Endothelins and carbon monoxide interact to regulate rat liver microcirculation after haemorrhagic shock

Abstract Background Upregulation of stress-induced vascular mediators such as endothelin (ET) 1, nitric oxide synthase (NOS)–nitric oxide or the haem oxygenase (HO)–carbon monoxide pathway may contribute to altered microvascular responsiveness after ischaemia and reperfusion. A profound induction of HO-1 and an increase in portal resistance after blockade of the HO pathway has been shown to occur after haemorrhagic shock and resuscitation (H/R). This study investigated whether the observed increased portal resistance after blockade of the HO pathway was mediated by a concomitant upregulation of ET-l. Methods Sprague–Dawley rats (n = 10 per group) were subjected to H/R (mean arterial pressure 40 mmHg for l h, followed by 5 h of resuscitation). Expression of HO-1, inducible NOS (iNOS) and ET-1 was studied by standard Northern blot analysis and reverse transcriptase–polymerase chain reaction. At 6 h either the ET antagonist bosentan 10 mg kg−1 or vehicle was injected. After 10 min the HO pathway was blocked in all animals by tin protoporphyrin (SnPP) IX 50 μmol kg−1. Subsequently portal flow and portal pressure or sinusoidal liver blood flow (assessed by intravital epifluorescence microscopy) were measured for 30 min. Results A profound induction in ET-1 paralleled induced HO-1 messenger RNA (mRNA) gene expression after H/R (ET-1, mean(s.d.) 9·0(1·1)-fold; HO-1, 5·9(0·3)-fold induction at 6 h); iNOS mRNA was below the detection limit. Blockade of the HO pathway led to a significant peak increase in the portal vein resistance (ΔPVR; P < 0·05). There was a trend to a lower peak increase after administration of bosentan (P = 0·07) (ΔPVR: sham SnPP-IX, 0·17(0·05) mmHg min mF−1; shock vehicle SnPP-IX, 0·57(0·15) mmHg min mF−1; shock bosentan SnPP-IX, 0·29(0·05) mmHg min mF−1). Regarding liver microcirculation, pretreatment with bosentan significantly attenuated the observed decrease in perfused sinusoids (PS) and in perfusion index (PI) after blockade of the HO pathway (shock vehicle SnPP-IX: PS 23·1(1·1) mm−1, PI 1000(134) μm3 s−1 mm−1; shock bosentan SnPP-IX: PS 28·8(1·8) mm−1, PI 1483(159) μm3 s−1 mm−1; P < 0·05). Conclusion These results suggest a functional interaction of the unregulated vasodilator carbon monoxide and the vasoconstrictor ET-1 at the sinusoidal level in rat liver after H/R.