Hepatic microvascular regulatory mechanisms. VI. Effects of lodoxamide tromethamine or phentolamine-HCl on early hemodynamic and glucoregulatory alterations evoked by endotoxin.
Initial changes in hepatic microvasculature and systemic arterial blood pressure were measured in non-fasted and anesthetized Sprague-Dawley rats receiving an i.v. infusion, or a topical application to the surface of the liver, of endotoxin (S. typhimurium) and/or phentolamine or lodoxamide. Circulating blood glucose and hepatic glycogen content were determined in infused rats. Injection of 10 mg per kg b.w. endotoxin, or topical administration of 10 micrograms endotoxin and/or antagonists, elicited no change in carotid (arterial) blood pressure. Infusion was accompanied by an elevation in blood glucose within 15 min and a decrease in hepatic glycogen content by 35 min. Injection of 1.0 mg per kg b.w. phentolamine blocked the endotoxin-induced hyperglycemia without affecting hepatic glycogenolysis. However, the alpha-adrenergic antagonist by itself provoked systemic hypotension, mild hypoglycemia, and hepatic glycogen depletion within 35 min. In vivo microscopy revealed that 10 micrograms endotoxin evoked immediate constriction of portal venules and periportal sinusoids. Vasoconstriction was accompanied by an increase in the percentage of microvascular segments containing decreased cellular blood flow velocity. These responses were blocked by 0.1 microgram lodoxamide but not by 100 micrograms phentolamine. The lodoxamide-induced inhibition was reversed by reapplication of 10 micrograms endotoxin 15 min following blockade. Given these results, it is suggested that (a) microvascular responses elicited by endotoxin were mediated by released constituents from intrahepatic mast cells and not by activation of alpha-adrenergic receptors, and (b) phentolamine blocked endotoxin-induced initial hyperglycemia by virtue of its hypoglycemic, glycogenolytic and/or hypotensive effects.
D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D004731:Endotoxins / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D008099:Liver / Q000098:blood supply* / Q000187:drug effects; D008112:Liver Glycogen / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000502:physiology; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D009570:Nitriles; D010072:Oxamic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D010646:Phentolamine / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D014325:Tromethamine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000596:Amino Acids; D001786:Blood Glucose; D004731:Endotoxins; D008112:Liver Glycogen; D009570:Nitriles; D014325:Tromethamine; C022028:lodoxamide tromethamine; D010072:Oxamic Acid; D010646:Phentolamine