title: Regulation of coronary venular barrier function by blood borne inflammatory mediators and pharmacological tools: insights from novel microvascular wall models.
abstract: We hypothesized that postcapillary venules play a central role in the control of the tightness of the coronary system as a whole, particularly under inflammatory conditions. Sandwich cultures of endothelial cells and pericytes of precapillary arteriolar or postcapillary venular origin from human myocardium as models of the respective vascular walls (sandwich cultures of precapillary arteriolar or postcapillary venular origin) were exposed to thrombin and components of the acutely activatable inflammatory system, and their hydraulic conductivity (L(P)) was registered. L(P) of SC-PAO remained low under all conditions (3.24 ± 0.52·10(-8)cm·s(-1)·cmH(2)O(-1)). In contrast, in the venular wall model, PGE(2), platelet-activating factor (PAF), leukotriene B(4) (LTB(4)), IL-6, and IL-8 induced a prompt, concentration-dependent, up to 10-fold increase in L(P) with synergistic support when combined. PAF and LTB(4) released by metabolically cooperating platelets, and polymorphonuclear leucocytes (PMNs) caused selectively venular endothelial cells to contract and to open their clefts widely. This breakdown of the barrier function was preventable and even reversible within 6-8 h by the presence of 50 μM quercetin glucuronide (QG). LTB(4) synthesis was facilitated by biochemical involvement of erythrocytes. Platelets segregated in the arterioles and PMNs in the venules of blood-perfused human myocardium (histological studies on donor hearts refused for heart transplantation). Extrapolating these findings to the coronary microcirculation in vivo would imply that the latter's complex functionality after accumulation of blood borne inflammatory mediators can change rapidly due to selective breakdown of the postcapillary venular barrier. The resulting inflammatory edema and venulo-thrombosis will severely impair myocardial performance. The protection afforded by QG could be of particular relevance in the context of cardiosurgical intervention.
authors.affiliation: Dept. of Physiology, Univ. of Munich (LMU), Schillerstr. 44, 80336 Munich, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Juchem
authors.forename: Dominik R
authors.initials: DR
authors.lastname: Weiss
authors.forename: Maria
authors.initials: M
authors.lastname: Knott
authors.forename: Anton
authors.initials: A
authors.lastname: Senftl
authors.forename: Stefan
authors.initials: S
authors.lastname: Förch
authors.forename: Theodor
authors.initials: T
authors.lastname: Fischlein
authors.forename: Eckart
authors.initials: E
authors.lastname: Kreuzer
authors.forename: Bruno
authors.initials: B
authors.lastname: Reichart
authors.forename: Stefan
authors.initials: S
authors.lastname: Laufer
authors.forename: Stephan
authors.initials: S
authors.lastname: Nees
mesh_terms: D000199:Actins / Q000378:metabolism; D001160:Arterioles / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001798:Blood Proteins / Q000494:pharmacology*; D002196:Capillaries / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D003326:Coronary Circulation / Q000187:drug effects / Q000276:immunology*; D015232:Dinoprostone / Q000494:pharmacology; D004357:Drug Synergism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006490:Hemostatics / Q000494:pharmacology; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology; D016209:Interleukin-8 / Q000494:pharmacology; D007975:Leukotriene B4 / Q000494:pharmacology; D009205:Myocarditis / Q000276:immunology / Q000378:metabolism*; D020286:Pericytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010972:Platelet Activating Factor / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology; D014699:Venules / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D000199:Actins; D001798:Blood Proteins; C508606:CXCL8 protein, human; D006490:Hemostatics; C508600:IL6 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6; D016209:Interleukin-8; D010972:Platelet Activating Factor; D007975:Leukotriene B4; D013917:Thrombin; D015232:Dinoprostone