TIN???Mesoporphyrin for Inhibition of Heme Oxygenase During Long-Term Hyperdynamic Porcine Endotoxemia

Abstract

Heme oxygenase (HO) has both deleterious and protective effects in various shock models. Most of these data have been derived from experiments with hypodynamic shock states associated with depressed cardiac output. Therefore we studied the role of HO during long-term porcine hyperdynamic endotoxemia characterized by a sustained increase in cardiac output resulting from colloid resuscitation to maintain mean arterial pressure > 60 mmHg. Systemic, pulmonary, and hepatosplanchnic hemodynamic and metabolic effects of the HO-inhibitor tin-mesoporphyrin (SnMP) were assessed in anesthetized and mechanically ventilated animals. After 12 h of continuous intravenous lipopolysaccharide (LPS), animals received either vehicle (n = 6) or SnMP (n = 8; 6 micromol kg(-1) i.v. over 30 min at 12 and 18 h of LPS). Measurements were performed before LPS, before SnMP infusion, and at 24 h of LPS. SnMP did not influence systemic hemodynamics but significantly increased mean pulmonary artery pressure. Although liver blood flow was not affected, SnMP markedly impaired liver lactate clearance. HO inhibition was associated with increased plasma nitrate levels likely the result of increased NO production. Our results suggest a protective role of HO activation during hyperdynamic porcine endotoxemia possibly as a result of an interaction with the LPS-induced increase in NO formation.

Does carbon monoxide treatment alter cytokine levels after endotoxin infusion in pigs? A randomized controlled study

“…Also, different breeds of pigs probably have different sensitivity to endotoxin. The MPAP levels in our study were high in comparison with other authors [ 11 , 20 ] or similar [ 21 ]. This acute increase in MPAP associated with endotoxin administration (Figure 1 ) was close or similar to levels found in cardiovascular decompensation.…”

Glycyrrhizin protects against porcine endotoxemia through modulation of systemic inflammatory response

“…The additional intravenous fluid for the four groups was as follows: sham 6.95 ± 0.79, con 9.86 ± 1.28, EP 9.62 ± 0.55, and GL 9.07 ± 0.71 ml/kg/hr. Hydroxyethylstarch (HAES-Steril ® 6% 200/0.5, Fresenius Kabi, Erlangen, Germany) was administered as required to maintain MAP > 60 mmHg, and 5% glucose solution was infused to keep arterial blood glucose levels between 5 to 7 mmol/L [1,26]. Con, EP and GL groups received similar amount of HAES (con, 64.0 ± 8.19, EP, 67.33 ± 6.66, and GL, 63.33 ± 4.93 ml).…”

The Hepatic Microcirculation: Mechanistic Contributions and Therapeutic Targets in Liver Injury and Repair

“…A protective role of HO activation has been shown, possibly as a result of an interaction with the LPS-induced increase in NO formation (584). At the same time, CO, produced by excessively induced HO-1 after cecal ligation and puncture, promotes an immoderate dilation of the sinusoidal space through the upregulation of cGMP, resulting in liver dysfunction.…”

“…Then the supply of the gases is turned off, and their clearance rates are determined polarographically through platinum electrodes placed on or into the liver to a depth of 3-6 mm (783). The H 2 clearance technique has been successfully applied in various experimental models for the study of liver blood flow in rats, dogs and pigs (304,436,584,783,790). In clinical practice, the temporal changes in radiographic enhancement produced by xenon gas inhalation are measured by sequential computer tomography and then the time-dependent xenon concentrations within the various tissue segments are used to achieve local liver blood flow maps (263,264,735).…”