Effects of iloprost, a stable prostacyclin analog, and its combination with NW-nitro-L-arginine on early events following lipopolysaccharide injection: observations in the hamster cheek pouch microcirculation.
The effects of iloprost, a stable prostacyclin analog, and of its combination with NW-nitro-L-arginine (L-NAG) on the microcirculatory changes observed in early stages of endotoxemia were investigated in male hamsters treated with Escherichia coli lipopolysaccharide (LPS). The cheek pouch was studied in vivo by means of intravital microscopy and mean arterial and venous pressures, mean arteriolar internal diameter, spontaneous arteriolar vasomotion, microvascular blood flow, macromolecular permeability, leukocyte adhesion and mean survival time were evaluated in animals treated with LPS alone or with the combination of LPS+iloprost and LPS+iloprost+L-NAG. Intravenous injection of LPS (100 mg/kg) per se elicited a significant reduction in mean arterial blood pressure (MABP) and arteriolar blood flow. The observed arterioles dilated and spontaneous vasomotion ceased. Iloprost (40 ng/kg/min) prevented LPS-induced reduction of MABP, ameliorated the decrease in arteriolar blood flow and reduced the vasodilation. Arteriolar vasomotion was reduced but it did not cease. The combination of L-NAG (0.5 mg/kg) + iloprost (40 ng/kg/min) with LPS (100 mg/kg) did not improve the results obtained with iloprost alone, except that it prevented the vasodilation and the vasomotion ceased 1 h after the bolus injection of LPS+L-NAG. The mean survival time compared to LPS alone (57 +/- 7 h) was significantly increased by the combination of LPS+iloprost (102 +/- 6 h) and it did not change significantly with the combination L-NAG+iloprost (64 +/- 9 h). Topical addition of iloprost (10 ng/kg/min) evoked an early increase in macromolecular permeability and a significant decrease in leukocyte adhesion compared with animals treated with topical LPS (0.7 microgram/ml/min) alone. The combination of L-NAG+iloprost (1.3 + 10 ng/ml/min) enhanced the early increase in macromolecular permeability even further, tended to increase the macromolecular permeability and evoked a smaller decrease in leukocyte adhesion than the one observed with iloprost combined with LPS. Our results, in the hamster cheek pouch microcirculation, suggest that the use of prostacyclin could be beneficial in the treatment of early changes in endotoxic shock, but L-NAG showed no benefit in this preparation.
Bouskela
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Laboratório de Pesquisas em Microcirculação, Universidade do Estado do Rio de Janeiro, Brazil.
Rubanyi
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GM
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects; D002610:Cheek / Q000098:blood supply; D006224:Cricetinae; D004355:Drug Stability; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D016285:Iloprost / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors*; D008647:Mesocricetus; D008833:Microcirculation / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019335:Nitroarginine; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D014665:Vasodilator Agents; D019335:Nitroarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D016285:Iloprost