconstriction stimulated by dex, through the activation of 5-HT2 receptors and that the [Ca2+]i increase in rat PASMCs caused by dex/nordex is due to both influx of extracellular Ca2+ and release of Ca2+ from the sarcoplasmic reticulum. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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