HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 286/3/L531    most recent 00247.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (10) Citing Articles via Google Scholar Google Scholar Articles by Hong, Z. Articles by Weir, E. K. Search for Related Content PubMed PubMed Citation Articles by Hong, Z. Articles by Weir, E. K.

Nordexfenfluramine causes more severe pulmonary vasoconstriction than dexfenfluramine

¹Veterans Affairs Medical Center and ⁴University of Minnesota, Minneapolis 55417; ³Guidant Corporation, St. Paul, Minnesota 55112; and ²Justus Liebig University, 35392 Giessen, Germany

Submitted 23 July 2003 ; accepted in final form 5 November 2003

The anorectic agent dexfenfluramine (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 dose-dependent 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.

anorectic agent; primary pulmonary hypertension; 5-HT₂ receptor; potassium channels

This article has been cited by other articles:

				E. K. Weir, J. Lopez-Barneo, K. J. Buckler, and S. L. Archer Acute Oxygen-Sensing Mechanisms. N. Engl. J. Med., November 10, 2005; 353(19): 2042 - 2055. [Full Text] [PDF]