title: The putative mechanistic basis for the modulatory role of endothelin-1 in the altered vascular tone induced by Trypanosoma cruzi.
abstract: Chagas' disease, caused by Trypanosoma cruzi, is an important cause of heart disease in Latin America. T. cruzi-induced microvascular compromise, in turn, is thought to play a major role in chagasic heart disease. Previous in vitro studies have implicated endothelin-1 (ET-1) as a potentially important vasomodulator present in increased levels in the supernatant of T. cruzi infected cultured human umbilical vein endothelial cells (HUVEC). Thus, the goal of the present investigation was to further evaluate the potentially important contribution of ET-1 to T. cruzi-induced alterations in vascular tone in vitro. Bioassay studies once again documented that exposure of isolated rat aortic rings to infected HUVEC supernatants elicited contractile responses whose steady-state magnitude was significantly greater than contractile responses elicited by exposure of aortic rings to uninfected HUVEC supernatants. Furthermore, the increased aortic contractility was significantly attenuated by the presence of the ET(A) subtype selective antagonists BMS-182,874 or BQ-123. Additionally, incubation of HUVEC with either verapamil or phosphoramidon prior to infection was also associated with reduced aortic contractility, upon exposure to the supernatant. Phosphoramidon, but not verapamil, produced a significant decrease in the measured ET-1 levels in the HUVEC supernatant. Consistent with the bioassay results, preincubation of Fura-2-loaded cultured rat aortic vascular smooth muscle cells with verapamil resulted in a near complete ablation of ET-1-induced transmembrane Ca2+ flux. Taken together, these data are consistent with the hypothesis that ET-1-induced vasoconstriction may play an important modulatory role in the vascular compromise characteristic of T. cruzi infection.
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: H B
authors.initials: HB
authors.lastname: Tanowitz
authors.forename: M
authors.initials: M
authors.lastname: Wittner
authors.forename: S A
authors.initials: SA
authors.lastname: Morris
authors.forename: W
authors.initials: W
authors.lastname: Zhao
authors.forename: L M
authors.initials: LM
authors.lastname: Weiss
authors.forename: V B
authors.initials: VB
authors.lastname: Hatcher
authors.forename: V L
authors.initials: VL
authors.lastname: Braunstein
authors.forename: H
authors.initials: H
authors.lastname: Huang
authors.forename: S A
authors.initials: SA
authors.lastname: Douglas
authors.forename: M
authors.initials: M
authors.lastname: Valcic
authors.forename: M
authors.initials: M
authors.lastname: Spektor
authors.forename: G J
authors.initials: GJ
authors.lastname: Christ
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002598:Chagas Cardiomyopathy / Q000378:metabolism / Q000503:physiopathology*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000096:biosynthesis / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism / Q000469:parasitology / Q000503:physiopathology*; D006020:Glycopeptides / Q000494:pharmacology; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D010456:Peptides, Cyclic / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D044022:Receptor, Endothelin A; D014349:Trypanosoma cruzi / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D006020:Glycopeptides; D010456:Peptides, Cyclic; D011480:Protease Inhibitors; D044022:Receptor, Endothelin A; D014665:Vasodilator Agents; D014700:Verapamil; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D002118:Calcium; C008890:phosphoramidon