Amelioration by mercaptoethylguanidine of the vascular and energetic failure in haemorrhagic shock in the anesthetised rat.
The effects of mercaptoethylguanidine, a dual inhibitor of the inducible nitric oxide (NO) synthase and cyclooxygenase with scavenging effect on peroxynitrite, was studied on the delayed vascular decompensation and cellular energetic failure in a rat model of haemorrhagic shock. Shock was induced by bleeding of the animals to a mean arterial blood pressure of 50 mmHg. At 3 h, animals were resuscitated with Ringers-lactate and monitored for a subsequent 3 h period. In the treated group mercaptoethylguanidine (10 mg/kg/i.v. bolus, followed by 10 mg/kg/i.v. infusion) was administered from the beginning of the resuscitation. Haemorrhagic shock resulted in the upregulation of both the constitutive and the inducible NO synthase, as measured in the lung. In shocked rats mercaptoethylguanidine prevented the increase in plasma nitrite/nitrate and 6-keto-prostaglandin F1alpha levels, ameliorated the decrease in mean arterial blood pressure, and inhibited the development of vascular hyporeactivity of the thoracic aorta ex vivo. A significant nitrotyrosine staining, an indicator of peroxynitrite formation, was found in thoracic aortic rings from shocked animals, which was prevented by mercaptoethylguanidine treatment. In ex vivo experiments in peritoneal macrophages obtained from shocked rats, treatment with mercaptoethylguanidine prevented the reduction in the intracellular NAD+ content, ameliorated the suppression of mitochondrial respiration and reduced the development of DNA single strand breaks. Our data suggest that mercaptoethylguanidine may be an useful tool for the experimental therapy of haemorrhagic shock.
Zingarelli
B
B
Children's Hospital Medical Center, Division of Critical Care, Cincinnati, OH 45229, USA.
Ischiropoulos
H
H
Salzman
A L
AL
Szabó
C
C
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D019791:Guanidine / Q000031:analogs & derivatives*; D007552:Isotonic Solutions / Q000627:therapeutic use; D008297:Male; D008954:Models, Biological; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012151:Resuscitation / Q000379:methods; D000077325:Ringer's Lactate; D012771:Shock, Hemorrhagic / Q000097:blood / Q000503:physiopathology / Q000628:therapy*; D013438:Sulfhydryl Compounds / Q000627:therapeutic use*
D007552:Isotonic Solutions; D009566:Nitrates; D000077325:Ringer's Lactate; D013438:Sulfhydryl Compounds; D015121:6-Ketoprostaglandin F1 alpha; D019001:Nitric Oxide Synthase; D019791:Guanidine