Involvement of platelet activating factor in immediate heart response to lipopolysaccharide.
Although lipopolysaccharide (LPS) is recognized to induce a biphasic cardiovascular response its mechanism is not fully elucidated. In this study we analysed the involvement of PAF, TXA(2) and cysteinyl leukotrienes (cysLTs) in the acute cardiovascular effects of LPS in the isolated rat heart as well as in delayed phase of LPS response using a surrogate cellular model of the induction of NOS-2 by LPS in mouse macrophages. Perfusion of rat hearts with LPS resulted, in an immediate fall in heart contractility and coronary flow by 2.5 +/- 0.59 ml x min(-1) and 560 +/- 81 mmHg x sec(-1), respectively. This response was fully blocked by platelet activating factor (PAF) antagonist - WEB 2170 and partially inhibited, by inhibitor of cyclooxygenase (indomethacin) or by inhibitor of thromboxane synthase (camonagrel). The inhibition of leukotriene synthesis (BAY x1005) or cysLTs receptors (BAY x7195) was without effect. Administration of stable PAF analog (methylcarbamyl-PAF - MC-PAF) alone, mimicked heart response to LPS. In cultured mouse macrophages, MC-PAF did not induce NOS-2 expression and when given with LPS it slightly potentiated NOS-2 induction by LPS. However, in presence of WEB 2170 NOS-2 induction by LPS was inhibited in a dose-dependent manner. Inhibition of cyclooxygenase and leukotriene pathways had no effect on NOS-2 induced by LPS. These results indicate that PAF and TXA(2) but not cysLTs mediate the instant heart response induced by LPS, while PAF alone mediates a delayed NOS-2 induction by LPS. Accordingly, PAF may constitute the mediator that links acute and delayed phases of LPS-induced cardiovascular response.
Jakubowski
A
A
Department of Experimental Pharmacology, Jagiellonian University Medical College, Cracow, Poland.
Olszanecki
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R
Chlopicki
S
S
D000818:Animals; D001381:Azepines / Q000494:pharmacology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D004926:Escherichia coli; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D010742:Phospholipid Ethers / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D018077:Receptors, Leukotriene / Q000378:metabolism; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology
D001381:Azepines; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D010742:Phospholipid Ethers; D010972:Platelet Activating Factor; D018077:Receptors, Leukotriene; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D014230:Triazoles; C053479:1-O-hexadecyl-2-N-methylcarbamylphosphatidylcholine; C063964:bepafant; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C083169:leukotriene D4 receptor