Differential effect of 2-aminoethyl-isothiourea, an inhibitor of the inducible nitric oxide synthase, on microvascular blood flow and organ injury in models of hepatic ischemia-reperfusion and endotoxemia.
The vasodilator nitric oxide (NO) is involved in the regulation of systemic blood pressure and local organ blood flow. Inhibitors of the constitutively expressed nitric oxide synthase in endothelial cells (eNOS), e.g., Nomega-nitro-L-arginine methyl ester hydrochloride (L-NAME), aggravated liver injury in a variety of models. On the other hand, inhibitors of the inducible NOS (iNOS), e.g., 2-aminoethyl-isothiourea (AET), were found to be beneficial during endotoxemia. The aim of this investigation was to study the effect of AET compared with L-NAME on liver microvascular blood flow and injury in more complex models with multiple insults, i.e., ischemia (20 min)-reperfusion (8 h) in combination with .5 mg/kg endotoxin (IRE). Male Fisher rats were treated with 10 mg/kg AET or L-NAME and subjected to IRE. At 8 h, liver injury (plasma ALT: 1320+/-164 U/L) was significantly increased in AET-treated (5,018+/-1,379 U/L) and L-NAME-treated groups (2,429+/-228 U/L). Each inhibitor attenuated microvascular blood flow (assessed by laser Doppler flowmetry) to a similar degree. In striking contrast, AET completely reversed the endotoxin-induced impairment of the microvascular blood flow and significantly protected against an endotoxin-induced liver injury (plasma ALT: 3,007+/-268 U/L (ET); 460+/-39 U/L (ET+AET)). Infusion of endothelin-1 reduced microvascular blood flow by 50-60% and caused liver injury. Our data demonstrated that an inhibitor of eNOS (L-NAME) has a consistent detrimental effect on liver injury during ischemia-reperfusion and endotoxemia mainly because it can cause additional ischemia by reducing the microvascular blood flow. However, selective inhibitors of iNOS (AET) can impair hepatic blood flow and aggravate the injury or improve blood flow and attenuate organ injury depending on the experimental model. These results suggest that iNOS inhibitors may not be universally beneficial and should be tested in a variety of experimental models of sepsis/endotoxemia before used in clinical settings.
Department of Pharmacology, Pharmacia & Upjohn, Inc., Kalamazoo, Michigan 49007, USA.
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Wang
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Lawson
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Jaeschke
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001775:Blood Circulation; D001794:Blood Pressure / Q000187:drug effects; D019332:Endothelin-1 / Q000494:pharmacology; D019446:Endotoxemia / Q000097:blood / Q000188:drug therapy*; D005978:Glutathione / Q000097:blood; D007511:Ischemia / Q000188:drug therapy*; D008099:Liver / Q000098:blood supply* / Q000187:drug effects / Q000293:injuries*; D008102:Liver Circulation / Q000187:drug effects; D008297:Male; D009102:Multiple Organ Failure / Q000188:drug therapy; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000097:blood; D051381:Rats; D011919:Rats, Inbred Strains; D015424:Reperfusion; D000338:beta-Aminoethyl Isothiourea / Q000494:pharmacology*
D019332:Endothelin-1; D009566:Nitrates; D009573:Nitrites; D000338:beta-Aminoethyl Isothiourea; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D000410:Alanine Transaminase; D005978:Glutathione; D019331:NG-Nitroarginine Methyl Ester